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There are currently no biomarkers for autism spectrum disorder (ASD). This neurodevelopmental condition has previously been associated with histopathological findings, including increased neuronal packing density in the amygdala, abnormal laminar cytoarchitecture and increased average neuronal density in the prefrontal cortex. The present study examined whether new brain imaging technologies could reveal in vivo, in adults with ASD, the manifestation of previously described histopathological changes. Using quantitative mapping at ultra-high field (7 Tesla), we show that we can observe microstructural alterations in the right lateral orbito-frontal cortex and the bilateral amygdala in adult individuals with ASD in vivo. These imaging alterations point to an abnormal laminar cytoarchitecture and to an increased neuronal density, similar to what has been previously described in post-mortem data in ASD. Our data demonstrate that it is possible to visualize, in vivo and at the individual level, alterations of cortical and subcortical microstructure in ASD. Future studies will be needed to extend these findings to a larger group of individuals, and evaluate their association with symptomatology as well as their specificity among the different neurodevelopmental disorders.

ObjectiveTo determine if migraine with aura is associated with neuroinflammation, which has been suggested by preclinical models of cortical spreading depression (CSD) as well as imaging of human pain conditions.MethodsThirteen migraineurs with aura and 16 healthy controls received integrated PET/MRI brain scans with [11C]PBR28, a radioligand that binds to the 18 kDa translocator protein, a marker of glial activation. Standardized uptake value ratio (SUVR) was compared between groups, and regressed against clinical variables, using region of interest and whole-brain voxelwise analyses.ResultsCompared to healthy controls, migraineurs demonstrated SUVR elevations in nociceptive processing areas (e.g., thalamus and primary/secondary somatosensory and insular cortices) as well as in areas previously shown to be involved in CSD generation (visual cortex). SUVR levels in frontoinsular cortex, primary/secondary somatosensory cortices, and basal ganglia were correlated with frequency of migraine attacks.ConclusionsThese findings demonstrate that migraine with aura is associated with neuroimmune activation/neuroinflammation, and support a possible link between CSD and glial activation, previously observed in animals.

Reading the prevailing emotion of groups of people (“crowd emotion”) is critical to understanding their overall intention and disposition. It alerts us to potential dangers, such as angry mobs or panicked crowds, giving us time to escape. A critical aspect of processing crowd emotion is that it must occur rapidly, because delays often are costly. Although knowing the timing of neural events is crucial for understanding how the brain guides behaviors using coherent signals from a glimpse of multiple faces, this information is currently lacking in the literature on face ensemble coding. Therefore, we used magnetoencephalography to examine the neurodynamics in the dorsal and ventral visual streams and the periamygdaloid cortex to compare perception of groups of faces versus individual faces. Forty-six participants compared two groups of four faces or two individual faces with varying emotional expressions and chose which group or individual they would avoid. We found that the dorsal stream was activated as early as 68 msec after the onset of stimuli containing groups of faces. In contrast, the ventral stream was activated later and predominantly for individual face stimuli. The latencies of the dorsal stream activation peaks correlated with participants’ response times for facial crowds. We also found enhanced connectivity earlier between the periamygdaloid cortex and the dorsal stream regions for crowd emotion perception. Our findings suggest that ensemble coding of facial crowds proceeds rapidly and in parallel by engaging the dorsal stream to mediate adaptive social behaviors, via a distinct route from single face perception.

The parallel pathways of the human visual system differ in their tuning to luminance, color, and spatial frequency. These attunements recently have been shown to propagate to differential processing of higher-order stimuli, facial threat cues, in the magnocellular (M) and parvocellular (P) pathways, with greater sensitivity to clear and ambiguous threat, respectively. The role of the third, koniocellular (K) pathway in facial threat processing, however, remains unknown. To address this gap in knowledge, we briefly presented peripheral face stimuli psychophysically biased towards M, P, or K pathways. Observers were instructed to report via a key-press whether the face was angry or neutral while their eye movements and manual responses were recorded. We found that short-latency saccades were made more frequently to faces presented in the K channel than to P or M channels. Saccade latencies were not significantly modulated by expressive and identity cues. In contrast, manual response latencies and accuracy were modulated by both pathway biasing and by interactions of facial expression with facial masculinity, such that angry male faces elicited the fastest, and angry female faces, the least accurate, responses. We conclude that face stimuli can evoke fast saccadic and manual responses when projected to the K pathway.

