Resting state functional connectivity MRI (fcMRI) is widely used to investigate brain networks that exhibit correlated fluctuations. While fcMRI does not provide direct measurement of anatomic connectivity, accumulating evidence suggests it is sufficiently constrained by anatomy to allow the architecture of distinct brain systems to be characterized. fcMRI is particularly useful for characterizing large-scale systems that span distributed areas (e.g., polysynaptic cortical pathways, cerebro-cerebellar circuits, cortical-thalamic circuits) and has complementary strengths when contrasted with the other major tool available for human connectomics-high angular resolution diffusion imaging (HARDI). We review what is known about fcMRI and then explore fcMRI data reliability, effects of preprocessing, analysis procedures, and effects of different acquisition parameters across six studies (n = 98) to provide recommendations for optimization. Run length (2-12 min), run structure (1 12-min run or 2 6-min runs), temporal resolution (2.5 or 5.0 s), spatial resolution (2 or 3 mm), and the task (fixation, eyes closed rest, eyes open rest, continuous word-classification) were varied. Results revealed moderate to high test-retest reliability. Run structure, temporal resolution, and spatial resolution minimally influenced fcMRI results while fixation and eyes open rest yielded stronger correlations as contrasted to other task conditions. Commonly used preprocessing steps involving regression of nuisance signals minimized nonspecific (noise) correlations including those associated with respiration. The most surprising finding was that estimates of correlation strengths stabilized with acquisition times as brief as 5 min. The brevity and robustness of fcMRI positions it as a powerful tool for large-scale explorations of genetic influences on brain architecture. We conclude by discussing the strengths and limitations of fcMRI and how it can be combined with HARDI techniques to support the emerging field of human connectomics.

The blood oxygenation level-dependent (BOLD) contrast is widely used in functional magnetic resonance imaging (fMRI) studies aimed at investigating neuronal activity. However, the BOLD signal reflects changes in blood volume and oxygenation rather than neuronal activity per se. Therefore, understanding the transformation of microscopic vascular behavior into macroscopic BOLD signals is at the foundation of physiologically informed noninvasive neuroimaging. Here, we use oxygen-sensitive two-photon microscopy to measure the BOLD-relevant microvascular physiology occurring within a typical rodent fMRI voxel and predict the BOLD signal from first principles using those measurements. The predictive power of the approach is illustrated by quantifying variations in the BOLD signal induced by the morphological folding of the human cortex. This framework is then used to quantify the contribution of individual vascular compartments and other factors to the BOLD signal for different magnet strengths and pulse sequences.

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Stress has significant adverse effects on health and is a risk factor for many illnesses. Neurobiological studies have implicated the amygdala as a brain structure crucial in stress responses. Whereas hyperactive amygdala function is often observed during stress conditions, cross-sectional reports of differences in gray matter structure have been less consistent. We conducted a longitudinal MRI study to investigate the relationship between changes in perceived stress with changes in amygdala gray matter density following a stress-reduction intervention. Stressed but otherwise healthy individuals (N = 26) participated in an 8-week mindfulness-based stress reduction intervention. Perceived stress was rated on the perceived stress scale (PSS) and anatomical MR images were acquired pre- and post-intervention. PSS change was used as the predictive regressor for changes in gray matter density within the bilateral amygdalae. Following the intervention, participants reported significantly reduced perceived stress. Reductions in perceived stress correlated positively with decreases in right basolateral amygdala gray matter density. Whereas prior studies found gray matter modifications resulting from acquisition of abstract information, motor and language skills, this study demonstrates that neuroplastic changes are associated with improvements in a psychological state variable.

