DSC MRI in the human brain using deoxyhemoglobin and gadolinium-Simulations and validations at 3T.

Introduction: Dynamic susceptibility contrast (DSC) MRI allows clinicians to determine perfusion parameters in the brain, such as cerebral blood flow, cerebral blood volume, and mean transit time. To enable quantification, susceptibility changes can be induced using gadolinium (Gd) or deoxyhemoglobin (dOHb), the latter just recently introduced as a contrast agent in DSC. Previous investigations found that experimental parameters and analysis choices, such as the susceptibility amplitude and partial volume, affect perfusion quantification. However, the accuracy and precision of DSC MRI has not been systematically investigated, particularly in the lower susceptibility range. Methods: In this study, we compared perfusion values determined using Gd with values determined using a contrast agent with a lower susceptibility-dOHb-under different physiological conditions, such as varying the baseline blood oxygenation and/or magnitude of hypoxic bolus, by utilizing numerical simulations and conducting experiments on healthy subjects at 3T. The simulation framework we developed for DSC incorporates MRI signal contributions from intravascular and extravascular proton spins in arterial, venous, and cerebral tissue voxels. This framework allowed us to model the MRI signal in response to both Gd and dOHb. Results and discussion: We found, both in the experimental results and simulations, that a reduced intravascular volume of the selected arterial voxel, reduced baseline oxygen saturation, greater susceptibility of applied contrast agent (Gd vs. dOHb), and/or larger magnitude of applied hypoxic bolus reduces the overestimation and increases precision of cerebral blood volume and flow. As well, we found that normalizing tissue to venous rather than arterial signal increases the accuracy of perfusion quantification across experimental paradigms. Furthermore, we found that shortening the bolus duration increases the accuracy and reduces the calculated values of mean transit time. In summary, we experimentally uncovered an array of perfusion quantification dependencies, which agreed with the simulation framework predictions, using a wider range of susceptibility values than previously investigated. We argue for caution when comparing absolute and relative perfusion values within and across subjects obtained from a standard DSC MRI analysis, particularly when employing different experimental paradigms and contrast agents.

Physiological modeling of the BOLD signal and implications for effective connectivity: A primer.

In this primer, I provide an overview of the physiological processes that contribute to the observed BOLD signal (i.e., the generative biophysical model), including their time course properties within the framework of the physiologically-informed dynamic causal modeling (P-DCM). The BOLD signal is primarily determined by the change in paramagnetic deoxygenated hemoglobin, which results from combination of changes in oxygen metabolism, and cerebral blood flow and volume. Specifically, the physiological origin of the so-called BOLD signal "transients" will be discussed, including the initial overshoot, steady-state activation and the post-stimulus undershoot. I argue that incorrect physiological assumptions in the generative model of the BOLD signal can lead to incorrect inferences pertaining to both local neuronal activity and effective connectivity between brain regions. In addition, I introduce the recent laminar BOLD signal model, which extends P-DCM to cortical depths-resolved BOLD signals, allowing for laminar neuronal activity to be determined using high-resolution fMRI data.

Magnetic resonance imaging at 9.4 T: the Maastricht journey.

The 9.4 T scanner in Maastricht is a whole-body magnet with head gradients and parallel RF transmit capability. At the time of the design, it was conceptualized to be one of the best fMRI scanners in the world, but it has also been used for anatomical and diffusion imaging. 9.4 T offers increases in sensitivity and contrast, but the technical ultra-high field (UHF) challenges, such as field inhomogeneities and constraints set by RF power deposition, are exacerbated compared to 7 T. This article reviews some of the 9.4 T work done in Maastricht. Functional imaging experiments included blood oxygenation level-dependent (BOLD) and blood-volume weighted (VASO) fMRI using different readouts. BOLD benefits from shorter T2* at 9.4 T while VASO from longer T1. We show examples of both ex vivo and in vivo anatomical imaging. For many applications, pTx and optimized coils are essential to harness the full potential of 9.4 T. Our experience shows that, while considerable effort was required compared to our 7 T scanner, we could obtain high-quality anatomical and functional data, which illustrates the potential of MR acquisitions at even higher field strengths. The practical challenges of working with a relatively unique system are also discussed.

