10.1073͞pnas.0504604102), the authors note that Eq. 1 was incorrectly given as P ϭ f ssͩ ͩ1 ϩ m ͪ ϩ Dͩ 2 ϩ m ͪͪ both in the text and in Fig. 2. The correct equation is as follows:The corrected figure and its legend appear below. The error does not affect the conclusions of the article. Fig. 2.Comprehensive characterization of the promoter library. Several orthogonal metrics were used to characterize the promoter library and ensure the consistent behavior of all its members for various genes and culturing conditions. We show here three metrics that were chosen for quantifying transcriptional of the promoters: (i) the dynamics of GFP production based on fluorescence, (ii) measurement of the relative mRNA transcript levels in the cultures, and (iii) testing of the MIC for chloramphenicol in an additional library of constructs where the promoter drove the expression of chloramphenicol acetyltransferase. The overall strong correlation between the various metrics suggests a broad-range utility of the promoter library for a variety of genes and conditions. (A) Mouse C127 cells were transduced with retrovirus expressing BPV-1 E7 with a FLAG͞HA epitope tag at either the C terminus (E7-C) or N terminus (E7-N), or with no tag (E7). Cells were lysed, and proteins were immunoprecipitated by using either an anti-FLAG antibody (Left) or an anti-BPV-1 E7 antibody (Right). Proteins were resolved by SDS͞PAGE on a 15% polyacrylamide gel and probed by immunoblotting using the anti-E7 antibody. (B) Cells were assayed for anchorage-independent growth with transduced BPV-1 oncogenes: C127 control cells, cells expressing BPV-1 E7 alone, BPV-1 E6 alone, E6 and E7, E6 and C-terminal FLAG͞HA-tagged E7 (E7-C), and E6 and N-terminal FLAG͞HA-tagged E7 (E7-N). Cells were suspended in 0.3% Noble agar, DMEM, and 10% FBS and grown for 14 days. Representative fields are shown at ϫ10 magnification. For further details, see Cortical analysis related to visual object recognition is traditionally thought to propagate serially along a bottom-up hierarchy of ventral areas. Recent proposals gradually promote the role of top-down processing in recognition, but how such facilitation is triggered remains a puzzle. We tested a specific model, proposing that low spatial frequencies facilitate visual object recognition by initiating top-down processes projected from orbitofrontal to visual cortex. The present study combined magnetoencephalography, which has superior temporal resolution, functional magnetic resonance imaging, and a behavioral task that yields successful recognition with stimulus repetitions. Object recognition elicited differential activity that developed in the left orbitofrontal cortex 50 ms earlier than it did in recognition-related areas in the temporal cortex. This early orbitofrontal activity was directly modulated by the presence of low spatial frequencies in the image. Taken together, the dynamics we revealed provide strong support for the proposal of how top-down facilitation of object recognition is initiated, and our observations a...

Object recognition is traditionally viewed as a hierarchical, bottom-up neural process. This view has been challenged recently by theoretical models and by findings indicating that top-down processes are involved in facilitating recognition. However, how such high-level information can be activated quickly enough to facilitate the bottom-up processing is yet unknown. We propose that such top-down facilitation is triggered by magnocellular information projected early and rapidly to the orbitofrontal cortex. Using human neuroimaging, we show that stimuli designed to bias processing toward the magnocellular pathway differentially activated the orbitofrontal cortex compared with parvocellular-biased stimuli. Although the magnocellular stimuli had a lower contrast than the parvocellular stimuli, they were recognized faster and just as accurately. Moreover, orbitofrontal activity predicted the performance advantage for the magnocellular, but not for the parvocellular-biased, stimuli, whereas the opposite was true in the fusiform gyrus. Last, analyses of effective connectivity using dynamic causal modeling showed that magnocellular-biased stimuli significantly activated pathways from occipital visual cortex to orbitofrontal cortex and from orbitofrontal cortex to fusiform gyrus. Conversely, parvocellular-biased stimuli significantly activated a pathway from the occipital visual cortex to fusiform gyrus. Our findings support the proposal that fast magnocellular projections linking early visual and inferotemporal object recognition regions with the orbitofrontal cortex facilitate object recognition by enabling the generation of early predictions.

Summary Objective The periaqueductal gray matter (PAG), a known modulator of somatic pain transmission, shows evidence of interictal functional and structural abnormalities in migraineurs, which may contribute to hyperexcitability along spinal and trigeminal nociceptive pathways, and lead to the migraine attack. The aim of this study was to examine functional connectivity of the PAG in migraine. Methods Using resting-state functional MRI, we compared functional connectivity between PAG and a subset of brain areas involved in nociceptive/somatosensory processing and pain modulation in 17 subjects with migraine, during a pain free state, versus 17 gender- and age-matched controls. We also assessed the relation between intrinsic resting-state correlations within PAG networks and the average monthly frequency of migraine attacks, as well as allodynia. Results Our findings show stronger connectivity between the PAG and several brain areas within nociceptive and somatosensory processing pathways in migraineurs versus controls. In addition, as the monthly frequency of migraine attacks worsens, the strength of the connectivity in some areas within these pathways increases while a significant decrease in functional resting-state connectivity between the PAG and brain regions with a predominant role in pain modulation (prefrontal cortex, anterior cingulate, amygdala) can be evidenced. Finally, migraineurs with a history of allodynia exhibit significantly reduced connectivity between PAG, prefrontal regions and anterior cingulate compared to migraineurs without allodynia. Conclusions These data reveal interictal dysfunctional dynamics within pain pathways in migraine manifested as an impairment of the descending pain modulatory, likely leading to loss of pain inhibition, and hyperexcitability primarily in nociceptive areas.

