Distance from main arteries influences microstructural and functional brain tissue characteristics.

Given the substantial dependence of neurons on continuous supply of energy, the distribution of major cerebral arteries opens a question whether the distance from the main supply arteries constitutes a modulating factor for the microstructural and functional properties of brain tissue. To tackle this question, multimodal MRI acquisitions of 102 healthy volunteers over the full adult age span were utilised. Relaxation along a fictitious field in the rotating frame of rank n = 4 (RAFF4), adiabatic T1ρ, T2ρ,  and intracellular volume fraction (fICVF) derived from diffusion-weighted imaging were implemented to quantify microstructural (cellularity, myelin density, iron concentration) tissue characteristics and degree centrality and fractional amplitude of low-frequency fluctuations to probe for functional metrics. Inverse correlation of arterial distance with robust homogeneity was detected for T1ρ, T2ρ and RAFF4 for cortical grey matter and white matter, showing substantial complex microstructural differences between brain tissue close and farther from main arterial trunks. Albeit with wider variability, functional metrics pointed to increased connectivity and neuronal activity in areas farther from main arteries. Surprisingly, multiple of these microstructural and functional distance-based gradients diminished with higher age, pointing to uniformization of brain tissue with ageing. All in all, this pilot study provides a novel insight on brain regionalisation based on artery distance, which merits further investigation to validate its biological underpinnings.

Age-related differences in macromolecular resonances observed in ultra-short-TE STEAM MR spectra at 7T.

PURPOSE: To understand how macromolecular content varies in the human brain with age in a large cohort of healthy subjects. METHODS: In-vivo 1H-MR spectra were acquired using ultra-short TE STEAM at 7T in the posterior cingulate cortex. Macromolecular content was studied in 147 datasets from a cohort ranging in age from 19 to 89 y. Three fitting approaches were used to evaluate the macromolecular content: (1) a macromolecular resonances model developed for this study; (2) LCModel-simulated macromolecules; and (3) a combination of measured and LCModel-simulated macromolecules. The effect of age on the macromolecular content was investigated by considering age both as a continuous variable (i.e., linear regressions) and as a categorical variable (i.e., multiple comparisons among sub-groups obtained by stratifying data according to age by decade). RESULTS: While weak age-related effects were observed for macromolecular peaks at ˜0.9 (MM09), ˜1.2 (MM12), and ˜1.4 (MM14) ppm, moderate to strong effects were observed for peaks at ˜1.7 (MM17), and ˜2.0 (MM20) ppm. Significantly higher MM17 and MM20 content started from 30 to 40 y of age, while for MM09, MM12, and MM14, significantly higher content started from 60 to 70 y of age. CONCLUSIONS: Our findings provide insights into age-related differences in macromolecular contents and strengthen the necessity of using age-matched measured macromolecules during quantification.

Neurovascular coupling is optimized to compensate for the increase in proton production from nonoxidative glycolysis and glycogenolysis during brain activation and maintain homeostasis of pH, pCO2 , and pO2.

During transient brain activation cerebral blood flow (CBF) increases substantially more than cerebral metabolic rate of oxygen consumption (CMRO2 ) resulting in blood hyperoxygenation, the basis of BOLD fMRI contrast. Explanations for the high CBF vs. CMRO2 slope, termed neurovascular coupling (NVC) constant, focused on maintainenance of tissue oxygenation to support mitochondrial ATP production. However, paradoxically the brain has a 3-fold lower oxygen extraction fraction (OEF) than other organs with high energy requirements, like heart and muscle during exercise. Here, we hypothesize that the NVC constant and the capillary oxygen mass transfer coefficient (which in combination determine OEF) are co-regulated during activation to maintain simultaneous homeostasis of pH and partial pressure of CO2 and O2 (pCO2 and pO2 ). To test our hypothesis, we developed an arteriovenous flux balance model for calculating blood and brain pH, pCO2 , and pO2 as a function of baseline OEF (OEF0 ), CBF, CMRO2 , and proton production by nonoxidative metabolism coupled to ATP hydrolysis. Our model was validated against published brain arteriovenous difference studies and then used to calculate pH, pCO2, and pO2 in activated human cortex from published calibrated fMRI and PET measurements. In agreement with our hypothesis, calculated pH, pCO2, and pO2 remained close to constant independently of CMRO2 in correspondence to experimental measurements of NVC and OEF0 . We also found that the optimum values of the NVC constant and OEF0 that ensure simultaneous homeostasis of pH, pCO2, and pO2 were remarkably similar to their experimental values. Thus, the high NVC constant is overall determined by proton removal by CBF due to increases in nonoxidative glycolysis and glycogenolysis. These findings resolve the paradox of the brain's high CBF yet low OEF during activation, and may contribute to explaining the vulnerability of brain function to reductions in blood flow and capillary density with aging and neurovascular disease.