Dynamic Effective Connectivity using Physiologically informed Dynamic Causal Model with Recurrent Units: A functional Magnetic Resonance Imaging simulation study.

Functional MRI (fMRI) is an indirect reflection of neuronal activity. Using generative biophysical model of fMRI data such as Dynamic Causal Model (DCM), the underlying neuronal activities of different brain areas and their causal interactions (i.e., effective connectivity) can be calculated. Most DCM studies typically consider the effective connectivity to be static for a cognitive task within an experimental run. However, changes in experimental conditions during complex tasks such as movie-watching might result in temporal variations in the connectivity strengths. In this fMRI simulation study, we leverage state-of-the-art Physiologically informed DCM (P-DCM) along with a recurrent window approach and discretization of the equations to infer the underlying neuronal dynamics and concurrently the dynamic (time-varying) effective connectivities between various brain regions for task-based fMRI. Results from simulation studies on 3- and 10-region models showed that functional magnetic resonance imaging (fMRI) blood oxygenation level-dependent (BOLD) responses and effective connectivity time-courses can be accurately predicted and distinguished from faulty graphical connectivity models representing cognitive hypotheses. In summary, we propose and validate a novel approach to determine dynamic effective connectivity between brain areas during complex cognitive tasks by combining P-DCM with recurrent units.

Investigations of hypoxia-induced deoxyhemoglobin as a contrast agent for cerebral perfusion imaging.

The assessment of resting perfusion measures (mean transit time, cerebral blood flow, and cerebral blood volume) with magnetic resonance imaging currently requires the presence of a susceptibility contrast agent such as gadolinium. Here, we present an initial comparison between perfusion measures obtained using hypoxia-induced deoxyhemoglobin and gadolinium in healthy study participants. We hypothesize that resting cerebral perfusion measures obtained using precise changes of deoxyhemoglobin concentration will generate images comparable to those obtained using a clinical standard, gadolinium. Eight healthy study participants were recruited (6F; age 23-60). The study was performed using a 3-Tesla scanner with an eight-channel head coil. The experimental protocol consisted of a high-resolution T1-weighted scan followed by two BOLD sequence scans in which each participant underwent a controlled bolus of transient pulmonary hypoxia, and subsequently received an intravenous bolus of gadolinium. The resting perfusion measures calculated using hypoxia-induced deoxyhemoglobin and gadolinium yielded maps that looked spatially comparable. There was no statistical difference between methods in the average voxel-wise measures of mean transit time, relative cerebral blood flow and relative cerebral blood volume, in the gray matter or white matter within each participant. We conclude that perfusion measures generated with hypoxia-induced deoxyhemoglobin are spatially and quantitatively comparable to those generated from a gadolinium injection in the same healthy participant.

Feasibility of high-resolution perfusion imaging using arterial spin labeling MRI at 3 Tesla.

Cerebral blood flow (CBF) is a critical physiological parameter of brain health, and it can be non-invasively measured with arterial spin labeling (ASL) MRI. In this study, we evaluated and optimized whole-brain, high-resolution ASL as an alternative to the low-resolution ASL employed in the routine assessment of CBF in both healthy participants and patients. Two high-resolution protocols (i.e., pCASL and FAIR-Q2TIPS (PASL) with 2 mm isotropic voxels) were compared to a default clinical pCASL protocol (3.4 × 3.4 × 4 mm 3), all of whom had an acquisition time of ≈ 5 min. We assessed the impact of high-resolution acquisition on reducing partial voluming and improving sensitivity to the perfusion signal, and evaluated the effectiveness of z-deblurring on the ASL data. We compared the quality of whole-brain ASL acquired using three available head coils with differing number of receive channels (i.e., 20, 32, and 64ch). We found that using higher coil counts (32 and 64ch coils as compared to 20ch) offers improved signal-to-noise ratio (SNR) and acceleration capabilities that are beneficial for ASL imaging at 3 Tesla (3 T). The inherent reduction in partial voluming effects with higher resolution acquisitions improves the resolving power of perfusion without impacting the sensitivity. In conclusion, our results suggest that high-resolution ASL (2 to 2.5 mm isotropic voxels) has the potential to become a new standard for perfusion imaging at 3 T and increase its adoption into clinical research and cognitive neuroscience applications.