Background Migraine is a neurovascular disorder, in which altered functional connectivity between pain-modulating circuits and the limbic system may play a role. Cortical spreading depression (CSD), which underlies migraine aura induces C-fos expression in the amygdala. The role of CSD, and amygdala connectivity, in migraine without aura (MwoA) is less clear and may differentiate migraine from other chronic pain disorders. Results Amygdala connectivity in both migraine with aura (MWA) and MWoA was increased to the visceroceptive insula relative to healthy subjects and two other chronic pain conditions not associated with CSD: trigeminal neuralgia (TGN) and carpal tunnel syndrome (CTS). Conclusion The observed increased connectivity within the limbic/viscerosensory network, present only in migraineurs, adds to the evidence of a neurolimbic pain network dysfunction, and may reflect repetitive episodes of CSD leading to the development of migraine pain.

Intuitive grasping of the meaning of subtle social cues is particularly affected in autism spectrum disorders (ASD). Despite their relevance in social communication, the effect of averted gaze in fearful faces in conveying a signal of environmental threat has not been investigated using real face stimuli in adults with ASD. Here, using functional MRI, we show that briefly presented fearful faces with averted gaze, previously shown to be a strong communicative signal of environmental danger, produce different patterns of brain activation than fearful faces with direct gaze in a group of 26 normally intelligent adults with ASD compared with 26 matched controls. While implicit cue of threat produces brain activation in attention, emotion processing and mental state attribution networks in controls, this effect is absent in individuals with ASD. Instead, individuals with ASD show activation in the subcortical face-processing system in response to direct eye contact. An effect of differences in looking behavior was excluded in a separate eye tracking experiment. Our data suggest that individuals with ASD are more sensitive to direct eye contact than to social signals of danger conveyed by averted fearful gaze.

Most theories of emotion hold that negative stimuli are threatening and aversive. Yet in everyday experiences some negative sights (e.g. car wrecks) attract curiosity, whereas others repel (e.g. a weapon pointed in our face). To examine the diversity in negative stimuli, we employed four classes of visual images (Direct Threat, Indirect Threat, Merely Negative and Neutral) in a set of behavioral and functional magnetic resonance imaging studies. Participants reliably discriminated between the images, evaluating Direct Threat stimuli most quickly, and Merely Negative images most slowly. Threat images evoked greater and earlier blood oxygen level-dependent (BOLD) activations in the amygdala and periaqueductal gray, structures implicated in representing and responding to the motivational salience of stimuli. Conversely, the Merely Negative images evoked larger BOLD signal in the parahippocampal, retrosplenial, and medial prefrontal cortices, regions which have been implicated in contextual association processing. Ventrolateral as well as medial and lateral orbitofrontal cortices were activated by both threatening and Merely Negative images. In conclusion, negative visual stimuli can repel or attract scrutiny depending on their current threat potential, which is assessed by dynamic shifts in large-scale brain network activity.

Facial expression and eye gaze provide a shared signal about threats. While a fear expression with averted gaze clearly points to the source of threat, direct-gaze fear renders the source of threat ambiguous. Separable routes have been proposed to mediate these processes, with preferential attunement of the magnocellular (M) pathway to clear threat, and of the parvocellular (P) pathway to threat ambiguity. Here we investigated how observers’ trait anxiety modulates M- and P-pathway processing of clear and ambiguous threat cues. We scanned subjects (N = 108) widely ranging in trait anxiety while they viewed fearful or neutral faces with averted or directed gaze, with the luminance and color of face stimuli calibrated to selectively engage M- or P-pathways. Higher anxiety facilitated processing of clear threat projected to M-pathway, but impaired perception of ambiguous threat projected to P-pathway. Increased right amygdala reactivity was associated with higher anxiety for M-biased averted-gaze fear, while increased left amygdala reactivity was associated with higher anxiety for P-biased, direct-gaze fear. This lateralization was more pronounced with higher anxiety. Our findings suggest that trait anxiety differentially affects perception of clear (averted-gaze fear) and ambiguous (direct-gaze fear) facial threat cues via selective engagement of M and P pathways and lateralized amygdala reactivity.

An older adult positivity effect, i.e., the tendency for older adults to favor positive over negative stimulus information more than do younger adults, has been previously shown in attention, memory, and evaluations. This effect has been attributed to greater emotion regulation in older adults. In the case of attention and memory, this explanation has been supported by some evidence that the older adult positivity effect is most pronounced for negative stimuli, which would motivate emotion regulation, and that it is reduced by cognitive load, which would impede emotion regulation. We investigated whether greater older adult positivity in the case of evaluative responses to faces is also enhanced for negative stimuli and attenuated by cognitive load, as an emotion regulation explanation would predict. In two studies, younger and older adults rated trustworthiness of faces that varied in valence both under low and high cognitive load, with the latter manipulated by a distracting backwards counting task. In Study 1, face valence was manipulated by attractiveness (low /disfigured faces, medium, high/fashion models’ faces). In Study 2, face valence was manipulated by trustworthiness (low, medium, high). Both studies revealed a significant older adult positivity effect. However, contrary to an emotion regulation account, this effect was not stronger for more negative faces, and cognitive load increased rather than decreased the rated trustworthiness of negatively valenced faces. Although inconsistent with emotion regulation, the latter effect is consistent with theory and research arguing that more cognitive resources are required to process negative stimuli, because they are more cognitively elaborated than positive ones. The finding that increased age and increased cognitive load both enhanced the positivity of trustworthy ratings suggests that the older adult positivity effect in evaluative ratings of faces may reflect age-related declines in cognitive capacity rather than increases in the regulation of negative emotions.