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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.

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.

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.

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., 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. We demonstrate that high resolution longitudinal relaxometry measurements at high magnetic field strength (7 T) can be used to delineate the ZI from surrounding white matter structures. Our findings pave the way for increasingly detailed in vivo study and provide a structural foundation for precise functional and neuromodulatory investigation.

Locus Coeruleus (LC) is a neuromelanin-rich brainstem structure that is the source of noradrenaline in the cortex and is thought to modulate attention and memory. LC imaging in vivo is commonly performed with a 2D T 1-weighted Turbo Spin Echo (TSE) MRI sequence, an approach that suffers from several drawbacks at 3T, including long acquisition times and highly anisotropic spatial resolution. In this study, we developed a high-resolution Magnetization Transfer (MT) sequence for LC imaging at both 7T and 3T and compared its performance to a TSE sequence. Results indicate that LC imaging can be achieved with an MT sequence at both 7 and 3T at higher spatial resolution than the 3T TSE. Furthermore, we investigated whether the currently disputed source of contrast in the LC region with a TSE sequence relates to MT effects or shortened T 1 and T 2* due to increased iron concentration. Our results suggest that the contrast in the LC area relates to MT effects. To conclude, in this study we managed to image the LC, for the first time, at 7T and at an increased resolution compared to the current state-of-the-art. Imaging the LC is highly relevant for clinical diagnostics as structural tissue properties of the LC may hold promise as a biomarker in neurodegenerative diseases.

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.

The blood oxygenation level-dependent (BOLD) fMRI response to neuronal activation results from a complex interplay of induced metabolic and vascular changes. Thus, its transients, such as initial overshoot and post-stimulus undershoot, provide a window into the dynamic relationships of the underlying physiological variables. In this study, we propose multi-echo fMRI as a tool to investigate the physiological underpinnings of the BOLD signal, in particular, and brain functional physiology, in general. In the human visual cortex at 3 T, we observed that the BOLD response is nonlinearly dependent on echo-time (TE) and the amount of nonlinearity varies during the entire time-course. Fitting a linear model to this nonlinear relationship resulted in a positive intercept at TE = 0 ms. The time-course of the intercept exhibited fast and slow modulations, distinctly different both from the BOLD response and cerebral blood flow (CBF). In order to shed light on the TE-dependence of the BOLD signal and the intercept time-course, we performed simulations based on a nonlinear two-compartmental BOLD signal model combined with the dynamic balloon model. The modeling suggests that the intercept time-course reflects a weighted sum of deoxyhemoglobin concentration and venous CBV signal changes. We demonstrate that only CBF-venous blood volume (CBV) uncoupling but not CBF-oxygen metabolism (CMRO2) uncoupling can fully account for our experimental observations. In particular, these results strongly argue for a slow evolution of the venous CBV together with stimulus-type-dependent CBF transients (the latter being tightly coupled with CMRO2) to be responsible for the BOLD signal adaptation during stimulation and for the post-stimulus undershoot. Thus, BOLD signal transients are composed of smoothed version of neuronal time-course as reflected in CBF and CMRO2 and secondary vascular processes due to biomechanics of venous blood vessels, and multi-echo fMRI in combination with modeling provides invaluable insights into these physiological processes.

Effective connectivity is commonly assessed using blood oxygenation level-dependent (BOLD) signals. In (Havlicek et al., 2015), we presented a novel, physiologically informed dynamic causal model (P-DCM) that extends current generative models. We demonstrated the improvements afforded by P-DCM in terms of the ability to model commonly observed neuronal and vascular transients in single regions. Here, we assess the ability of the novel and previous DCM variants to estimate effective connectivity among a network of five ROIs driven by a visuo-motor task. We demonstrate that connectivity estimates depend sensitively on the DCM used, due to differences in the modeling of hemodynamic response transients; such as the post-stimulus undershoot or adaptation during stimulation. In addition, using a novel DCM for arterial spin labeling (ASL) fMRI that measures BOLD and CBF signals simultaneously, we confirmed our findings (by using the BOLD data alone and in conjunction with CBF). We show that P-DCM provides better estimates of effective connectivity, regardless of whether it is applied to BOLD data alone or to ASL time-series, and that all new aspects of P-DCM (i.e. neuronal, neurovascular, hemodynamic components) constitute an improvement compared to those in the previous DCM variants. In summary, (i) accurate modeling of fMRI response transients is crucial to obtain valid effective connectivity estimates and (ii) any additional hemodynamic data, such as provided by ASL, increases the ability to disambiguate neuronal and vascular effects present in the BOLD signal.