Whole-brain studies of spontaneous behavior in head-fixed rats enabled by zero echo time MB-SWIFT fMRI.

Understanding the link between the brain activity and behavior is a key challenge in modern neuroscience. Behavioral neuroscience, however, lacks tools to record whole-brain activity in complex behavioral settings. Here we demonstrate that a novel Multi-Band SWeep Imaging with Fourier Transformation (MB-SWIFT) functional magnetic resonance imaging (fMRI) approach enables whole-brain studies in spontaneously behaving head-fixed rats. First, we show anatomically relevant functional parcellation. Second, we show sensory, motor, exploration, and stress-related brain activity in relevant networks during corresponding spontaneous behavior. Third, we show odor-induced activation of olfactory system with high correlation between the fMRI and behavioral responses. We conclude that the applied methodology enables novel behavioral study designs in rodents focusing on tasks, cognition, emotions, physical exercise, and social interaction. Importantly, novel zero echo time and large bandwidth approaches, such as MB-SWIFT, can be applied for human behavioral studies, allowing more freedom as body movement is dramatically less restricting factor.

Infantile status epilepticus disrupts myelin development.

Temporal lobe epilepsy (TLE) is the most prevalent type of epilepsy in adults; it often starts in infancy or early childhood. Although TLE is primarily considered to be a grey matter pathology, a growing body of evidence links this disease with white matter abnormalities. In this study, we explore the impact of TLE onset and progression in the immature brain on white matter integrity and development utilising the rat model of Li-pilocarpine-induced TLE at the 12th postnatal day (P). Diffusion tensor imaging (DTI) and Black-Gold II histology uncovered disruptions in major white matter tracks (corpus callosum, internal and external capsules, and deep cerebral white matter) spreading through the whole brain at P28. These abnormalities were mostly not present any longer at three months after TLE induction, with only limited abnormalities detectable in the external capsule and deep cerebral white matter. Relaxation Along a Fictitious Field in the rotating frame of rank 4 indicated that white matter changes observed at both timepoints, P28 and P72, are consistent with decreased myelin content. The animals affected by TLE-induced white matter abnormalities exhibited increased functional connectivity between the thalamus and medial prefrontal and somatosensory cortex in adulthood. Furthermore, histological analyses of additional animal groups at P15 and P18 showed only mild changes in white matter integrity, suggesting a gradual age-dependent impact of TLE progression. Taken together, TLE progression in the immature brain distorts white matter development with a peak around postnatal day 28, followed by substantial recovery in adulthood. This developmental delay might give rise to cognitive and behavioural comorbidities typical for early-onset TLE.

Hemispheric functional segregation facilitates target detection during sustained visuospatial attention.

Visuospatial attention is strongly lateralized, with the right hemisphere commonly exhibiting stronger activation and connectivity patterns than the left hemisphere during attentive processes. However, whether such asymmetry influences inter-hemispheric information transfer and behavioral performance is not known. Here we used a region of interest (ROI) and network-based approach to determine steady-state fMRI functional connectivity (FC) in the whole cerebral cortex during a leftward/rightward covert visuospatial attention task. We found that the global FC topology between either ROIs or networks was independent on the attended side. The side of attention significantly modulated FC strength between brain networks, with leftward attention primarily involving the connections of the right visual network with dorsal and ventral attention networks in both the left and right hemisphere. High hemispheric functional segregation significantly correlated with faster target detection response times (i.e., better performance). Our findings suggest that the dominance of the right hemisphere in visuospatial attention is associated with an hemispheric functional segregation that is beneficial for behavioral performance.

