From Blood Oxygenation Level Dependent (BOLD) Signals to Brain Temperature Maps

A theoretical framework is presented for converting Blood Oxygenation Level Dependent (BOLD) images to brain temperature maps, based on the idea that disproportional local changes in cerebral blood flow (CBF) as compared with cerebral metabolic rate of oxygen consumption (CMRO ₂) during functional brain activity, lead to both brain temperature changes and the BOLD effect. Using an oxygen limitation model and a BOLD signal model, we obtain a transcendental equation relating CBF and CMRO ₂ changes with the corresponding BOLD signal, which is solved in terms of the Lambert W function. Inserting this result in the dynamic bioheat equation describing the rate of temperature changes in the brain, we obtain a nonautonomous ordinary differential equation that depends on the BOLD response, which is solved numerically for each brain voxel. Temperature maps obtained from a real BOLD dataset registered in an attention to visual motion experiment were calculated, obtaining temperature variations in the range: (−0.15, 0.1) which is consistent with experimental results. The statistical analysis revealed that significant temperature activations have a similar distribution pattern than BOLD activations. An interesting difference was the activation of the precuneus in temperature maps, a region involved in visuospatial processing, an effect that was not observed on BOLD maps. Furthermore, temperature maps were more localized to gray matter regions than the original BOLD maps, showing less activated voxels in white matter and cerebrospinal fluid.     

Using High Spatial Resolution to Improve BOLD fMRI Detection at 3T

For different functional magnetic resonance imaging experiments using blood oxygenation level-dependent (BOLD) contrast, the acquisition of T ₂*-weighted scans at a high spatial resolution may be advantageous in terms of time-course signal-to-noise ratio and of BOLD sensitivity when the regions are prone to susceptibility artifacts. In this study, we explore this solution by examining how spatial resolution influences activations elicited when appetizing food pictures are viewed. Twenty subjects were imaged at 3 T with two different voxel volumes, 3.4 μl and 27 μl. Despite the diminution of brain coverage, we found that high-resolution acquisition led to a better detection of activations. Though known to suffer to different degrees from susceptibility artifacts, the activations detected by high spatial resolution were notably consistent with those reported in published activation likelihood estimation meta-analyses, corresponding to taste-responsive regions. Furthermore, these regions were found activated bilaterally, in contrast with previous findings. Both the reduction of partial volume effect, which improves BOLD contrast, and the mitigation of susceptibility artifact, which boosts the signal to noise ratio in certain regions, explained the better detection noted with high resolution. The present study provides further evidences that high spatial resolution is a valuable solution for human BOLD fMRI, especially for studying food-related stimuli.     

Reproducibility of swallow-induced cortical BOLD positive and negative fMRI activity

Functional MRI (fMRI) studies have demonstrated that a number of brain regions (cingulate, insula, prefrontal, and sensory/motor cortices) display blood oxygen level-dependent (BOLD) positive activity during swallow. Negative BOLD activations and reproducibility of these activations have not been systematically studied. The aim of our study was to investigate the reproducibility of swallow-related cortical positive and negative BOLD activity across different fMRI sessions. We studied 16 healthy volunteers utilizing an fMRI event-related analysis. Individual analysis using a general linear model was used to remove undesirable signal changes correlated with motion, white matter, and cerebrospinal fluid. The group analysis used a mixed-effects multilevel model to identify active cortical regions. The volume and magnitude of a BOLD signal within each cluster was compared between the two study sessions. All subjects showed significant clustered BOLD activity within the known areas of cortical swallowing network across both sessions. The cross-correlation coefficient of percent fMRI signal change and the number of activated voxels across both positive and negative BOLD networks were similar between the two studies (r ≥ 0.87, P < 0.0001). Swallow-associated negative BOLD activity was comparable to the well-defined "default-mode" network, and positive BOLD activity had noticeable overlap with the previously described "task-positive" network. Swallow activates two parallel cortical networks. These include a positive and a negative BOLD network, respectively, correlated and anticorrelated with swallow stimulus. Group cortical activity maps, as well as extent and amplitude of activity induced by volitional swallowing in the cortical swallowing network, are reproducible between study sessions.     