We examined older adult (OA) and younger adult (YA) neural sensitivity to face trustworthiness in reward circuit regions, previously found to respond to trustworthiness in YA. Interactions of face trustworthiness with age revealed effects exclusive to OA in the amygdala and caudate, and an effect that was not moderated by age in the dorsal anterior cingulate cortex (dACC). OA, but not YA, showed a nonlinear amygdala response to face trustworthiness, with significantly stronger activation response to high than to medium trustworthy faces, and no difference between low and medium or high. This may explain why an earlier study investigating OA amygdala activation to trustworthiness failed to find a significant effect, since only the linear low versus high trustworthiness difference was assessed. OA, but not YA, also showed significantly stronger activation to high than to low trustworthy faces in the right caudate, indicating a positive linear effect, consistent with previous YA research, as well as significantly stronger activation to high than to medium but not low trustworthy faces in the left caudate, indicating a nonlinear effect. Activation in dACC across both age groups showed a positive linear effect consistent with previous YA research. Finally, OA rated the faces as more trustworthy than did YA across all levels of trustworthiness. Future research should examine whether the null effects for YA were due to our inclusion of older faces. Research also should investigate possible implications of our findings for more ecologically valid OA responses to people who vary in facial trustworthiness.

Eye-contact modifies how we perceive emotions and modulates activity in the social brain network. Here, using fMRI, we demonstrate that adding a fixation cross in the eye region of dynamic facial emotional stimuli significantly increases activation in the social brain of healthy, neurotypical participants when compared with activation for the exact same stimuli observed in a free-viewing mode. In addition, using PPI analysis, we show that the degree of amygdala connectivity with the rest of the brain is enhanced for the constrained view for all emotions tested except for fear, and that anxiety and alexithymia modulate the strength of amygdala connectivity for each emotion differently. Finally, we show that autistic traits have opposite effects on amygdala connectivity for fearful and angry emotional expressions, suggesting that these emotions should be treated separately in studies investigating facial emotion processing.

Objective Cortical spreading depression (CSD) underlies the neurobiology of migraine with aura (MWA). Animal studies reveal networks of microvessels linking brain-meninges-bone marrow. CSD activates the trigeminovascular system, evoking a meningeal inflammatory response. Accordingly, this study examines the upregulation of an inflammatory marker in extra-axial tissues in migraine with visual aura. Methods We used simultaneously acquired 11 C-PBR28 positron emission tomography/magnetic resonance imaging data of 18kDa translocator protein (an inflammatory marker) in MWA patients (n = 11) who experienced headaches and visual aura in the preceding month. We measured mean tracer uptake (standardized uptake value ratio [SUVR]) in 4 regions of interest comprising the meninges plus the adjacent overlying skull bone (parameningeal tissues [PMT]). These data were compared to healthy controls and patients with pain (chronic low back pain). Results MWA had significantly higher mean SUVR in PMT overlying occipital cortex than both other groups, although not in the PMT overlying 3 other cortical areas. A positive correlation was also found between the number of visual auras and tracer uptake in occipital PMT. Interpretation A strong persistent extra-axial inflammatory signal was found in meninges and calvarial bone overlying the occipital lobe in migraine with visual auras. Our findings are reminiscent of CSD-induced meningeal inflammation and provide the first imaging evidence implicating inflammation in the pathophysiology of migraine meningeal symptoms. We suspect that this inflammatory focus results from a signal that migrates from underlying brain and if so, may implicate newly discovered bridging vessels that crosstalk between brain and skull marrow, a finding of potential relevance to migraine and other neuroinflammatory brain disorders. ANN NEUROL 2020;87:939-949.

Recently, speed of presentation of facially expressive stimuli was found to influence the processing of compound threat cues (e.g., anger/fear/gaze). For instance, greater amygdala responses were found to clear (e.g., direct gaze anger/averted gaze fear) versus ambiguous (averted gaze anger/direct gaze fear) combinations of threat cues when rapidly presented (33 and 300ms), but greater to ambiguous versus clear threat cues when presented for more sustained durations (1, 1.5, and 2s). A working hypothesis was put forth (Adams et al., 2012) that these effects were due to differential magnocellular versus parvocellular pathways contributions to the rapid versus sustained processing of threat, respectively. To test this possibility directly here, we restricted visual stream processing in the fMRI environment using facially expressive stimuli specifically designed to bias visual input exclusively to the magnocellular versus parvocellular pathways. We found that for magnocellular-biased stimuli, activations were predominantly greater to clear versus ambiguous threat-gaze pairs (on par with that previously found for rapid presentations of threat cues), whereas activations to ambiguous versus clear threat-gaze pairs were greater for parvocellular-biased stimuli (on par with that previously found for sustained presentations). We couch these findings in an adaptive dual process account of threat perception and highlight implications for other dual process models within psychology.