Neurodegenerative and functional signatures of the cerebellar cortex in m.3243A > G patients.

Mutations of the mitochondrial DNA are an important cause of inherited diseases that can severely affect the tissue's homeostasis and integrity. The m.3243A > G mutation is the most commonly observed across mitochondrial disorders and is linked to multisystemic complications, including cognitive deficits. In line with in vitro experiments demonstrating the m.3243A > G's negative impact on neuronal energy production and integrity, m.3243A > G patients show cerebral grey matter tissue changes. However, its impact on the most neuron dense, and therefore energy-consuming brain structure-the cerebellum-remains elusive. In this work, we used high-resolution structural and functional data acquired using 7 T MRI to characterize the neurodegenerative and functional signatures of the cerebellar cortex in m.3243A > G patients. Our results reveal altered tissue integrity within distinct clusters across the cerebellar cortex, apparent by their significantly reduced volume and longitudinal relaxation rate compared with healthy controls, indicating macroscopic atrophy and microstructural pathology. Spatial characterization reveals that these changes occur especially in regions related to the frontoparietal brain network that is involved in information processing and selective attention. In addition, based on resting-state functional MRI data, these clusters exhibit reduced functional connectivity to frontal and parietal cortical regions, especially in patients characterized by (i) a severe disease phenotype and (ii) reduced information-processing speed and attention control. Combined with our previous work, these results provide insight into the neuropathological changes and a solid base to guide longitudinal studies aimed to track disease progression.

Perfusion MRI using endogenous deoxyhemoglobin as a contrast agent: Preliminary data.

PURPOSE: To demonstrate the feasibility of mapping cerebral perfusion metrics with BOLD MRI during modulation of pulmonary venous oxygen saturation. METHODS: A gas blender with a sequential gas delivery breathing circuit was used to implement rapid isocapnic changes in the partial pressure of oxygen of the arterial blood. Partial pressure of oxygen was initially lowered to a baseline of 40 mmHg. It was then rapidly raised to 95 mmHg for 20 s before rapidly returning to baseline. The induced cerebral changes in deoxyhemoglobin concentration were tracked over time using BOLD MRI in 6 healthy subjects and 1 patient with cerebral steno-occlusive disease. BOLD signal change, contrast-to-noise ratio, and time delay metrics were calculated. Perfusion metrics such as mean transit time, relative cerebral blood volume, and relative cerebral blood flow were calculated using a parametrized method with a mono-exponential residue function. An arterial input function from within the middle cerebral artery was used to scale relative cerebral blood volume and calculate absolute cerebral blood volume and cerebral blood flow. RESULTS: In normal subjects, average gray and white matter were: BOLD change = 6.3 ± 1.2% and 2.5 ± 0.6%, contrast-to-noise ratio = 4.3 ± 1.3 and 2.6 ± 0.7, time delay = 2.3 ± 0.6 s and 3.6 ± 0.7 s, mean transit time = 3.9 ± 0.6 s and 5.5 ± 0.6 s, relative cerebral blood volume = 3.7 ± 0.9 and 1.6 ± 0.4, relative cerebral blood flow = 70.1 ± 8.3 and 20.6 ± 4.0, cerebral blood flow volume = 4.1 ± 0.9 mL/100 g and 1.8 ± 0.5 mL/100 g, and cerebral blood flow = 97.2 ± 18.7 mL/100 g/min and 28.7 ± 5.9 mL/100 g/min. CONCLUSION: This study demonstrates that induced abrupt changes in deoxyhemoglobin can function as a noninvasive vascular contrast agent that may be used for cerebral perfusion imaging.

Sub-millimetre resolution laminar fMRI using Arterial Spin Labelling in humans at 7 T.