Manipulations of sleep-like slow-wave activity by noninvasive brain stimulation.

Sleep is a universal and evolutionarily conserved behavior among many animal species, yet we do not have a fundamental understanding of why animals need to sleep. What we do know, however, is that sleep is critical for behavioral performance during the waking period and for long-term brain health. Here we provide an overview of some putative mechanisms that mediate the restorative effects of sleep, namely metabolic biosynthesis, fluid perfusion, and synaptic homeostasis. We then review recent experimental findings that advance the possibility of inducing sleep-like slow-wave activity (SWA) during wakefulness or enhance SWA during sleep in a top-down manner using noninvasive brain stimulation. SWA induction and SWA enhancement are believed to recapitulate the beneficial effects of sleep independent of the actual state of the subjects. If confirmed, these observations will change the way in which we investigate the neural correlates of sleep, thus paving the way for comprehending and actively controlling its restorative function.

Event-recurring multiband SWIFT functional MRI with 200-ms temporal resolution during deep brain stimulation and isoflurane-induced burst suppression in rat.

PURPOSE: To develop a high temporal resolution functional MRI method for tracking repeating events in the brain. METHODS: We developed a novel functional MRI method using multiband sweep imaging with Fourier transformation (SWIFT), termed event-recurring SWIFT (EVER-SWIFT). The method is able to image similar repeating events with subsecond temporal resolution. Here, we demonstrate the use of EVER-SWIFT for detecting functional MRI responses during deep brain stimulation of the medial septal nucleus and during spontaneous isoflurane-induced burst suppression in the rat brain at 9.4 T with 200-ms temporal resolution. RESULTS: The EVER-SWIFT approach showed that the shapes and time-to-peak values of the response curves to deep brain stimulation significantly differed between downstream brain regions connected to the medial septal nucleus, resembling findings obtained with traditional 2-second temporal resolution. In contrast, EVER-SWIFT allowed for detailed temporal measurement of a spontaneous isoflurane-induced bursting activity pattern, which was not achieved with traditional temporal resolution. CONCLUSION: The EVER-SWIFT technique enables subsecond 3D imaging of both stimulated and spontaneously recurring brain activities, and thus holds great potential for studying the mechanisms of neuromodulation and spontaneous brain activity.

Different FreeSurfer versions might generate different statistical outcomes in case-control comparison studies.

PURPOSE: Neuroimaging pipelines have long been known to generate mildly differing results depending on various factors, including software version. While considered generally acceptable and within the margin of reasonable error, little is known about their effect in common research scenarios such as inter-group comparisons between healthy controls and various pathological conditions. The aim of the presented study was to explore the differences in the inferences and statistical significances in a model situation comparing volumetric parameters between healthy controls and type 1 diabetes patients using various FreeSurfer versions. METHODS: T1- and T2-weighted structural scans of healthy controls and type 1 diabetes patients were processed with FreeSurfer 5.3, FreeSurfer 5.3 HCP, FreeSurfer 6.0 and FreeSurfer 7.1, followed by inter-group statistical comparison using outputs of individual FreeSurfer versions. RESULTS: Worryingly, FreeSurfer 5.3 detected both cortical and subcortical volume differences out of the preselected regions of interest, but newer versions such as FreeSurfer 5.3 HCP and FreeSurfer 6.0 reported only subcortical differences of lower magnitude and FreeSurfer 7.1 failed to find any statistically significant inter-group differences. CONCLUSION: Since group averages of individual FreeSurfer versions closely matched, in keeping with previous literature, the main origin of this disparity seemed to lie in substantially higher within-group variability in the model pathological condition. Ergo, until validation in common research scenarios as case-control comparison studies is included into the development process of new software suites, confirmatory analyses utilising a similar software based on analogous, but not fully equivalent principles, might be considered as supplement to careful quality control.

Orientation-selective and directional deep brain stimulation in swine assessed by functional MRI at 3T.