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, very 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 consciousness itself., This is the final manuscript as it was accepted by the journal Progress in Neurobiology.

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 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 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 model cortical depth-dependence of BOLD signal amplitudes during steady state, and to model the dependencies of transient features (i.e. early-overshoot, post-stimulus undershoot or initial dip) on 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 ascending vein. In summary, the model provides a conceptual framework for the biophysical interpretation of common experimental observations in high-resolution fMRI data. Finally, using Bayesian model inversion, the model will allow deconvolution of the spatiotemporal hemodynamic bias of the LBR and provide estimate of the underlying laminar excitatory and inhibitory neuronal activity.

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 eight 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 (VO2peak), 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 VO2peak 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: 1008mm3; P < 0.05), while CBF was reduced by 19% in the right medial temporal lobe, mainly temporal fusiform gyrus (cluster volume: 408mm3; 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.org as NCT03272061 (https://clinicaltrials.gov/ct2/show/NCT03272061).

Introduction The goal of European Ultrahigh-Field Imaging Network in Neurodegenerative Diseases (EUFIND) is to identify opportunities and challenges of 7 Tesla (7T) MRI for clinical and research applications in neurodegeneration. EUFIND comprises 22 European and one US site, including over 50 MRI and dementia experts as well as neuroscientists. Methods EUFIND combined consensus workshops and data sharing for multisite analysis, focusing on 7 core topics: clinical applications/clinical research, highest resolution anatomy, functional imaging, vascular systems/vascular pathology, iron mapping and neuropathology detection, spectroscopy, and quality assurance. Across these topics, EUFIND considered standard operating procedures, safety, and multivendor harmonization. Results The clinical and research opportunities and challenges of 7T MRI in each subtopic are set out as a roadmap. Specific MRI sequences for each subtopic were implemented in a pilot study presented in this report. Results show that a large multisite 7T imaging network with highly advanced and harmonized imaging sequences is feasible and may enable future multicentre ultrahigh-field MRI studies and clinical trials. Discussion The EUFIND network can be a major driver for advancing clinical neuroimaging research using 7T and for identifying use-cases for clinical applications in neurodegeneration.

The locus coeruleus is the site of the earliest pathological changes in many neurodegenerative diseases. Betts et al. describe how in vivo locus coeruleus imaging can be used as a biomarker for noradrenergic dysfunction in neurodegenerative diseases, and outline a strategy for achieving reliable and biologically validated imaging approaches., Pathological alterations to the locus coeruleus, the major source of noradrenaline in the brain, are histologically evident in early stages of neurodegenerative diseases. Novel MRI approaches now provide an opportunity to quantify structural features of the locus coeruleus in vivo during disease progression. In combination with neuropathological biomarkers, in vivo locus coeruleus imaging could help to understand the contribution of locus coeruleus neurodegeneration to clinical and pathological manifestations in Alzheimer’s disease, atypical neurodegenerative dementias and Parkinson’s disease. Moreover, as the functional sensitivity of the noradrenergic system is likely to change with disease progression, in vivo measures of locus coeruleus integrity could provide new pathophysiological insights into cognitive and behavioural symptoms. Locus coeruleus imaging also holds the promise to stratify patients into clinical trials according to noradrenergic dysfunction. In this article, we present a consensus on how non-invasive in vivo assessment of locus coeruleus integrity can be used for clinical research in neurodegenerative diseases. We outline the next steps for in vivo, post-mortem and clinical studies that can lay the groundwork to evaluate the potential of locus coeruleus imaging as a biomarker for neurodegenerative diseases.