Air hunger (uncomfortable urge to breathe) is a component of dyspnea (shortness of breath). Three human H(2)(15)O positron emission tomography (PET) studies have identified activation of phylogenetically ancient structures in limbic and paralimbic regions during dyspnea. Other studies have shown activation of these structures during other sensations that alert the organism to urgent homeostatic imbalance: pain, thirst, and hunger for food. We employed blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) to examine activation during air hunger. fMRI conferred several advantages over PET: enhanced signal-to-noise, greater spatial resolution, and lack of ionizing radiation, enabling a greater number of trials in each subject. Six healthy men and women were mechanically ventilated at 12-14 breaths/min. The primary experiment was conducted at mean end-tidal PCO(2) of 41 Torr. Moderate to severe air hunger was evoked during 42-s epochs of lower tidal volume (mean = 0.75 L). Subjects described the sensation as "like breath-hold," "urge to breathe," and "starved for air." In the baseline condition, air hunger was consistently relieved by epochs of higher tidal volume (mean = 1.47 L). A control experiment in the same subjects under a background of mild hypocapnia (mean end-tidal PCO(2) = 33 Torr) employed similar tidal volumes but did not evoke air hunger, controlling for stimulus variables not related to dyspnea. During each experiment, we maintained constant end-tidal PCO(2) and PO(2) to avoid systematic changes in global cerebral blood flow. Whole-brain images were acquired every 5 s (T2*, 56 slices, voxel resolution 3 x 3 x 3 mm). Activations associated with air hunger were determined using voxel-based interaction analysis of covariance that compared data between primary and control experiments (SPM99). We detected activations not seen in the earlier PET study using a similar air hunger stimulus (Banzett et al. 2000). Limbic and paralimbic loci activated in the present study were within anterior insula (seen in all 3 published studies of dyspnea), anterior cingulate, operculum, cerebellum, amygdala, thalamus, and basal ganglia. Elements of frontoparietal attentional networks were also identified. The consistency of anterior insular activation across subjects in this study and across published studies suggests that the insula is essential to dyspnea perception, although present data suggest that the insula acts in concert with a larger neural network.

Near-infrared spectroscopy (NIRS) and diffuse correlation spectroscopy (DCS) are two diffuse optical technologies for brain imaging that are sensitive to changes in hemoglobin concentrations and blood flow, respectively. Measurements for both modalities are acquired on the scalp, and therefore hemodynamic processes in the extracerebral vasculature confound the interpretation of cortical hemodynamic signals. The sensitivity of NIRS to the brain versus the extracerebral tissue and the contrast-to-noise ratio (CNR) of NIRS to cerebral hemodynamic responses have been well characterized, but the same has not been evaluated for DCS. This is important to assess in order to understand their relative capabilities in measuring cerebral physiological changes. We present Monte Carlo simulations on a head model that demonstrate that the relative brain-to-scalp sensitivity is about three times higher for DCS (0.3 at 3 cm) than for NIRS (0.1 at 3 cm). However, because DCS has higher levels of noise due to photon-counting detection, the CNR is similar for both modalities in response to a physiologically realistic simulation of brain activation. Even so, we also observed higher CNR of the hemodynamic response during graded hypercapnia in adult subjects with DCS than with NIRS.

Neuroimaging studies using angry or contemptuous human facial photographic stimuli have suggested amygdala hyper-responsivity in social anxiety disorder (SAD). We sought to determine if an angry "schematic face" (simple line drawing) would evoke exaggerated amygdalar responses in SAD patients compared with healthy control (HC) subjects. Angry, happy, and neutral schematic faces were overtly presented to matched cohorts of 11 SAD and 11 HC subjects for passive viewing, whereas brain functional magnetic resonance imaging signal was measured at 1.5 Tesla. Voxel-wise analyses were performed using a random effects model in SPM99. Compared with HC subjects, SAD patients exhibited exaggerated responses in the right amygdala for the Angry versus Neutral contrast. The findings of exaggerated amygdala responses to angry schematic faces in SAD converge with results from earlier neuroimaging studies and illustrate the potential utility of schematic faces for probing amygdala function in psychiatric disorders. One prospective advantage of schematic faces is that they may minimize confounds related to gender, age, or race effects. However, extending earlier findings in healthy subjects, schematic faces appear more effective for probing amygdala responses to arousal-based (Angry versus Neutral) as opposed to valence-based (Angry versus Happy) contrasts.

1. Functional magnetic resonance imaging (fMRI) provides a means of studying neuronal circuits that control respiratory muscles in humans with better spatial and temporal resolution than in previous positron emission tomography (PET) studies. 2. Whole brain blood oxygenation level-dependent (BOLD) changes determined by fMRI were used to identify areas of neuronal activation associated with volitional inspiration in five healthy men. Four series of scans of each subject were acquired during voluntary breathing (active task) and mechanical ventilation (passive task). Ventilation and end-tidal PCOµ were similar between tasks. Scan data were re-aligned to correct for movement artefacts and cross-referenced breath by breath to respiratory data for selective averaging of inspiratory and expiratory images. 3. Group analysis identified significant increases in the fMRI signal with volitional inspiration in the superior motor cortex, premotor cortex and supplementary motor area at loci similar to those detected in earlier studies that used PET. Additional regions activated by volitional inspiration included inferolateral sensorimotor cortex, prefrontal cortex and striatum (these foci were only revealed by PET under significant inspiratory load). 4. This study represents the first synchronised breath-by-breath analysis of respiratory-related neuronal activity with whole brain imaging in humans. Temporal resolution is sufficient to distinguish individual breaths at a normal breathing frequency.