Functional MRI (fMRI) has become an important tool for probing network-level effects of deep brain stimulation (DBS). Previous DBS-fMRI studies have shown that electrical stimulation of the ventrolateral (VL) thalamus can modulate sensorimotor cortices in a frequency and amplitude dependent manner. Here, we investigated, using a swine animal model, how the direction and orientation of the electric field, induced by VL-thalamus DBS, affects activity in the sensorimotor cortex. Adult swine underwent implantation of a novel 16-electrode (4 rows x 4 columns) directional DBS lead in the VL thalamus. A within-subject design was used to compare fMRI responses for (1) directional stimulation consisting of monopolar stimulation in four radial directions around the DBS lead, and (2) orientation-selective stimulation where an electric field dipole was rotated 0°-360° around a quadrangle of electrodes. Functional responses were quantified in the premotor, primary motor, and somatosensory cortices. High frequency electrical stimulation through leads implanted in the VL thalamus induced directional tuning in cortical response patterns to varying degrees depending on DBS lead position. Orientation-selective stimulation showed maximal functional response when the electric field was oriented approximately parallel to the DBS lead, which is consistent with known axonal orientations of the cortico-thalamocortical pathway. These results demonstrate that directional and orientation-selective stimulation paradigms in the VL thalamus can tune network-level modulation patterns in the sensorimotor cortex, which may have translational utility in improving functional outcomes of DBS therapy.

Evaluation of denoising strategies for task-based functional connectivity: Equalizing residual motion artifacts between rest and cognitively demanding tasks.

In-scanner head motion represents a major confounding factor in functional connectivity studies and it raises particular concerns when motion correlates with the effect of interest. One such instance regards research focused on functional connectivity modulations induced by sustained cognitively demanding tasks. Indeed, cognitive engagement is generally associated with substantially lower in-scanner movement compared with unconstrained, or minimally constrained, conditions. Consequently, the reliability of condition-dependent changes in functional connectivity relies on effective denoising strategies. In this study, we evaluated the ability of common denoising pipelines to minimize and balance residual motion-related artifacts between resting-state and task conditions. Denoising pipelines-including realignment/tissue-based regression, PCA/ICA-based methods (aCompCor and ICA-AROMA, respectively), global signal regression, and censoring of motion-contaminated volumes-were evaluated according to a set of benchmarks designed to assess either residual artifacts or network identifiability. We found a marked heterogeneity in pipeline performance, with many approaches showing a differential efficacy between rest and task conditions. The most effective approaches included aCompCor, optimized to increase the noise prediction power of the extracted confounding signals, and global signal regression, although both strategies performed poorly in mitigating the spurious distance-dependent association between motion and connectivity. Censoring was the only approach that substantially reduced distance-dependent artifacts, yet this came at the great cost of reduced network identifiability. The implications of these findings for best practice in denoising task-based functional connectivity data, and more generally for resting-state data, are discussed.

Spinal cord fMRI with MB-SWIFT for assessing epidural spinal cord stimulation in rats.

PURPOSE: Electrical epidural spinal cord stimulation (SCS) is used as a treatment for chronic pain as well as to partially restore motor function after a spinal cord injury. Monitoring the spinal cord activity during SCS with fMRI could provide important and objective measures of integrative responses to treatment. Unfortunately, spinal cord fMRI is severely challenged by motion and susceptibility artifacts induced by the implanted electrode and bones. This pilot study introduces multi-band sweep imaging with Fourier transformation (MB-SWIFT) technique for spinal cord fMRI during SCS in rats. Given the close to zero acquisition delay and high bandwidth in 3 dimensions, MB-SWIFT is demonstrated to be highly tolerant to motion and susceptibility-induced artifacts and thus holds promise for fMRI during SCS. METHODS: MB-SWIFT with 0.78 × 0.78 × 1.50 mm3 spatial resolution and 3-s temporal resolution was used at 9.4 Tesla in rats undergoing epidural SCS at different frequencies. Its performance was compared with spin echo EPI. The origin of the functional contrast was also explored using suppression bands. RESULTS: MB-SWIFT was tolerant to electrode-induced artifacts and respiratory motion, leading to substantially higher fMRI sensitivity than spin echo fMRI. Clear stimulation frequency-dependent responses to SCS were detected in the rat spinal cord close to the stimulation site. The origin of MB-SWIFT fMRI signals was consistent with dominant inflow effects. CONCLUSION: fMRI of the rat spinal cord during SCS can be consistently achieved with MB-SWIFT, thus providing a valuable experimental framework for assessing the effects of SCS on the central nervous system.