Addition of song-related neurons in swamp sparrows coincides with memorization, not production, of learned songs

During song learning in birds, neurons are added to some song nuclei and lost from others. Previous studies have been unable to distinguish whether these neural changes are uniquely associated with memorizing a song model (sensory acquisition) or vocal practice (sensorimotor learning). In this study we measured changes in neuron number within song nuclei of swamp sparrows, a species in which the two phases of song learning are nonoverlapping. Male swamp sparrows were collected as hatchlings and tape-tutored from approximately 22 to 62 days of age. Swamp sparrows memorize about 60% of their song material during this period, but do not begin practicing this learned material until approximately 275 days of age. Birds were sacrificed at 23, 41, 61, 71, 274, or 340 days of age. During sensory acquisition, neuron number increased drastically in both the caudal nucleus of the ventral hyperstriatum (HVc) and Area X. The period of sensorimotor learning was not associated with any further changes in neuron number within these regions. We were unable to detect any significant changes in neuron number within the magnocellular nucleus of the neostriatum or the robust nucleus of the archistriatum during either stage of song learning. These results raise the possibility that ongoing addition of HVc and Area X neurons may encourage, and thereby temporally restrict, song acquisition.     

A novel transcutaneous vagus nerve stimulation leads to brainstem and cerebral activations measured by functional MRI]

BACKGROUND: Left cervical vagus nerve stimulation (VNS) using the implanted NeuroCybernetic Prosthesis (NCP) can reduce epileptic seizures and has recently been shown to give promising results for treating therapy-resistant depression. To address a disadvantage of this state-of-the-art VNS device, the use of an alternative transcutaneous electrical nerve stimulation technique, designed for muscular stimulation, was studied. Functional magnetic resonance imaging (MRI) has been used to test non-invasively access nerve structures associated with the vagus nerve system. The results and their impact are unsatisfying due to missing brainstem activations. These activations, however, are mandatory for reasoning, higher subcortical and cortical activations of vagus nerve structures. The objective of this study was to test a new parameter setting and a novel device for performing specific (well-controlled) transcutaneous VNS (tVNS) at the inner side of the tragus. This paper shows the feasibility of these and their potential for brainstem and cerebral activations as measured by blood oxygenation level dependent functional MRI (BOLD fMRI). MATERIALS AND METHODS: In total, four healthy male adults were scanned inside a 1.5-Tesla MR scanner while undergoing tVNS at the left tragus. We ensured that our newly developed tVNS stimulator was adapted to be an MR-safe stimulation device. In the experiment, cortical and brainstem representations during tVNS were compared to a baseline. RESULTS: A positive BOLD response was detected during stimulation in brain areas associated with higher order relay nuclei of vagal afferent pathways, respectively the left locus coeruleus, the thalamus (left > right), the left prefrontal cortex, the right and the left postcentral gyrus, the left posterior cingulated gyrus and the left insula. Deactivations were found in the right nucleus accumbens and the right cerebellar hemisphere. CONCLUSION: The method and device are feasible and appropriate for accessing cerebral vagus nerve structures, respectively. As functional patterns share features with fMRI BOLD, the effects previously studied with the NCP are discussed and new possibilities of tVNS are hypothesised.     

High-resolution fMRI maps of cortical activation in nonhuman primates: correlation with intrinsic signal optical images

One of the most widely used functional brain mapping tools is blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI). This method has contributed to new understandings of the functional roles of different areas in the human brain. However, its ability to map cerebral cortex at high spatial (submillimeter) resolution is still unknown. Other methods such as single- and multiunit electrophysiology and intrinsic signal optical imaging have revealed submillimeter resolution of sensory topography and cortical columnar activations. However, they are limited either by spatial scale (electrophysiology characterizes only local groups of neurons) or by the inability to monitor deep structures in the brain (i.e., cortical regions buried in sulci or subcortical structures). A method that could monitor all regions of the brain at high spatial resolution would be ideal. This capacity would open the doors to investigating, for example, how networks of cerebral cortical columns relate to or produce behavior. In this article we demonstrate that, without benefit of contrast agents, at a magnetic field strength of 9.4 tesla, BOLD fMRI can reveal millimeter-sized topographic maps of digit representation in the somatosensory cortex of the anesthetized squirrel monkey. Furthermore, by mapping the "funneling illusion," it is possible to detect even submillimeter shifts in activation in the cortex. Our data suggest that at high magnetic field strength, the positive BOLD signal can be used to reveal high spatial resolution maps of brain activity, a finding that weakens previous notions about the ultimate spatial specificity of the positive BOLD signal.     