Laminar fMRI at ultra-high magnetic field strength is typically carried out using the Blood Oxygenation Level-Dependent (BOLD) contrast. Despite its unrivalled sensitivity to detecting activation, the BOLD contrast is limited in its spatial specificity due to signals stemming from intra-cortical ascending and pial veins. Alternatively, regional changes in perfusion (i.e., cerebral blood flow through tissue) are colocalised to neuronal activation, which can be non-invasively measured using Arterial Spin Labelling (ASL) MRI. In addition, ASL provides a quantitative marker of neuronal activation in terms of perfusion signal, which is simultaneously acquired along with the BOLD signal. However, ASL for laminar imaging is challenging due to the lower SNR of the perfusion signal and higher RF power deposition i.e., specific absorption rate (SAR) of ASL sequences. In the present study, we present for the first time in humans, isotropic sub-millimetre spatial resolution functional perfusion images using Flow-sensitive Alternating Inversion Recovery (FAIR) ASL with a 3D-EPI readout at 7 T. We show that robust statistical activation maps can be obtained with perfusion-weighting in a single session. We observed the characteristic BOLD amplitude increase towards the superficial laminae, and, in apparent discrepancy, the relative perfusion profile shows a decrease of the amplitude and the absolute perfusion profile a much smaller increase towards the cortical surface. Considering the draining vein effect on the BOLD signal using model-based spatial "convolution", we show that the empirically measured perfusion and BOLD profiles are, in fact, consistent with each other. This study demonstrates that laminar perfusion fMRI in humans is feasible at 7 T and that caution must be exercised when interpreting BOLD signal laminar profiles as direct representation of the cortical distribution of neuronal activity.

Determining laminar neuronal activity from BOLD fMRI using a generative model.

Laminar fMRI using the BOLD contrast enables the non-invasive investigation of mesoscopic functional circuits in the human brain. However, the laminar neuronal activity is spatiotemporally biased in the observed cortical depth profiles of the BOLD signal. In this study, we propose a generative fMRI signal model, comprehensively covering the relationship between cortical depth-dependent changes in excitatory and inhibitory neuronal activity with the sampling of the BOLD signal with finite voxels. The generative model allowed us to investigate pertinent questions regarding the accuracy of the laminar BOLD signal relative to the neuronal activity, and we found that: a) condition differences in laminar BOLD signals may be more reflective of neuronal activity than single condition BOLD signal depth profiles; b) angular dependence of the BOLD signal induces significant signal variability, which can mask underlying activity profiles; c) even if only three neuronal depths are of interest, more BOLD signal depths should be considered in the analysis. In addition, we recommend that the laminar BOLD data should be displayed using the centroid method to appreciate its spatial distribution in the original resolution. Finally, we showed that Bayesian model inversion of the generative model can improve sensitivity and specificity of assessing depth-dependent neuronal changes both for steady-state and dynamically.

Quantitative and simultaneous measurement of oxygen consumption rates in rat brain and skeletal muscle using 17 O MRS imaging at 16.4T.

PURPOSE: Oxygen-17 (17 O) MRS imaging, successfully used in the brain, is extended by imaging the oxygen metabolic rate in the resting skeletal muscle and used to determine the total whole-body oxygen metabolic rate in the rat. METHODS: During and after inhalations of 17 O2 gas, dynamic 17 O MRSI was performed in rats (n = 8) ventilated with N2 O or N2 at 16.4 T. Time courses of the H217 O concentration from regions of interest located in brain and muscle tissue were examined and used to fit an animal-adapted 3-phase metabolic model of oxygen consumption. CBF was determined with an independent washout method. Finally, body oxygen metabolic rate was calculated using a global steady-state approach. RESULTS: Cerebral metabolic rate of oxygen consumption was 1.97 ± 0.19 µmol/g/min on average. The resting metabolic rate of oxygen consumption in skeletal muscle was 0.32 ± 0.12 µmol/g/min and >6 times lower than cerebral metabolic rate of oxygen consumption. Global oxygen consumed by the body was 24.2 ± 3.6 mL O2 /kg body weight/min. CBF was estimated to be 0.28 ± 0.02 mL/g/min and 0.34 ± 0.06 mL/g/min for the N2 and N2 O ventilation condition, respectively. CONCLUSION: We have evaluated the feasibility of 17 O MRSI for imaging and quantifying the oxygen consumption rate in low metabolizing organs such as the skeletal muscle at rest. Additionally, we have shown that CBF is slightly increased in the case of ventilation with N2 O. We expect this study to be beneficial to the application of 17 O MRSI to a wider range of organs, although further validation is advised.