Human faces evolved to signal emotions, with their meaning contextualized by eye gaze. For instance, a fearful expression paired with averted gaze clearly signals both presence of threat and its probable location. Conversely, direct gaze paired with facial fear leaves the source of the fear-evoking threat ambiguous. Given that visual perception occurs in parallel streams with different processing emphases, our goal was to test a recently developed hypothesis that clear and ambiguous threat cues would differentially engage the magnocellular (M) and parvocellular (P) pathways, respectively. We employed two-tone face images to characterize the neurodynamics evoked by stimuli that were biased toward M or P pathways. Human observers (N = 57) had to identify the expression of fearful or neutral faces with direct or averted gaze while their magnetoencephalogram was recorded. Phase locking between the amygdaloid complex, orbitofrontal cortex (OFC) and fusiform gyrus increased early (0–300 ms) for M-biased clear threat cues (averted-gaze fear) in the β-band (13–30 Hz) while P-biased ambiguous threat cues (direct-gaze fear) evoked increased θ (4–8 Hz) phase locking in connections with OFC of the right hemisphere. We show that M and P pathways are relatively more sensitive toward clear and ambiguous threat processing, respectively, and characterize the neurodynamics underlying emotional face processing in the M and P pathways.

OBJECTIVE: To determine if migraine with aura is associated with neuroinflammation, which has been suggested by preclinical models of cortical spreading depression (CSD) as well as imaging of human pain conditions. METHODS: Thirteen migraineurs with aura and 16 healthy controls received integrated PET/MRI brain scans with [(11)C]PBR28, a radioligand that binds to the 18 kDa translocator protein, a marker of glial activation. Standardized uptake value ratio (SUVR) was compared between groups, and regressed against clinical variables, using region of interest and whole-brain voxelwise analyses. RESULTS: Compared to healthy controls, migraineurs demonstrated SUVR elevations in nociceptive processing areas (e.g., thalamus and primary/secondary somatosensory and insular cortices) as well as in areas previously shown to be involved in CSD generation (visual cortex). SUVR levels in frontoinsular cortex, primary/secondary somatosensory cortices, and basal ganglia were correlated with frequency of migraine attacks. CONCLUSIONS: These findings demonstrate that migraine with aura is associated with neuroimmune activation/neuroinflammation, and support a possible link between CSD and glial activation, previously observed in animals.

Research demonstrating responsiveness of the neural reward network to face trustworthiness has not assessed whether the effects are mediated by dopaminergic function. We filled this gap in the literature by investigating whether dietary dopamine depletion would blunt the sensitivity of neural activation to faces varying in trustworthiness across reward regions as well as the sensitivity of behavioral responses to those faces. As prolactin release is negatively regulated by dopamine, peripheral prolactin levels confirmed the efficacy of our manipulation. The dopamine depletion manipulation moderated neural activation to face trustworthiness in the amygdala, medial orbital frontal cortex, and ventral medial prefrontal cortex. Control participants ( n=20) showed nonlinear and linear neural activation to face trustworthiness in the amygdala and ventral medial prefrontal cortex, and nonlinear activation in the medial orbital frontal cortex, while depleted participants ( n=20) showed only a linear effect in the amygdala. Controls also showed stronger amygdala activation to high trustworthy faces than depleted participants. In contrast to effects on neural activation, dopamine depletion did not blunt the sensitivity of behavioral ratings. While this is the first study to demonstrate that dopamine depletion blunts the sensitivity of the neural reward system to social stimuli, namely faces varying in trustworthiness, future research should investigate behavioral measures that may be more responsive to dopaminergic effects than face ratings. Such research would shed further light on the possibility that individual differences in dopaminergic function that were simulated by our manipulation influence social interactions with people who vary in facial trustworthiness.