Hemodynamic responses, in general, and the blood oxygenation level-dependent (BOLD) fMRI signal, in particular, provide an indirect measure of neuronal activity. There is strong evidence that the BOLD response correlates well with post-synaptic changes, induced by changes in the excitatory and inhibitory (E-I) balance between active neuronal populations. Typical BOLD responses exhibit transients, such as the early-overshoot and post-stimulus undershoot, that can be linked to transients in neuronal activity, but they can also result from vascular uncoupling between cerebral blood flow (CBF) and venous cerebral blood volume (venous CBV). Recently, we have proposed a novel generative hemodynamic model of the BOLD signal within the dynamic causal modeling framework, inspired by physiological observations, called P-DCM (Havlicek et al., 2015). We demonstrated the generative model's ability to more accurately model commonly observed neuronal and vascular transients in single regions but also effective connectivity between multiple brain areas (Havlicek et al., 2017b). In this paper, we additionally demonstrate the versatility of the generative model to jointly explain dynamic relationships between neuronal and hemodynamic physiological variables underlying the BOLD signal using multi-modal data. For this purpose, we utilized three distinct data-sets of experimentally induced responses in the primary visual areas measured in human, cat, and monkey brain, respectively: (1) CBF and BOLD responses; (2) CBF, total CBV, and BOLD responses (Jin and Kim, 2008); and (3) positive and negative neuronal and BOLD responses (Shmuel et al., 2006). By fitting the generative model to the three multi-modal experimental data-sets, we showed that the presence or absence of dynamic features in the BOLD signal is not an unambiguous indication of presence or absence of those features on the neuronal level. Nevertheless, the generative model that takes into account the dynamics of the physiological mechanisms underlying the BOLD response allowed dissociating neuronal from vascular transients and deducing excitatory and inhibitory neuronal activity time-courses from BOLD data alone and from multi-modal data.

Over the last decades, extensive basic and clinical knowledge has been acquired on the use of subthalamic nucleus (STN) deep brain stimulation (DBS) for Parkinson’s disease (PD). It is now clear that mechanisms involved in the effects of this therapy are far more complex than previously anticipated. At frequencies commonly used in clinical practice, neural elements may be excited or inhibited and novel dynamic states of equilibrium are reached. Electrode contacts used for chronic DBS in PD are placed near the dorsal border of the nucleus, a highly cellular region. DBS may thus exert its effects by modulating these cells, hyperdirect projections from motor cortical areas, afferent and efferent fibers to the motor STN. Advancements in neuroimaging techniques may allow us to identify these structures optimizing surgical targeting. In this review, we provide an update on mechanisms and the neural elements modulated by STN DBS.

Introduction: The subthalamic nucleus, substantia nigra, and globus pallidus, three nuclei of the human basal ganglia, play an important role in motor, associative, and limbic processing. The network of the basal ganglia is generally characterized by a direct, indirect, and hyperdirect pathway. This study aims to investigate the mesoscopic nature of these connections between the subthalamic nucleus, substantia nigra, and globus pallidus and their surrounding structures. Methods: A human post mortem brain specimen including the substantia nigra, subthalamic nucleus, and globus pallidus was scanned on a 7 T MRI scanner. High resolution diffusion weighted images were used to reconstruct the fibers intersecting the substantia nigra, subthalamic nucleus, and globus pallidus. The course and density of these tracks was analyzed. Results: Most of the commonly established projections of the subthalamic nucleus, substantia nigra, and globus pallidus were successfully reconstructed. However, some of the reconstructed fiber tracks such as the connections of the substantia nigra pars compacta to the other included nuclei and the connections with the anterior commissure have not been shown previously. In addition, the quantitative tractography approach showed a typical degree of connectivity previously not documented. An example is the relatively larger projections of the subthalamic nucleus to the substantia nigra pars reticulata when compared to the projections to the globus pallidus internus. Discussion: This study shows that ultra-high field post mortem tractography allows for detailed 3D reconstruction of the projections of deep brain structures in humans. Although the results should be interpreted carefully, the newly identified connections contribute to our understanding of the basal ganglia.

This work utilises general numerical magnetic resonance imaging MRI simulations to predict the spatial specificity of the blood oxygenation level-dependent (BOLD) functional MRI (fMRI) signal. A Monte Carlo simulation approach was utilized on a microvascular structure consisting of randomly oriented cylinders representing blood vessels. This framework was employed to numerically investigate the spatial specificity, defined as ratio of pial vessel to microvascular signal, of the spin echo BOLD fMRI signal as a function of field strength, echo time and tissue types [grey matter (GM) and cerebrospinal fluid (CSF), respectively]. Spatial specificity of spin echo BOLD fMRI signal was determined to increase with field strength up to 16 T and with maximal specificity for echo time shorter than tissue T(2). In addition, it was found that, for large pial vessels, the extravascular signal decay could not be described using the oversimplified but nevertheless commonly employed mono-exponential signal decay approximation (MEA). Consequently, a recently proposed model relying on the MEA deviates substantially from our results on the spatial specificity. A refinement of this model is proposed based on an available, more detailed signal description. Finally, the effect of CSF on the spatial specificity was investigated. While a large spatial specificity of the spin echo BOLD fMRI signal is observed if a pial vessel is surrounded by grey matter, this is greatly reduced for a pial vessel situated on a GM/CSF interface, rendering the suppression of pial vessels on the cortex surface unlikely.