Effects of MP2RAGE B1+ sensitivity on inter-site T1 reproducibility and hippocampal morphometry at 7T.

Most neuroanatomical studies are based on T1-weighted MR images, whose intensity profiles are not solely determined by the tissue's longitudinal relaxation times (T1), but also affected by varying non-T1 contributions, hampering data reproducibility. In contrast, quantitative imaging using the MP2RAGE sequence, for example, allows direct characterization of the brain based on the tissue property of interest. Combined with 7 Tesla (7T) MRI, this offers unique opportunities to obtain robust high-resolution brain data characterized by a high reproducibility, sensitivity and specificity. However, specific MP2RAGE parameter choices - e.g., to emphasize intracortical myelin-dependent contrast variations - can substantially impact image quality and cortical analyses through remnants of B1+-related intensity variations, as illustrated in our previous work. To follow up on this: we (1) validate this protocol effect using a dataset acquired with a particularly B1+ insensitive set of MP2RAGE parameters combined with parallel transmission excitation; and (2) extend our analyses to evaluate the effects on hippocampal morphometry. The latter remained unexplored initially, but can provide important insights related to generalizability and reproducibility of neurodegenerative research using 7T MRI. We confirm that B1+ inhomogeneities have a considerably variable effect on cortical T1 estimates, as well as on hippocampal morphometry depending on the MP2RAGE setup. While T1 differed substantially across datasets initially, we show the inter-site T1 comparability improves after correcting for the spatially varying B1+ field using a separately acquired Sa2RAGE B1+ map. Finally, removal of B1+ residuals affects hippocampal volumetry and boundary definitions, particularly near structures characterized by strong intensity changes (e.g. cerebral spinal fluid). Taken together, we show that the choice of MP2RAGE parameters can impact T1 comparability across sites and present evidence that hippocampal segmentation results are modulated by B1+ inhomogeneities. This calls for careful (1) consideration of sequence parameters when setting acquisition protocols, as well as (2) acquisition of a B1+ map to correct MP2RAGE data for potential B1+ variations to allow comparison across datasets.

Layer-dependent functional connectivity methods.

Recent methodological advances in fMRI contrast and readout strategies have allowed researchers to approach the mesoscopic spatial regime of cortical layers. This has revolutionized the ability to map cortical information processing within and across brain systems. However, until recently, most layer-fMRI studies have been confined to primary cortices using basic block-design tasks and macro-vascular-contaminated sequence contrasts. To become an established method for user-friendly applicability in neuroscience practice, layer-fMRI acquisition and analysis methods need to be extended to more flexible connectivity-based experiment designs; they must be able to capture subtle changes in brain networks of higher-order cognitive areas, and they should not be spatially biased with unwanted vein signals. In this article, we review the most pressing challenges of layer-dependent fMRI for large-scale neuroscientific applicability and describe recently developed acquisition methodologies that can resolve them. In doing so, we review technical tradeoffs and capabilities of modern MR-sequence approaches to achieve measurements that are free of locally unspecific vein signal, with whole-brain coverage, sub-second sampling, high resolutions, and with a combination of those capabilities. The presented approaches provide whole-brain layer-dependent connectivity data that open a new window to investigate brain network connections. We exemplify this by reviewing a number of candidate tools for connectivity analyses that will allow future studies to address new questions in network neuroscience. The considered network analysis tools include: hierarchy mapping, directional connectomics, source-specific connectivity mapping, and network sub-compartmentalization. We conclude: Whole-brain layer-fMRI without large-vessel contamination is applicable for human neuroscience and opens the door to investigate biological mechanisms behind any number of psychological and psychiatric phenomena, such as selective attention, hallucinations and delusions, and even conscious perception.