Fearful faces convey threat cues whose meaning is contextualized by eye gaze: While averted gaze is congruent with facial fear (both signal avoidance), direct gaze is incongruent with it, as direct gaze signals approach. We have previously shown using fMRI that the amygdala is engaged more strongly by fear with averted gaze, which has been found to be processed more efficiently, during brief exposures. However, the amygdala also responds more to fear with direct gaze during longer exposures. Here we examined previously unexplored brain oscillatory responses to characterize the neurodynamics and connectivity during brief (∼250 ms) and longer (∼883 ms) exposures of fearful faces with direct or averted eye gaze. We replicated the exposure time by gaze direction interaction in fMRI (N=23), and observed greater early phase locking to averted-gaze fear (congruent threat signal) with MEG (N=60) in a network of face processing regions, with both brief and longer exposures. Phase locking to direct-gaze fear (incongruent threat signal) then increased significantly for brief exposures at ∼350 ms, and at ∼700 ms for longer exposures. Our results characterize the stages of congruent and incongruent facial threat signal processing and show that stimulus exposure strongly affects the onset and duration of these stages.

During face perception, we integrate facial expression and eye gaze to take advantage of their shared signals. For example, fear with averted gaze provides a congruent avoidance cue, signaling both threat presence and its location, whereas fear with direct gaze sends an incongruent cue, leaving threat location ambiguous. It has been proposed that the processing of different combinations of threat cues is mediated by dual processing routes: reflexive processing via magnocellular (M) pathway and reflective processing via parvocellular (P) pathway. Because growing evidence has identified a variety of sex differences in emotional perception, here we also investigated how M and P processing of fear and eye gaze might be modulated by observer’s sex, focusing on the amygdala, a structure important to threat perception and affective appraisal. We adjusted luminance and color of face stimuli to selectively engage M or P processing and asked observers to identify emotion of the face. Female observers showed more accurate behavioral responses to faces with averted gaze and greater left amygdala reactivity both to fearful and neutral faces. Conversely, males showed greater right amygdala activation only for M-biased averted-gaze fear faces. In addition to functional reactivity differences, females had greater bilateral amygdala volumes, which positively correlated with behavioral accuracy for M-biased fear. Conversely, in males only the right amygdala volume was positively correlated with accuracy for M-biased fear faces. Our findings suggest that M and P processing of facial threat cues is modulated by functional and structural differences in the amygdalae associated with observer’s sex.

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.

Facial expression and eye gaze provide a shared signal about threats. While averted-gaze fear clearly points to the source of threat, direct-gaze fear renders the source of threat ambiguous. Dual processing routes have been proposed to mediate these processes: reflexive processing via magnocellular (M-) pathway and reflective processing via parvocellular (P-) pathway. We investigated how observers’ trait anxiety modulates Mand P-pathway processing of clear and ambiguous threat cues. We performed fMRI on a large cohort (N=108) widely ranging in trait anxiety while they viewed fearful or neutral faces with averted or directed gaze. We adjusted luminance and color of the stimuli to selectively engage M- or P-pathway processing. We found that higher anxiety facilitated processing of averted-gaze fear projected to M-pathway, but impaired perception of direct-gaze fear projected to P-pathway. Increased right amygdala reactivity was associated with higher anxiety, only for averted-gaze fear presented to M-pathway. Conversely, 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 has differential effects on perception of clear and ambiguous facial threat cues via selective engagement of M and P pathways and lateralization of amygdala reactivity.

Previous studies that showed decreased brain activation in people with autism spectrum disorder (ASD) viewing expressive faces did not control that participants looked in the eyes. This is problematic because ASD is characterized by abnormal attention to the eyes. Here, we collected fMRI data from 48 participants (27 ASD) viewing pictures of neutral faces and faces expressing anger, happiness, and fear at low and high intensity, with a fixation cross between the eyes. Group differences in whole brain activity were examined for expressive faces at high and low intensity versus neutral faces. Group differences in neural activity were also investigated in regions of interest within the social brain, including the amygdala and the ventromedial prefrontal cortex (vmPFC). In response to low intensity fearful faces, ASD participants showed increased activation in the social brain regions, and decreased functional coupling between the amygdala and the vmPFC. This oversensitivity to low intensity fear coupled with a lack of emotional regulation capacity could indicate an excitatory/inhibitory imbalance in their socio‐affective processing system. This may result in social disengagement and avoidance of eye‐contact to handle feelings of strong emotional reaction. Our results also demonstrate the importance of careful control of gaze when investigating emotional processing in ASD. Hum Brain Mapp 38:5943–5957, 2017. © 2017 Wiley Periodicals, Inc.