Multi-band SWIFT enables quiet and artefact-free EEG-fMRI and awake fMRI studies in rat.

Functional magnetic resonance imaging (fMRI) studies in animal models provide invaluable information regarding normal and abnormal brain function, especially when combined with complementary stimulation and recording techniques. The echo planar imaging (EPI) pulse sequence is the most common choice for fMRI investigations, but it has several shortcomings. EPI is one of the loudest sequences and very prone to movement and susceptibility-induced artefacts, making it suboptimal for awake imaging. Additionally, the fast gradient-switching of EPI induces disrupting currents in simultaneous electrophysiological recordings. Therefore, we investigated whether the unique features of Multi-Band SWeep Imaging with Fourier Transformation (MB-SWIFT) overcome these issues at a high 9.4 T magnetic field, making it a potential alternative to EPI. MB-SWIFT had 32-dB and 20-dB lower peak and average sound pressure levels, respectively, than EPI with typical fMRI parameters. Body movements had little to no effect on MB-SWIFT images or functional connectivity analyses, whereas they severely affected EPI data. The minimal gradient steps of MB-SWIFT induced significantly lower currents in simultaneous electrophysiological recordings than EPI, and there were no electrode-induced distortions in MB-SWIFT images. An independent component analysis of the awake rat functional connectivity data obtained with MB-SWIFT resulted in near whole-brain level functional parcellation, and simultaneous electrophysiological and fMRI measurements in isoflurane-anesthetized rats indicated that MB-SWIFT signal is tightly linked to neuronal resting-state activity. Therefore, we conclude that the MB-SWIFT sequence is a robust preclinical brain mapping tool that can overcome many of the drawbacks of conventional EPI fMRI at high magnetic fields.

Orientation selective deep brain stimulation of the subthalamic nucleus in rats.

Deep brain stimulation (DBS) has become an important tool in the management of a wide spectrum of diseases in neurology and psychiatry. Target selection is a vital aspect of DBS so that only the desired areas are stimulated. Segmented leads and current steering have been shown to be promising additions to DBS technology enabling better control of the stimulating electric field. Recently introduced orientation selective DBS (OS-DBS) is a related development permitting sensitization of the stimulus to axonal pathways with different orientations by freely controlling the primary direction of the electric field using multiple contacts. Here, we used OS-DBS to stimulate the subthalamic nucleus (STN) in healthy rats while simultaneously monitoring the induced brain activity with fMRI. Maximal activation of the sensorimotor and basal ganglia-thalamocortical networks was observed when the electric field was aligned mediolaterally in the STN pointing in the lateral direction, while no cortical activation was observed with the electric field pointing medially to the opposite direction. Such findings are consistent with mediolateral main direction of the STN fibers, as seen with high resolution diffusion imaging and histology. The asymmetry of the OS-DBS dipolar field distribution using three contacts along with the potential stimulation of the internal capsule, are also discussed. We conclude that OS-DBS offers an additional degree of flexibility for optimization of DBS of the STN which may enable a better treatment response.

NMR shutter-speed elucidates apparent population inversion of 1 H2 O signals due to active transmembrane water cycling.

