Signal Fluctuation Sensitivity: An Improved Metric for Optimizing Detection of Resting-State fMRI Networks.

Task-free connectivity analyses have emerged as a powerful tool in functional neuroimaging. Because the cross-correlations that underlie connectivity measures are sensitive to distortion of time-series, here we used a novel dynamic phantom to provide a ground truth for dynamic fidelity between blood oxygen level dependent (BOLD)-like inputs and fMRI outputs. We found that the de facto quality-metric for task-free fMRI, temporal signal to noise ratio (tSNR), correlated inversely with dynamic fidelity; thus, studies optimized for tSNR actually produced time-series that showed the greatest distortion of signal dynamics. Instead, the phantom showed that dynamic fidelity is reasonably approximated by a measure that, unlike tSNR, dissociates signal dynamics from scanner artifact. We then tested this measure, signal fluctuation sensitivity (SFS), against human resting-state data. As predicted by the phantom, SFS-and not tSNR-is associated with enhanced sensitivity to both local and long-range connectivity within the brain's default mode network.

Sulfobutyl ether ß-cyclodextrin (Captisol(®) ) and methyl ß-cyclodextrin enhance and stabilize fluorescence of aqueous indocyanine green.

As the only FDA-approved near-infrared fluorophore, indocyanine green (ICG) is commonly used to image vasculature in vivo. ICG degrades rapidly in solution, which limits its usefulness in certain applications, including time-sensitive surgical procedures. We propose formulations that address this shortcoming via complexation with ß-cyclodextrin derivatives (ß-CyD), which are known to create stabilizing inclusion complexes with hydrophobic molecules. Here, we complexed ICG with highly soluble methyl ß-CyD and FDA-approved sulfobutyl ether ß-CyD (Captisol(®) ) in aqueous solution. We measured the fluorescence of the complexes over 24 h. We found that both CyD+ICG complexes exhibit sustained fluorescence increases of >2.0× versus ICG in water and >20.0× in PBS. Using transmission electron microscopy, we found evidence of reduced aggregation in complexes versus ICG alone. We thus conclude that this reduction in aggregation helps mitigate fluorescence autoquenching of CyD+ICG complexes compared in ICG alone. We also found that while ICG complexed with methyl ß-CyD severely reduced the viability of MRC-5 fibroblasts, ICG complexed with sulfobutyl ether ß-CyD had no effect on viability. These results represent an important first step toward enhancing the utility of aqueous ICG by reducing aggregation-dependent fluorescence degradation. © 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 104B: 1457-1464, 2016.

Hyper-reactive human ventral tegmental area and aberrant mesocorticolimbic connectivity in overgeneralization of fear in generalized anxiety disorder.

The ventral tegmental area (VTA) has been primarily implicated in reward-motivated behavior. Recently, aberrant dopaminergic VTA signaling has also been implicated in anxiety-like behaviors in animal models. These findings, however, have yet to be extended to anxiety in humans. Here we hypothesized that clinical anxiety is linked to dysfunction of the mesocorticolimbic circuit during threat processing in humans; specifically, excessive or dysregulated activity of the mesocorticolimbic aversion circuit may be etiologically related to errors in distinguishing cues of threat versus safety, also known as "overgeneralization of fear." To test this, we recruited 32 females with generalized anxiety disorder and 25 age-matched healthy control females. We measured brain activity using fMRI while participants underwent a fear generalization task consisting of pseudo-randomly presented rectangles with systematically varying widths. A mid-sized rectangle served as a conditioned stimulus (CS; 50% electric shock probability) and rectangles with widths of CS ±20%, ±40%, and ±60% served as generalization stimuli (GS; never paired with electric shock). Healthy controls showed VTA reactivity proportional to the cue's perceptual similarity to CS (threat). In contrast, patients with generalized anxiety disorder showed heightened and less discriminating VTA reactivity to GS, a feature that was positively correlated with trait anxiety, as well as increased mesocortical and decreased mesohippocampal coupling. Our results suggest that the human VTA and the mesocorticolimbic system play a crucial role in threat processing, and that abnormalities in this system are implicated in maladaptive threat processing in clinical anxiety.

Circuit-wide structural and functional measures predict ventromedial prefrontal cortex fear generalization: implications for generalized anxiety disorder.

The ventromedial prefrontal cortex (vmPFC) plays a critical role in a number of evaluative processes, including risk assessment. Impaired discrimination between threat and safety is considered a hallmark of clinical anxiety. Here, we investigated the circuit-wide structural and functional mechanisms underlying vmPFC threat-safety assessment in humans. We tested patients with generalized anxiety disorder (GAD; n = 32, female) and healthy controls (n = 25, age-matched female) on a task that assessed the generalization of conditioned threat during fMRI scanning. The task consisted of seven rectangles of graded widths presented on a screen; only the midsize one was paired with mild electric shock [conditioned stimulus (CS)], while the others, safety cues, systematically varied in width by ±20, 40, and 60% [generalization stimuli (GS)] compared with the CS. We derived an index reflecting vmPFC functioning from the BOLD reactivity on a continuum of threat (CS) to safety (GS least similar to CS); patients with GAD showed less discrimination between threat and safety cues, compared with healthy controls (Greenberg et al., 2013b). Using structural, functional (i.e., resting-state), and diffusion MRI, we measured vmPFC thickness, vmPFC functional connectivity, and vmPFC structural connectivity within the corticolimbic systems. The results demonstrate that all three factors predict individual variability of vmPFC threat assessment in an independent fashion. Moreover, these neural features are also linked to GAD, most likely via an vmPFC fear generalization. Our results strongly suggest that vmPFC threat processing is closely associated with broader corticolimbic circuit anomalies, which may synergistically contribute to clinical anxiety.

Acute stress eliminates female advantage in detection of ambiguous negative affect.

The human stress response evolved to maximize an individual's probability of survival when threatened. The present study addressed whether physical danger modulates perception of an unrelated ambiguous threat and, if so, to what extent this response is sex- specific. The authors utilized a first-time tandem skydive as a stressor, which had been previously validated as producing a highly-controlled, genuinely stressful environment. In a counter-balanced within-subjects design, participants wore a virtual reality helmet to complete an emotion-identification task during the plane's ascent (stress condition) and in the laboratory (control condition). Participants were presented static male faces morphed between 20-80% aggression, which gradually emerged from degraded images. Using a binary forced-choice design, participants identified each ambiguous face as aggressive or neutral. Results showed that participants characterized emotion more rapidly under stress versus control conditions. Unexpectedly, the results also show that while women were more sensitive to affect ambiguity than men under control conditions, they exhibited a marked decrease in sensitivity equivalent to men while under stress.