Insulin is an important modulator of brain functions such as memory and appetite regulation. Besides the effect on neuronal activity, it is also possible that insulin has a direct vasodilatory effect on cerebral blood flow (CBF). We investigated the impact of increased insulin levels in the central nervous system on basal and task‐induced CBF as well as blood oxygenation level‐dependent (BOLD) response in the visual cortex using pulsed arterial spin‐labeling MRI. An intranasal insulin application was used to avoid peripheral hyperinsulinaemia, which would lead to a cascade of hormonal changes. In a control experiment, caffeine was applied due to its well‐known impact on the vasculature of the brain leading to a reliable reduction of CBF. Eight lean subjects were included in the study. On 2 separate days, intranasal human insulin or caffeine tablets were given to the subjects after fasting over night. On each day, basal CBF and task‐induced CBF were measured before and 30 min after application of insulin or caffeine in each subject. During the task condition, a flickering checkerboard was presented. Insulin had no effect on basal CBF and task‐induced CBF in comparison with drug‐free baseline measurement in the visual cortex and control regions. After caffeine application, however, there was a significant decrease of CBF during stimulation in the visual cortex. The BOLD response was not altered by insulin or caffeine between pre‐ and postdose measurements. In conclusion, we found no evidence for a direct vasodilatory effect of intranasal insulin on the cerebral vascular system in this study. Hum Brain Mapp, 2012. © 2011 Wiley Periodicals, Inc.

A spatial mismatch of up to 14 mm between optimal transcranial magnetic stimulation (TMS) site and functional magnetic resonance imaging (fMRI) signal has consistently been reported for the primary motor cortex. The underlying cause might be the effect of magnetic susceptibility around large draining veins in Gradient-Echo blood oxygenation level-dependent (GRE-BOLD) fMRI. We tested whether alternative fMRI sequences such as Spin-Echo (SE-BOLD) or Arterial Spin-Labeling (ASL) assessing cerebral blood flow (ASL-CBF) may localize neural activity closer to optimal TMS positions and primary motor cortex than GRE-BOLD. GRE-BOLD, SE-BOLD, and ASL-CBF signal changes during right thumb abductions were obtained from 15 healthy subjects at 3 Tesla. In 12 subjects, tissue at fMRI maxima was stimulated with neuronavigated TMS to compare motor-evoked potentials (MEPs). Euclidean distances between the fMRI center-of-gravity (CoG) and the TMS motor mapping CoG were calculated. Highest SE-BOLD and ASL-CBF signal changes were located in the anterior wall of the central sulcus [Brodmann Area 4 (BA4)], whereas highest GRE-BOLD signal changes were significantly closer to the gyral surface. TMS at GRE-BOLD maxima resulted in higher MEPs which might be attributed to significantly higher electric field strengths. TMS-CoGs were significantly anterior to fMRI-CoGs but distances were not statistically different across sequences. Our findings imply that spatial differences between fMRI and TMS are unlikely to be caused by spatial unspecificity of GRE-BOLD fMRI but might be attributed to other factors, e.g., interactions between TMS-induced electric field and neural tissue. Differences between techniques should be kept in mind when using fMRI coordinates as TMS (intervention) targets. Hum Brain Mapp, 2010. (c) 2010 Wiley-Liss, Inc.