Enhancement of tumor oxygenation and radiation response by the allosteric effector of hemoglobin, RSR13

Prior studies using pO(2) microelectrodes have shown that RSR13, an allosteric modifier of hemoglobin, increases tissue oxygenation in vivo. Recently, measurements of tissue oxygenation have been performed by many investigators using blood oxygen level-dependent magnetic resonance imaging (BOLD MRI). In this study, we tested the hypothesis that the BOLD MRI signal ratio in tumors will change after administration of RSR13. NCI-H460 human lung carcinoma cells were used as a xenograft in athymic nude mice. Mice with 1-cm(3) tumors in the flank were anesthetized and mounted on the MRI apparatus, and various doses of RSR13 were administered intraperitoneally (i.p.). MR images were then acquired at 10-min intervals for up to 60 min after injection. The effect of RSR13 on tumor response was studied using the same mouse xenograft model with tumor growth delay measurements. RSR13 increased the MRI signal ratio [Intensity(t)/Intensity(t = 0)] in a dose-dependent manner, with maximum increases occurring 30 min after RSR13 was administered. An RSR13 dose of 200 mg/kg proved to be optimum. Since the MRI signal ratio has been shown previously to be linearly related to tissue oxygenation, the changes in the MRI signal ratio can be attributed to changes in tumor oxygen levels. Using a 200-mg/kg dose of RSR13, with a 10-Gy dose of radiation administered to tumors 30 min later, enhancement of radiation-induced tumor growth delay by RSR13 was observed (enhancement factor = 2.8). Thus our MRI results support and verify the previously reported RSR13-induced increase in tumor oxygenation obtained using pO(2) microelectrodes. Based upon these results and other previous studies, the mechanism of enhancement of the effect of radiation by RSR13 probably involves an increase in tumor oxygenation.     

Recovery of impaired songs following unilateral but not bilateral lesions of nucleus uvaeformis of adult zebra finches

Zebra finches utilize neural circuits in both cerebral hemispheres to produce their learned songs. Although direct reciprocal connections do not exist between song control nuclei across hemispheres, premotor activity in these nuclei during singing is precisely and continuously coordinated between the hemispheres. We hypothesized that this interhemispheric coordination is mediated by bilateral feedback projections from medullary and midbrain song control nuclei to the thalamic song control nucleus uvaeformis (Uva). Consistent with our hypothesis, bilateral lesions of Uva severely impaired singing. This impairment was long-lasting, as it persisted for at least 35 days after the lesions. Unilateral lesions of Uva on either side also resulted in an immediate singing impairment. However, song recovered substantially after less than 15 days, suggesting a possible compensation by the unlesioned side. Although the acoustic structure of individual syllables recovered fully after unilateral lesioning, subtle changes in the sequencing of syllables were observed after song recovery, suggesting that the lesion led to an alteration in the functioning of the remaining song control network. These results demonstrate that the adult songbird brain can adjust to damage to certain parts of the song control network and recover from their associated singing deficits. The well-identified and localized central neural pathways mediating birdsong production provide an advantageous model system to analyze systematically the sensorimotor contexts and the specific sites and mechanisms for behavioral recovery following partial damage to a behavior-producing neural circuit.     

Fast noninvasive functional diffuse optical tomography for brain imaging

Advances in epilepsy studies have shown that specific changes in hemodynamics precede and accompany seizure onset and propagation. However, it has been challenging to noninvasively detect these changes in real time and in humans, due to the lack of fast functional neuroimaging tools. In this study, we present a functional diffuse optical tomography (DOT) method with the guidance of an anatomical human head atlas for 3‐dimensionally mapping the brain in real time. Central to our DOT system is a human head interface coupled with a technique that can incorporate topological information of the brain surface into the DOT image reconstruction. The performance of the DOT system was tested by imaging motor tasks‐involved brain activities on N = 6 subjects (3 epilepsy patients and 3 healthy controls). We observed diffuse areas of activations from the reconstructed [HbT] images of patients, relative to more focal activations for healthy subjects. Moreover, significant pretask hemodynamic activations were also seen in the motor cortex of patients, which indicated abnormal activities persistent in the brain of an epilepsy patient. This work demonstrates that fast functional DOT is a valuable tool for noninvasive 3‐dimensional mapping of brain hemodynamics.      