PURPOSE: The desire to quantitatively discriminate the extra- and intracellular tissue 1 H2 O MR signals has gone hand-in-hand with the continual, historic increase in MRI instrument magnetic field strength [B0 ]. However, recent studies have indicated extremely valuable, novel metabolic information can be readily accessible at ultra-low B0 . The two signals can be distinguished, and the homeostatic activity of the cell membrane sodium/potassium pump (Na+ ,K+ ,ATPase) detected. The mechanism allowing 1 H2 O MRI to do this is the newly discovered active transmembrane water cycling (AWC) phenomenon, which we found using paramagnetic extracellular contrast agents at clinical B0 values. AWC is important because Na+ ,K+ ,ATPase can be considered biology's most vital enzyme, and its in vivo steady-state activity has not before been measurable, let alone amenable to mapping with high spatial resolution. Recent reports indicate AWC correlates with neuronal firing rate, with malignant tumor metastatic potential, and inversely with cellular reducing equivalent fraction. We wish to systematize the ways AWC can be precisely measured. METHODS: We present a theoretical longitudinal relaxation analysis of considerable scope: it spans the low- and high-field situations. RESULTS: We show the NMR shutter-speed organizing principle is pivotal in understanding how trans-membrane steady-state water exchange kinetics are manifest throughout the range. Our findings illuminate an aspect, apparent population inversion, which is crucial in understanding ultra-low field results. CONCLUSIONS: Without an appreciation of apparent population inversion, significant misinterpretations of future data are likely. These could have unfortunate diagnostic consequences.

Scale-invariant rearrangement of resting state networks in the human brain under sustained stimulation.

Brain activity at rest is characterized by widely distributed and spatially specific patterns of synchronized low-frequency blood-oxygenation level-dependent (BOLD) fluctuations, which correspond to physiologically relevant brain networks. This network behaviour is known to persist also during task execution, yet the details underlying task-associated modulations of within- and between-network connectivity are largely unknown. In this study we exploited a multi-parametric and multi-scale approach to investigate how low-frequency fluctuations adapt to a sustained n-back working memory task. We found that the transition from the resting state to the task state involves a behaviourally relevant and scale-invariant modulation of synchronization patterns within both task-positive and default mode networks. Specifically, decreases of connectivity within networks are accompanied by increases of connectivity between networks. In spite of large and widespread changes of connectivity strength, the overall topology of brain networks is remarkably preserved. We show that these findings are strongly influenced by connectivity at rest, suggesting that the absolute change of connectivity (i.e., disregarding the baseline) may not be the most suitable metric to study dynamic modulations of functional connectivity. Our results indicate that a task can evoke scale-invariant, distributed changes of BOLD fluctuations, further confirming that low frequency BOLD oscillations show a specialized response and are tightly bound to task-evoked activation.

Extending the Human Connectome Project across ages: Imaging protocols for the Lifespan Development and Aging projects.

The Human Connectome Projects in Development (HCP-D) and Aging (HCP-A) are two large-scale brain imaging studies that will extend the recently completed HCP Young-Adult (HCP-YA) project to nearly the full lifespan, collecting structural, resting-state fMRI, task-fMRI, diffusion, and perfusion MRI in participants from 5 to 100+ years of age. HCP-D is enrolling 1300+ healthy children, adolescents, and young adults (ages 5-21), and HCP-A is enrolling 1200+ healthy adults (ages 36-100+), with each study collecting longitudinal data in a subset of individuals at particular age ranges. The imaging protocols of the HCP-D and HCP-A studies are very similar, differing primarily in the selection of different task-fMRI paradigms. We strove to harmonize the imaging protocol to the greatest extent feasible with the completed HCP-YA (1200+ participants, aged 22-35), but some imaging-related changes were motivated or necessitated by hardware changes, the need to reduce the total amount of scanning per participant, and/or the additional challenges of working with young and elderly populations. Here, we provide an overview of the common HCP-D/A imaging protocol including data and rationales for protocol decisions and changes relative to HCP-YA. The result will be a large, rich, multi-modal, and freely available set of consistently acquired data for use by the scientific community to investigate and define normative developmental and aging related changes in the healthy human brain.

MB-SWIFT functional MRI during deep brain stimulation in rats.

Recently introduced 3D radial MRI pulse sequence entitled Multi-Band SWeep Imaging with Fourier Transformation (MB-SWIFT) having virtually zero acquisition delay was used to obtain functional MRI (fMRI) contrast in rat's brain at 9.4 T during deep brain stimulation (DBS). The results demonstrate that MB-SWIFT allows functional images free of susceptibility artifacts, and provides an excellent fMRI activation contrast in the brain. Flip angle dependence of the MB-SWIFT fMRI signal and elimination of the fMRI contrast while using saturation bands, indicate a blood flow origin of the observed fMRI contrast. MB-SWIFT fMRI modality permits activation studies in the close proximity to an implanted lead, which is not possible to achieve with conventionally used gradient echo and spin echo - echo planar imaging fMRI techniques. We conclude that MB-SWIFT fMRI is a powerful imaging modality for investigations of functional responses during DBS.