Background. Aerobic treadmill exercise (T-EX) therapy has been shown to benefit walking and cardiorespiratory fitness in stroke survivors with chronic gait impairment even long after their stroke. The response, however, varies between individuals. Objective . The purpose of this post hoc analysis of 2 randomized controlled T-EX trials was to identify predictors for therapy response. Methods. In all, 52 participants received T-EX for 3 (Germany) or 6 (United States) months. Improvements in overground walking velocity (10 m/6-min walk) and fitness (peak VO2) were indicators of therapy response. Lesion location and volume were measured on T1-weighted magnetic resonance scans. Results . T-EX significantly improved gait and fitness, with gains in 10-m walk tests ranging between +113% and −25% and peak VO2 between −12% and 88%. Baseline walking impairments or fitness deficits were not predictive of therapy response; 10-m walk velocity improved more in those with subcortical rather than cortical lesions and in patients with smaller lesions. Improvements in 6-minute walk velocity were greater in those with more recent strokes and left-sided lesions. No variable other than training intensity, which was different between trials, predicted fitness gains. Conclusions. Despite proving overall effectiveness, the response to T-EX varies markedly between individuals. Whereas intensity of aerobic training seems to be an important predictor of gains in cardiovascular fitness, lesion size and location as well as interval between stroke onset and therapy delivery likely affect therapy response. These findings may be used to guide the timing of training and identify subgroups of patients for whom training modalities could be optimized.

Noninvasive imaging at the molecular level is an emerging field in biomedical research. This paper introduces a new technology synergizing two leading imaging methodologies: positron emission tomography (PET) and magnetic resonance imaging (MRI). Although the value of PET lies in its high-sensitivity tracking of biomarkers in vivo, it lacks resolving morphology. MRI has lower sensitivity, but produces high soft-tissue contrast and provides spectroscopic information and functional MRI (fMRI). We have developed a three-dimensional animal PET scanner that is built into a 7-T MRI. Our evaluations show that both modalities preserve their functionality, even when operated isochronously. With this combined imaging system, we simultaneously acquired functional and morphological PET-MRI data from living mice. PET-MRI provides a powerful tool for studying biology and pathology in preclinical research and has great potential for clinical applications. Combining fMRI and spectroscopy with PET paves the way for a new perspective in molecular imaging.

The aim of this study is to overcome the current limits of brain coverage available with multi-slice echo planar imaging (EPI) for vascular space occupancy (VASO) mapping. By incorporating simultaneous multi-slice (SMS) EPI image acquisition into slice-saturation slab-inversion VASO (SS-SI VASO), many more slices can be acquired for non-invasive functional measurements of blood volume responses.Blood-volume-weighted VASO and gradient echo blood oxygenation level-dependent (GE-BOLD) data were acquired in humans at 7 T with a 32-channel head coil. SMS-VASO was applied in three scenarios: A) high-resolution acquisition of spatially distant brain areas in the visuo-motor network (V1/V5/M1/S1); B) high-resolution acquisition of an imaging slab covering the entire M1/S1 hand regions; and C) low-resolution acquisition with near whole-brain coverage.The results show that the SMS-VASO sequence provided images enabling robust detection of blood volume changes in up to 20 slices with signal readout durations shorter than 150 ms. High-resolution application of SMS-VASO revealed improved specificity of VASO to GM tissue without contamination from large draining veins compared to GE-BOLD in the visual cortex and in the sensory-motor cortex.It is concluded that VASO fMRI with SMS-EPI allows obtaining a reasonable three-dimensional coverage not achievable with standard VASO during the short time period when blood magnetization is approximately nulled. Due to the increased brain coverage and better spatial specificity to GM tissue of VASO compared to GE-BOLD signal, the proposed method may play an important role in high-resolution human fMRI at 7 T.

Most functional brain imaging methods detect neuronal activations indirectly through the accompanying neurovascular response. Here, we demonstrate that a novel methodological approach, the combination of DC-magnetoencephalography (DC-MEG) and near-infrared spectroscopy (NIRS), allows non-invasive assessment of the dynamics of neurovascular coupling in the human brain: detecting directly slow neuronal processes (with time constants of 30s), DC-MEG revealed, even in unaveraged recordings, sustained neuronal activations at pericentral hand cortices contralateral to repetitive finger movements; these were accompanied by the ensuing local vascular response showing similar dynamical features as quantified by simultaneously recorded NIRS. This non-invasive approach opens a new avenue for the understanding of neurovascular coupling during physiological tasks as well as in diseases involving slow neuronal depolarization shifts and alterations of blood flow, such as stroke or migraine.