Unraveling the contributions to the neuromelanin-MRI contrast.

The Locus Coeruleus (LC) and the Substantia Nigra (SN) are small brainstem nuclei that change with aging and may be involved in the development of various neurodegenerative and psychiatric diseases. Magnetization Transfer (MT) MRI has been shown to facilitate LC and the SN visualization, and the observed contrast is assumed to be related to neuromelanin accumulation. Imaging these nuclei may have predictive value for the progression of various diseases, but interpretation of previous studies is hindered by the fact that the precise biological source of the contrast remains unclear, though several hypotheses have been put forward. To inform clinical studies on the possible biological interpretation of the LC- and SN contrast, we examined an agar-based phantom containing samples of natural Sepia melanin and synthetic Cys-Dopa-Melanin and compared this to the in vivo human LC and SN. T1 and T2* maps, MT spectra and relaxation times of the phantom, the LC and the SN were measured, and a two-pool MT model was fitted. Additionally, Bloch simulations and a transient MT experiment were conducted to confirm the findings. Overall, our results indicate that Neuromelanin-MRI contrast in the LC likely results from a lower macromolecular fraction, thus facilitating interpretation of results in clinical populations. We further demonstrate that in older individuals T1 lengthening occurs in the LC.

Direct visualization and characterization of the human zona incerta and surrounding structures.

The zona incerta (ZI) is a small gray matter region of the deep brain first identified in the 19th century, yet direct in vivo visualization and characterization has remained elusive. Noninvasive detection of the ZI and surrounding region could be critical to further our understanding of this widely connected but poorly understood deep brain region and could contribute to the development and optimization of neuromodulatory therapies. We demonstrate that high resolution (submillimetric) longitudinal (T1) relaxometry measurements at high magnetic field strength (7 T) can be used to delineate the ZI from surrounding white matter structures, specifically the fasciculus cerebellothalamicus, fields of Forel (fasciculus lenticularis, fasciculus thalamicus, and field H), and medial lemniscus. Using this approach, we successfully derived in vivo estimates of the size, shape, location, and tissue characteristics of substructures in the ZI region, confirming observations only previously possible through histological evaluation that this region is not just a space between structures but contains distinct morphological entities that should be considered separately. Our findings pave the way for increasingly detailed in vivo study and provide a structural foundation for precise functional and neuromodulatory investigation.

Dynamic behavior of the locus coeruleus during arousal-related memory processing in a multi-modal 7T fMRI paradigm.

A body of animal and human evidence points to the norepinephrine (NE) locus coeruleus (LC) system in modulating memory for arousing experiences, but whether the LC would recast its role along memory stages remains unknown. Sedation precluded examination of LC dynamics during memory processing in animals. Here, we addressed the contribution of the LC during arousal-associated memory processing through a unique combination of dedicated ultra-high-field LC-imaging methods, a well-established emotional memory task, online physiological and saliva alpha-amylase measurements in young adults. Arousal-related LC activation followed amygdala engagement during encoding. During consolidation and recollection, activation transitioned to hippocampal involvement, reflecting learning and model updating. NE-LC activation is dynamic, plays an arousal-controlling role, and is not sufficient but requires interactions with the amygdala to form adaptive memories of emotional experiences. These findings have implications for understanding contributions of LC dysregulation to disruptions in emotional memory formation, observed in psychiatric and neurocognitive disorders.

Feedback contribution to surface motion perception in the human early visual cortex.

Human visual surface perception has neural correlates in early visual cortex, but the role of feedback during surface segmentation in human early visual cortex remains unknown. Feedback projections preferentially enter superficial and deep anatomical layers, which provides a hypothesis for the cortical depth distribution of fMRI activity related to feedback. Using ultra-high field fMRI, we report a depth distribution of activation in line with feedback during the (illusory) perception of surface motion. Our results fit with a signal re-entering in superficial depths of V1, followed by a feedforward sweep of the re-entered information through V2 and V3. The magnitude and sign of the BOLD response strongly depended on the presence of texture in the background, and was additionally modulated by the presence of illusory motion perception compatible with feedback. In summary, the present study demonstrates the potential of depth-resolved fMRI in tackling biomechanical questions on perception.