Effects of reduced oxygen availability on the vascular response and oxygen consumption of the activated human visual cortex.

PURPOSE: To identify the impact of reduced oxygen availability on the evoked vascular response upon visual stimulation in the healthy human brain by magnetic resonance imaging (MRI). MATERIALS AND METHODS: Functional MRI techniques based on arterial spin labeling (ASL), blood oxygenation level-dependent (BOLD), and vascular space occupancy (VASO)-dependent contrasts were utilized to quantify the BOLD signal, cerebral blood flow (CBF), and volume (CBV) from nine subjects at 3T (7M/2F, 27.3 ± 3.6 years old) during normoxia and mild hypoxia. Changes in visual stimulus-induced oxygen consumption rates were also estimated with mathematical modeling. RESULTS: Significant reductions in the extension of activated areas during mild hypoxia were observed in all three imaging contrasts: by 42.7 ± 25.2% for BOLD (n = 9, P = 0.002), 33.1 ± 24.0% for ASL (n = 9, P = 0.01), and 31.9 ± 15.6% for VASO images (n = 7, P = 0.02). Activated areas during mild hypoxia showed responses with similar amplitude for CBF (58.4 ± 18.7% hypoxia vs. 61.7 ± 16.1% normoxia, P = 0.61) and CBV (33.5 ± 17.5% vs. 25.2 ± 13.0%, P = 0.27), but not for BOLD (2.5 ± 0.8% vs. 4.1 ± 0.6%, P = 0.009). The estimated stimulus-induced increases of oxygen consumption were smaller during mild hypoxia as compared to normoxia (3.1 ± 5.0% vs. 15.5 ± 15.1%, P = 0.04). CONCLUSION: Our results demonstrate an altered vascular and metabolic response during mild hypoxia upon visual stimulation. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 2 J. MAGN. RESON. IMAGING 2017;46:142-149.

Computational Flux Balance Analysis Predicts that Stimulation of Energy Metabolism in Astrocytes and their Metabolic Interactions with Neurons Depend on Uptake of K+ Rather than Glutamate.

Brain activity involves essential functional and metabolic interactions between neurons and astrocytes. The importance of astrocytic functions to neuronal signaling is supported by many experiments reporting high rates of energy consumption and oxidative metabolism in these glial cells. In the brain, almost all energy is consumed by the Na+/K+ ATPase, which hydrolyzes 1 ATP to move 3 Na+ outside and 2 K+ inside the cells. Astrocytes are commonly thought to be primarily involved in transmitter glutamate cycling, a mechanism that however only accounts for few % of brain energy utilization. In order to examine the participation of astrocytic energy metabolism in brain ion homeostasis, here we attempted to devise a simple stoichiometric relation linking glutamatergic neurotransmission to Na+ and K+ ionic currents. To this end, we took into account ion pumps and voltage/ligand-gated channels using the stoichiometry derived from available energy budget for neocortical signaling and incorporated this stoichiometric relation into a computational metabolic model of neuron-astrocyte interactions. We aimed at reproducing the experimental observations about rates of metabolic pathways obtained by 13C-NMR spectroscopy in rodent brain. When simulated data matched experiments as well as biophysical calculations, the stoichiometry for voltage/ligand-gated Na+ and K+ fluxes generated by neuronal activity was close to a 1:1 relationship, and specifically 63/58 Na+/K+ ions per glutamate released. We found that astrocytes are stimulated by the extracellular K+ exiting neurons in excess of the 3/2 Na+/K+ ratio underlying Na+/K+ ATPase-catalyzed reaction. Analysis of correlations between neuronal and astrocytic processes indicated that astrocytic K+ uptake, but not astrocytic Na+-coupled glutamate uptake, is instrumental for the establishment of neuron-astrocytic metabolic partnership. Our results emphasize the importance of K+ in stimulating the activation of astrocytes, which is relevant to the understanding of brain activity and energy metabolism at the cellular level.