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 (MWA), 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. Methods Using resting-state functional MRI, we compared functional connectivity between the amygdala and the cortex in MWA and MWoA patients as well as in healthy subjects and in two other chronic pain conditions not associated with CSD: trigeminal neuralgia (TGN) and carpal tunnel syndrome (CTS). Results Amygdala connectivity in both MWA and MWoA was increased to the visceroceptive insula relative to all other groups examined. 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.

We used multimodal brain imaging to examine possible mediators of age-related neural dedifferentiation (less specific neural activation) to different categories of stimuli that had been shown in previous research. Specifically, we examined resting blood flow and brain activation in areas involved in object, place and face perception. We observed lower activation, specificity, and resting blood flow for older adults (OA) than younger adults (YA) in the fusiform face area (FFA) but not in the other regions of interest. Mediation analyses further revealed that FFA resting state blood flow mediated age differences in FFA specificity, whereas age differences in visual and cognitive function and cortical thickness did not. Whole brain analyses also revealed more activated voxels for all categories in OA, as well as more frontal activation for faces but not for the other categories in OA than YA. Less FFA specificity coupled with more frontal activation when passively viewing faces suggest that OA have more difficulty recruiting specialized face processing mechanisms, and the lower FFA metabolic activity even when faces are not being processed suggests an OA deficiency in the neural substrate underlying face processing. Our data point to a detuning of face-selective mechanisms in older adults.

Objective In multiple sclerosis (MS), using simultaneous magnetic resonance-positron emission tomography (MR-PET) imaging with 11C-PBR28, we quantified expression of the 18kDa translocator protein (TSPO), a marker of activated microglia/macrophages, in cortex, cortical lesions, deep gray matter (GM), white matter (WM) lesions and normal-appearing WM (NAWM) to investigate the in vivo pathological and clinical relevance of neuroinflammation. Methods Fifteen secondary-progressive MS (SPMS) and 12 relapsing-remitting MS (RRMS) cases, and 14 matched healthy controls underwent 11C-PBR28 MR-PET. MS subjects underwent 7 Tesla T2*-weighted imaging for cortical lesions segmentation; neurological and cognitive evaluation. 11C-PBR28 binding was measured using normalized 60-90-minutes standardized uptake values and volume of distribution ratios. Results Relative to controls, MS subjects exhibited abnormally high 11C-PBR28 binding across the brain, the greatest increases being in cortex and cortical lesions, thalamus, hippocampus, and NAWM. MS WM lesions showed relatively modest TSPO increases. With the exception of cortical lesions, where TSPO expression was similar, 11C-PBR28 uptake across the brain was greater in SPMS than in RRMS. In MS, increased 11C-PBR28 binding in cortex, deep GM, and NAWM correlated with neurological disability and impaired cognitive performance; cortical thinning correlated with increased thalamic TSPO levels. Interpretation In MS, neuroinflammation is present in the cortex, cortical lesions, deep GM, and NAWM, and closely linked to poor clinical outcome and, at least partly, to neurodegeneration. Distinct inflammatory-mediated factors may underlie accumulation of cortical and WM lesions. Quantification of TSPO levels in MS could prove a sensitive tool for evaluating in vivo the inflammatory component of GM pathology, particularly in cortical lesions. This article is protected by copyright. All rights reserved.

Previous studies that showed decreased brain activation in people with autism spectrum disorder (ASD) viewing expressive faces did not control that participants looked in the eyes. This is problematic because ASD is characterized by abnormal attention to the eyes. Here, we collected fMRI data from 48 participants (27 ASD) viewing pictures of neutral faces and faces expressing anger, happiness, and fear at low and high intensity, with a fixation cross between the eyes. Group differences in whole brain activity were examined for expressive faces at high and low intensity versus neutral faces. Group differences in neural activity were also investigated in regions of interest within the social brain, including the amygdala and the ventromedial prefrontal cortex (vmPFC). In response to low intensity fearful faces, ASD participants showed increased activation in the social brain regions, and decreased functional coupling between the amygdala and the vmPFC. This oversensitivity to low intensity fear coupled with a lack of emotional regulation capacity could indicate an excitatory/inhibitory imbalance in their socio-affective processing system. This may result in social disengagement and avoidance of eye-contact to handle feelings of strong emotional reaction. Our results also demonstrate the importance of careful control of gaze when investigating emotional processing in ASD. Hum Brain Mapp 38:5943-5957, 2017. © 2017 Wiley Periodicals, Inc.

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.