Evaluation of radiomic texture feature error due to MRI acquisition and reconstruction: A simulation study utilizing ground truth

The purpose of this study was to examine the dependence of image texture features on MR acquisition parameters and reconstruction using a digital MR imaging phantom. MR signal was simulated in a parallel imaging radiofrequency coil setting as well as a single element volume coil setting, with varying levels of acquisition noise, three acceleration factors, and four image reconstruction algorithms. Twenty-six texture features were measured on the simulated images, ground truth images, and clinical brain images. Subtle algorithm-dependent errors were observed on reconstructed phantom images, even in the absence of added noise. Sources of image error include Gibbs ringing at image edge gradients (tissue interfaces) and well-known artifacts due to high acceleration; two of the iterative reconstruction algorithms studied were able to mitigate these image errors. The difference of the texture features from ground truth, and their variance over reconstruction algorithm and parallel imaging acceleration factor, were compared to the clinical “effect size”, i.e., the feature difference between high- and low-grade tumors on T1- and T2-weighted brain MR images of twenty glioma patients. The measured feature error (difference from ground truth) was small for some features, but substantial for others. The feature variance due to reconstruction algorithm and acceleration factor were generally smaller than the clinical effect size. Certain texture features may be preserved by MR imaging, but adequate precautions need to be taken regarding their validity and reliability. We present a general simulation framework for assessing the robustness and accuracy of radiomic textural features under various MR acquisition/reconstruction scenarios.     

Functional mapping in the human brain using high magnetic fields.

An avidly pursued new dimension in magnetic resonance imaging (MRI) research is the acquisition of physiological and biochemical information non-invasively using the nuclear spins of the water molecules in the human body. In this trial, a recent and unique accomplishment was the introduction of the ability to map human brain function non-invasively. Today, functional images with subcentimetre resolution of the entire human brain can be generated in single subjects and in data acquisition times of several minutes using 1.5 tesla (T) MRI scanners that are often used in hospitals for clinical purposes. However, there have been accomplishments beyond this type of imaging using significantly higher magnetic fields such as 4 T. Efforts for developing high magnetic field human brain imaging and functional mapping using MRI (fMRI) were undertaken at about the same time. It has been demonstrated that high magnetic fields result in improved contrast and, more importantly, in elevated sensitivity to capillary level changes coupled to neuronal activity in the blood oxygenation level dependent (BOLD) contrast mechanism used in fMRI. These advantages have been used to generate, for example, high resolution functional maps of ocular dominance columns, retinotopy within the small lateral geniculate nucleus, true single-trial fMRI and early negative signal changes in the temporal evolution of the BOLD signal. So far these have not been duplicated or have been observed as significantly weaker effects at much lower field strengths. Some of these high-field advantages and accomplishments are reviewed in this paper.     

Physiological MR signal variations within the brain at 3 T.

The echoplanar technique in magnetic resonance (MR) imaging allows the acquisition of a series of images from a selected slice with a temporal resolution of 10/s. Simultaneous recording of physiological information on pulse and respiration allows correlation of the MR signal intensity with physiological signals, which can be obtained for each pixel examined. Such correlations can be found within the cerebrospinal fluid (CSF) spaces and within vessels if a flow-sensitive MR measurement technique is used. The use of an MR scanner with a field strength of 3 T improves the signal/noise ratio, but there is a stronger signal decay due to local magnetic inhomogeneities. This study shows that 3-T systems can be used for correlation of MR and physiological signals and that clear differentiation between signals from CSF and from vessels can be obtained due to their strongly different signal decays.     

Anti-TNFA (TNF-alpha) treatment abrogates radiation-induced changes in vacular density and tissue oxygenation

Ionizing radiation significantly alters the structure and function of microvasculature, which regulates delivery of oxygen to brain tissue. Previous experimental and modeling studies have shown that tissue oxygenation patterns are significantly different in irradiated normal tissue compared to age-matched controls, and the differences are apparent as early as 3 days postirradiation. However, oxygen delivery to irradiated tissue recovers within 6 months postirradiation. Changes in perfusion and oxygenation were studied in a bilaterally (both cerebral hemispheres) and unilaterally (only one hemisphere) irradiated mouse brain model at 6 and 24 h as well as 3, 7, 30, 60 and 120 days postirradiation. The results indicate that significant changes in the number of perfused vessels (as measured by fluorescent DiOC(7) staining) and anatomical vessels (as indicated by CD31 immunohistochemical staining) and tissue oxygenation (by immunohistochemical detection of a fluorescently conjugated monoclonal antibody to EF5) are most pronounced at 3 days postirradiation, while a degree of recovery is observed at later times. However, in the unilaterally irradiated animals, both irradiated and unirradiated (out-of-field) cerebral hemispheres showed similarly significant changes in oxygenation and/or perfusion compared to unirradiated controls. Anti-TNFA treatment inhibited radiation-induced local as well as abscopal effects in the brain tissue.     