A dynamical model of the laminar BOLD response.

High-resolution functional magnetic resonance imaging (fMRI) using blood oxygenation dependent level-dependent (BOLD) signal is an increasingly popular tool to non-invasively examine neuronal processes at the mesoscopic level. However, as the BOLD signal stems from hemodynamic changes, its temporal and spatial properties do not match those of the underlying neuronal activity. In particular, the laminar BOLD response (LBR), commonly measured with gradient-echo (GE) MRI sequence, is confounded by non-local changes in deoxygenated hemoglobin and cerebral blood volume propagated within intracortical ascending veins, leading to a unidirectional blurring of the neuronal activity distribution towards the cortical surface. Here, we present a new cortical depth-dependent model of the BOLD response based on the principle of mass conservation, which takes the effect of ascending (and pial) veins on the cortical BOLD responses explicitly into account. It can be used to dynamically model cortical depth profiles of the BOLD signal as a function of various baseline- and activity-related physiological parameters for any spatiotemporal distribution of neuronal changes. We demonstrate that the commonly observed spatial increase of LBR is mainly due to baseline blood volume increase towards the surface. In contrast, an occasionally observed local maximum in the LBR (i.e. the so-called "bump") is mainly due to spatially inhomogeneous neuronal changes rather than locally higher baseline blood volume. In addition, we show that the GE-BOLD signal laminar point-spread functions, representing the signal leakage towards the surface, depend on several physiological parameters and on the level of neuronal activity. Furthermore, even in the case of simultaneous neuronal changes at each depth, inter-laminar delays of LBR transients are present due to the ascending vein. In summary, the model provides a conceptual framework for the biophysical interpretation of common experimental observations in high-resolution fMRI data. In the future, the model will allow for deconvolution of the spatiotemporal hemodynamic bias of the LBR and provide an estimate of the underlying laminar excitatory and inhibitory neuronal activity.

Aerobic Exercise Training Improves Cerebral Blood Flow and Executive Function: A Randomized, Controlled Cross-Over Trial in Sedentary Older Men.

BACKGROUND: Physical activity may attenuate age-related cognitive decline by improving cerebrovascular function. The aim of this study was therefore to investigate effects of aerobic exercise training on cerebral blood flow (CBF), which is a sensitive physiological marker of cerebrovascular function, in sedentary older men. METHODS: Seventeen apparently healthy men, aged 60-70 years and with a BMI between 25 and 35 kg/m2, were included in a randomized, controlled cross-over trial. Study participants were randomly allocated to a fully-supervised, progressive, aerobic exercise training or no-exercise control period for 8 weeks, separated by a 12-week wash-out period. Measurements at the end of each period included aerobic fitness evaluated using peak oxygen consumption during incremental exercise (VO2 peak), CBF measured with pseudo-continuous arterial spin labeling magnetic resonance imaging, and post-load glucose responses determined using an oral glucose tolerance test (OGTT). Furthermore, cognitive performance was assessed in the domains of executive function, memory, and psychomotor speed. RESULTS: VO2 peak significantly increased following aerobic exercise training compared to no-exercise control by 262 ± 236 mL (P < 0.001). CBF was increased by 27% bilaterally in the frontal lobe, particularly the subcallosal and anterior cingulate gyrus (cluster volume: 1008 mm3; P < 0.05), while CBF was reduced by 19% in the right medial temporal lobe, mainly temporal fusiform gyrus (cluster volume: 408 mm3; P < 0.05). Mean post-load glucose concentrations determined using an OGTT decreased by 0.33 ± 0.63 mmol/L (P = 0.049). Furthermore, executive function improved as the latency of response was reduced by 5% (P = 0.034), but no changes were observed in memory or psychomotor speed. CONCLUSION: Aerobic exercise training improves regional CBF in sedentary older men. These changes in CBF may underlie exercise-induced beneficial effects on executive function, which could be partly mediated by improvements in glucose metabolism. This clinical trial is registered on ClinicalTrials.gov as NCT03272061.