In the human, visually evoked potentials (VEP) and cerebral oxygenation changes, as measured by near-infrared spectroscopy (NIRS), are assessed to elucidate the relation between electrophysiological and vascular responses to a checkerboard stimulus reversing at 3 Hz. Habituation of either response is analysed on two time scales. Within the 1-min stimulation period we find a decrease in P100N135-component amplitude, closely coupled to a decrease in the amplitude of the oxygenation parameters (concentration changes in oxygenated and deoxygenated haemoglobin, [oxy-Hb] and [deoxy-Hb]). The N75P100-component amplitude exhibits a different behaviour along the 1-min stimulation period. An initial increase is overridden by an overall decrease, the latter not reaching statistical significance. The analysis across the 13 successive stimulation blocks separated by resting periods of equal duration yields a trend for an decrease in the VEP-components' amplitude, not reflected in the vascular response. When calculating a ratio between the amplitude of the P100N135-component and the concentration changes in the haemoglobins a "coupling index" of a 0.2 microM decrease in [deoxy-Hb] and an increase of 0.6 microM in [oxy-Hb] is found per 1 microV increase in VEP-component amplitude. The ratio is the same irrespective of its assessment from the difference stimulation/ rest or from the habituation effect, i.e., the difference between the amplitudes at the beginning and towards the end of the stimulation period. Although supporting the notion that the coupling between neuronal activation and the vascular response exhibits linear aspects, our findings cannot be taken as a proof of such a linearity across all brain regions and activation types. On the contrary, tentatively calculating a coupling index for the data assessed in the visual system, we intend to stress the necessity to assess both neuronal and vascular response to allow for a comparison between different systems and conditions in whom neurovascular coupling is expected to be altered (Miller et al, 2001; Mechelli et al, 2001).

Natural and behaviorally relevant sounds are characterized by temporal modulations of their waveforms, which carry important cues for sound segmentation and communication. Still, there is little consensus as to how this temporal information is represented in auditory cortex. Here, by using functional magnetic resonance imaging (fMRI) optimized for studying the auditory system, we report the existence of a topographically ordered spatial representation of temporal sound modulation rates in human auditory cortex. We found a topographically organized sensitivity within auditory cortex to sounds with varying modulation rates, with enhanced responses to lower modulation rates (2 and 4 Hz) on lateral parts of Heschl's gyrus (HG) and faster modulation rates (16 and 32 Hz) on medial HG. The representation of temporal modulation rates was distinct from the representation of sound frequencies (tonotopy) that was orientated roughly orthogonal. Moreover, the combination of probabilistic anatomical maps with a previously proposed functional delineation of auditory fields revealed that the distinct maps of temporal and spectral sound features both prevail within two presumed primary auditory fields hA1 and hR. Our results reveal a topographically ordered representation of temporal sound cues in human primary auditory cortex that is complementary to maps of spectral cues. They thereby enhance our understanding of the functional parcellation and organization of auditory cortical processing.

Functional magnetic resonance imaging (fMRI) and transcranial magnetic stimulation (TMS) are well-established tools for investigating the human motor system in-vivo. We here studied the relationship between movement-related fMRI signal changes in the primary motor cortex (M1) and electrophysiological properties of the hand motor area assessed with neuronavigated TMS in 17 healthy subjects. The voxel showing the highest task-related BOLD response in the left hand motor area during right hand movements was identified for each individual subject. This fMRI peak voxel in M1 served as spatial target for coil positioning during neuronavigated TMS. We performed correlation analyses between TMS parameters, BOLD signal estimates and effective connectivity parameters of M1 assessed with dynamic causal modeling (DCM). The results showed a negative correlation between the movement-related BOLD signal in left M1 and resting as well as active motor threshold (MT) obtained for left M1. The DCM analysis revealed that higher excitability of left M1 was associated with a stronger coupling between left supplementary motor area (SMA) and M1. Furthermore, BOLD activity in left M1 correlated with ipsilateral silent period (ISP), i.e. the stronger the task-related BOLD response in left M1, the higher interhemispheric inhibition effects targeting right M1. DCM analyses revealed a positive correlation between the coupling of left SMA with left M1 and the duration of ISP. The data show that TMS parameters assessed for the hand area of M1 do not only reflect the intrinsic properties at the stimulation site but also interactions with remote areas in the human motor system. Hum Brain Mapp, 2011. (c) 2011 Wiley-Liss, Inc.