Enumeration of Carnobacterium divergens V41, Carnobacterium piscicola V1 and Lactobacillus brevis LB62 by in situ hybridizationflow cytometry

The specific detection and enumeration of Lactobacillus brevis LB62, Carnobacterium divergens V14 and Carnobacterium piscicola VI were studied by in situ hybridizationflow cytometry. The method was performed on the exponential growth phase with three probes targeting 16S rRNA labelled with fluorescein isothicyanate (FITC) : EUB338 probe universal for Eubacteria, Lb probe specific for Lact. brevis and Cb probe specific for the genus Carnobacterium . EUB338 was used to determine the permeabilization and hybridization conditions for the cells. The Lb probe gave no hybridization signal whereas the Cb probe allowed the detection and quantification by flow cytometry at 520 nm of the two Carnobacterium strains in pure culture or in mixtures with Listeria innocua F.     

High-Resolution Structural and Functional Assessments of Cerebral Microvasculature Using 3D Gas ΔR2*-mMRA

The ability to evaluate the cerebral microvascular structure and function is crucial for investigating pathological processes in brain disorders. Previous angiographic methods based on blood oxygen level-dependent (BOLD) contrast offer appropriate visualization of the cerebral vasculature, but these methods remain to be optimized in order to extract more comprehensive information. This study aimed to integrate the advantages of BOLD MRI in both structural and functional vascular assessments. The BOLD contrast was manipulated by a carbogen challenge, and signal changes in gradient-echo images were computed to generate ΔR₂* maps. Simultaneously, a functional index representing the regional cerebral blood volume was derived by normalizing the ΔR₂* values of a given region to those of vein-filled voxels of the sinus. This method is named 3D gas ΔR₂*-mMRA (microscopic MRA). The advantages of using 3D gas ΔR₂*-mMRA to observe the microvasculature include the ability to distinguish air–tissue interfaces, a high vessel-to-tissue contrast, and not being affected by damage to the blood–brain barrier. A stroke model was used to demonstrate the ability of 3D gas ΔR₂*-mMRA to provide information about poststroke revascularization at 3 days after reperfusion. However, this technique has some limitations that cannot be overcome and hence should be considered when it is applied, such as magnifying vessel sizes and predominantly revealing venous vessels.     

Functional magnetic resonance study of deliberate deception

The goal of the study was analysis of the cerebral mechanisms of deliberate deception. The eventrelated functional magnetic resonance (ER fMRI) imaging technique was used to assess the changes in the functional brain activity by means of recording the blood oxygen level-dependent (BOLD) signal. Twelve right-handed healthy volunteers aged 19–44 years participated in the study. The BOLD images were obtained during three experimental trials: deliberate deception, manipulative honest and control truthful trials (catch trials). The deliberate deception and manipulative honest actions were characterized by a BOLD signal increase in the anterior cingulate (Brodmann’s area (BA) 32), frontal (BAs 9/10, 6), and parietal (BA 40) cortices as compared with a truthful response. Comparison of the ER fMRI data with the results of earlier studies where event-related potentials (ERPs) were recorded under similar conditions indicates the involvement of the brain mechanism of error detection in deliberate deception.     

Impaired GABAergic transmission and altered hippocampal synaptic plasticity in collybistin-deficient mice

Collybistin (Cb) is a brain-specific guanine nucleotide exchange factor that has been implicated in plasma membrane targeting of the postsynaptic scaffolding protein gephyrin found at glycinergic and GABAergic synapses. Here we show that Cb-deficient mice display a region-specific loss of postsynaptic gephyrin and GABA(A) receptor clusters in the hippocampus and the basolateral amygdala. Cb deficiency is accompanied by significant changes in hippocampal synaptic plasticity, due to reduced dendritic GABAergic inhibition. Long-term potentiation is enhanced, and long-term depression reduced, in Cb-deficient hippocampal slices. Consistent with the anatomical and electrophysiological findings, the animals show increased levels of anxiety and impaired spatial learning. Together, our data indicate that Cb is essential for gephyrin-dependent clustering of a specific set of GABA(A) receptors, but not required for glycine receptor postsynaptic localization.     