BackgroundIn the graph theoretical analysis of anatomical brain connectivity, the white matter connections between regions of the brain are identified and serve as basis for the assessment of regional connectivity profiles, for example, to locate the hubs of the brain. But regions of the brain can be characterised further with respect to their gray matter volume or resting state perfusion. Local anatomical connectivity, gray matter volume and perfusion are traits of each brain region that are likely to be interdependent, however, particular patterns of systematic covariation have not yet been identified.Methodology/principal findingsWe quantified the covariation of these traits by conducting an integrative MRI study on 23 subjects, utilising a combination of Diffusion Tensor Imaging, Arterial Spin Labeling and anatomical imaging. Based on our hypothesis that local connectivity, gray matter volume and perfusion are linked, we correlated these measures and particularly isolated the covariation of connectivity and perfusion by statistically controlling for gray matter volume. We found significant levels of covariation on the group- and regionwise level, particularly in regions of the Default Brain Mode Network.Conclusions/significanceConnectivity and perfusion are systematically linked throughout a number of brain regions, thus we discuss these results as a starting point for further research on the role of homology in the formation of functional connectivity networks and on how structure/function relationships can manifest in the form of such trait interdependency.

Continuous Arterial Spin Labeling (CASL) offers the possibility to quantitatively measure the regional cerebral blood flow (rCBF). We demonstrate, for the first time, the feasibility of interleaving Transcranial Magnetic Stimulation (TMS) with CASL at 3 T. Two different repetitive TMS (rTMS) protocols were applied to the motor cortex in 10 subjects and the effect on rCBF was measured using a CASL sequence with separate RF coils for labeling the inflowing blood. Each subject was investigated, using a block design, under 7 different conditions: continuous 2 Hz rTMS (3 intensities: 100%, 110% and 120% resting motor threshold [MT]), short 10 Hz rTMS trains at 110% MT (8 pulses per train; 3 different numbers of trains per block with 2, 4 and 12 s intervals between trains) and volitional movement (acoustically triggered by 50% MT stimuli). We show robust rCBF increases in motor and premotor areas due to rTMS, even at the lowest stimulation intensity of 100% MT. RCBF exhibited a linear positive dependency on stimulation intensity (for continuous 2 Hz rTMS) and the number of 10 Hz trains in the stimulated M1/S1 as well as in premotor and supplementary motor areas. Interestingly, the 2 different rTMS protocols yielded markedly different rCBF activation time courses, which did not correlate with the electromyographic recordings of the muscle responses. In future, this novel combination of TMS with ASL will offer the possibility to investigate the immediate and after-effects of rTMS stimulation on rCBF, which previously was only possible using PET.

Functional magnetic resonance imaging (fMRI) has become a powerful tool for investigating the working human brain based on the blood oxygenation level dependent (BOLD) effect on the MR signal. However, despite the widespread use of fMRI techniques for mapping brain activation, the basic physiological mechanisms underlying the observed signal changes are still poorly understood. Arterial spin labeling (ASL) techniques, which measure cerebral blood flow (CBF) and the BOLD effect simultaneously, provide a useful tool for investigating these physiological questions. In this paper, recent results of studies manipulating the baseline CBF both pharmacologically and physiologically will be discussed. These data are consistent with a feed-forward mechanism of neurovascular coupling, and suggest that the CBF change itself may be a more robust reflection of neural activity changes than the BOLD effect. Consistent with these data, a new thermodynamic hypothesis is proposed for the physiological function of CBF regulation: maintenance of the [O 2 ]/[CO 2 ] concentration ratio at the mitochondria in order to preserve the free energy available from oxidative metabolism. A kinetic model based on this hypothesis provides a reasonable quantitative description of the CBF changes associated with neural activity and altered blood gases (CO 2 and O 2 ).

The blood oxygenation level-dependent (BOLD) responses to visual stimuli, using both a 1-s long single trial stimulus and a 20-s long block stimulus, were measured in a 4-T magnetic field both before and immediately after a 200-mg caffeine dose. In addition, resting levels of cerebral blood flow (CBF) were measured using arterial spin labeling. For the single trial stimulus, the caffeine dose significantly (p0.05) reduced the time to peak (TTP), the time after the peak at which the response returned to 50% of the peak amplitude (TA50), and the amplitude of the poststimulus undershoot in all subjects (N=5). Other parameters, such as the full-width half-maximum (FWHM) and the peak amplitude, also showed significant changes in the majority of subjects. For the block stimulus, the TTP, TA50, and the time for the response to reach 50% of the peak amplitude (T50) were significantly reduced. In some subjects, oscillations were observed in the poststimulus portion of the response with median peak periods of 9.1 and 9.5 s for the single trial and block responses, respectively. Resting CBF was reduced by an average of 24%. The reproducibility of the results was verified in one subject who was scanned on 3 different days. The dynamic changes are similar to those previously reported for baseline CBF reductions induced by hypocapnia and hyperoxia.

Echo-contrast "bolus tracking" by ultrasound (US) is an exciting new tool to study cerebral haemodynamics. In the present study, a global cerebral circulation time (CCT) was measured by extracranial Doppler as the time difference of contrast bolus arrival between the internal carotid artery and internal jugular vein. A total of 64 healthy volunteers and 9 patients with an angiographically diagnosed arteriovenous malformation (AVM) were studied. CCT in volunteers and patients was calculated as the time interval between the points of 10% rise (CCT(1)) and 90% rise (CCT(3)) of the total intensity increase and between the turning points (CCT(2)) of the resulting time-intensity curves. In the volunteer group, CCT(1) was 5.4 +/- 1.8 s, CCT(2) was 7 +/- 1.3 s and CCT(3) 7.5 +/- 1.8 s. CCT results in the AVM group were 2.8 +/- 2.5 s, 3.0 +/- 1.3 s and 4.5 +/- 2.1 s, respectively, and differed significantly from the controls. For the first time, we could confirm a significant shortening of CCT in patients with cerebral AVM by US. The presented test might become a new, additional tool for AVM evaluation and follow-up of treatment in these patients.

The validity of measured Cytochrome-c-oxidase changes during physiological activation of the cerebral cortex using near-infrared light has been questioned by us in a previous theoretical study. Here, we use differential activation of visual areas rich and poor in Cytochrome-c-oxidase to further clarify this issue.

Tracking a bolus of contrast agent travelling through the cerebral vasculature provides a measure of the blood supply and the blood flow velocity in the respective cerebral tissue. This principle has been the basis for the first approaches in functional MR imaging and is of great value when investigating stroke and other vascularly compromised patients. While the bolus measurement is a standard procedure in clinical MR imaging, optical bolus tracking has not yet become a reliable protocol. Here optical absorption changes induced by bolus signals of the dye indocyanine-green (ICG) are studied by near infrared spectroscopy (NIRS) on volunteers. The aim is to assess the latency and shape of the absorption change. For an application on the human brain the differentiation of extra- and intracerebral vascular compartments is essential. For this purpose frequency domain measurements are analysed by a Monte Carlo based model for the photon transport in tissue. We show that based on measurements of the photon-mean time of flight (phase) in addition to intensity the bolus signal of the deeper tissue layers (cortical signals) has a peak of about 10 s width, while the absorption change in the upper layers, i.e. extracortical tissue, has a much longer recovery time. This is in qualitative agreement with Gd-MR bolus measurements. The potential clinical interest of this study is to monitor cerebral perfusion changes induced by pathological conditions i.e, stroke or cerebral occlusion.

Tracking a bolus of contrast agent traveling through the cerebral vasculature provides a measure of the blood flow velocity in the respective cerebral tissue. This principle has been the basis for the first approaches in functional magnetic resonance (MR) imaging and is of great value for investigating patients with vascular disease, especially stroke. While bolus measurements are a standard procedure in MR imaging, optical bolus tracking is as yet not established. Here we study optical absorption changes induced by a bolus of the dye indocyanine-green with near infrared spectroscopy in healthy volunteers. The aim is to assess the latency and shape of the change in absorption. Since application in the adult human critically depends on differentiation between extra- and intracerebral vascular compartments we focus on an approach for such a separation. To do this frequency-domain and multidistance measurements are analyzed by a Monte Carlo based model for photon transport in tissue. Based on measurements of both the photon's mean time of flight (phase) and the intensity, our results allow differentiation between an upper (skin and skull) and a lower layer (brain). The bolus in the deeper tissue layers has a peak of about 10 s width, while the change in absorption in the upper layers shows a much longer recovery time. This is in qualitative agreement with MR imaging results using a gadolinium bolus. This result is promising with respect to the potential of bedside monitoring of mean transit time (MTT) changes in patients with stroke or related vascular disease.