Feasibility of 4D T2* quantification in the lung with oxygen gas challenge in patients with non-small cell lung cancer

Blood oxygen level-dependent (BOLD) MRI is a non-invasive diagnostic method for assessing tissue oxygenation level, by changes in the transverse relaxation time T2*. 3D BOLD imaging of lung tumours is challenging, because respiratory motion can lead to significant image quality degradation. The purpose of this work was to explore the feasibility of a three dimensional (3D) Cartesian multi gradient echo (MGRE) sequence for T2* measurements of non-small cell lung tumours during free-breathing. A non-uniform quasi-random reordering of the pahse encoding lines that allocates more sampling points near the k-space origin resulting in efficient undersampling pattern for parallel imaging was combined with multi echo acquisition and self-gating. In a series of three patients 3D T2* maps of lung carcinomas were generated with isotropic spatial resolution and full tumour coverage at air inhalation and after hyperoxic gas challenge in arbitrary respiratory phases using the proposed self-gated MGRE acquisition. The changes in T2* on the inhalation of hyperoxic gas relative to air were quantified. Significant changes in T2* were observed following oxygen inhalation in the tumour (p < 0.02). Thus, the self-gated MGRE sequence can be used for assessment of BOLD signal with isotropic resolution and arbitrary respiratory phases in non-small cell lung cancer.     

A human cell model for dynamic testing of MR contrast agents

To determine the initial feasibility of using magnetic resonance (MR) imaging to detect early atherosclerosis, we investigated inflammatory cells labeled with a positive contrast agent in an endothelial cell-based testing system. The human monocytic cell line THP-1 was labeled by overnight incubation with a gadolinium colloid (Gado CELLTrack) prior to determination of the in vitro release profile from T1-weighted MR images. Next, MR signals arising from both a synthetic model of THP-1/human umbilical vein endothelial cell (HUVEC) accumulation and the dynamic adhesion of THP-1 cells to activated HUVECs under flow were obtained. THP-1 cells were found to be successfully--but not optimally--labeled with gadolinium colloid, and MR images demonstrated increased signal from labeled cells in both the synthetic and dynamic THP-1/HUVEC models. The observed THP-1 contrast release profile was rapid, suggesting the need for an agent that is optimized for retention in the target cells for use in further studies. Detection of labeled THP-1 cells was accomplished with no signal enhancement from unlabeled cells. These achievements demonstrate the feasibility of targeting early atherosclerosis with MR imaging, and suggest that using an in vitro system like the one described provides a rapid, efficient, and cost-effective way to support the development and evaluation of novel MR contrast agents.     

Apnea-Induced Cortical BOLD-fMRI and Peripheral Sympathoneural Firing Response Patterns of Awake Healthy Humans

End-expiratory breath-holds (BH) and Mueller manoeuvres (MM) elicit large increases in muscle sympathetic nerve activity (MSNA). In 16 healthy humans (9♀, 35±4 years) we used functional magnetic resonance imaging with blood oxygen level-dependent (BOLD) contrast to determine the cortical network associated with such sympathoexcitation. We hypothesized that increases in MSNA evoked by these simulated apneas are accompanied by BOLD contrast changes in the insular cortex, thalamus and limbic cortex. A series of 150 whole-brain images were collected during 3 randomly performed 16-second end-expiratory BHs and MMs (-30 mmHg). The identical protocol was repeated separately with MSNA recorded from the fibular nerve. The time course of the sympathoexcitatory response to both breathing tasks were correlated with whole-brain BOLD signal changes. Brain sites demonstrating both positive (activation) and negative (deactivation) correlations with the MSNA time course were identified. Sympathetic burst incidence increased (p<0.001) from 29±6 (rest) to 49±6 (BH) and 47±6 bursts/100 heartbeats (MM). Increased neural activity (Z-scores) was identified in the right posterior and anterior insular cortices (3.74, 3.64), dorsal anterior cingulate (3.42), fastigial and dentate cerebellar nuclei (3.02, 3.34). Signal intensity decreased in the left posterior insula (3.28) and ventral anterior cingulate (3.01). Apnea both activates and inhibits elements of a cortical network involved in the generation of sympathetic outflow. These findings identify a neuroanatomical substrate to guide future investigations into central mechanisms contributing to disorders characterized by elevated basal MSNA and exaggerated sympathetic responses to simulated apneas such as sleep apnea and heart failure.