Noreen Ward

The missing link: Enhanced functional connectivity between amygdala and visceroceptive cortex in migraine:

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.

The neuroinflammatory component of gray matter pathology in multiple sclerosis

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.

If it bleeds, it leads: separating threat from mere negativity

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.

Look me in the eyes: constraining gaze in the eye-region provokes abnormally high subcortical activation in autism

Individuals with Autism Spectrum Disorder (ASD) seem to have difficulties looking others in the eyes, but the substrate for this behavior is not well understood. The subcortical pathway, which consists of superior colliculus, pulvinar nucleus of the thalamus, and amygdala, enables rapid and automatic face processing. A specific component of this pathway – i.e., the amygdala – has been shown to be abnormally activated in paradigms where individuals had to specifically attend to the eye-region; however, a direct examination of the effect of manipulating the gaze to the eye-regions on all the components of the subcortical system altogether has never been performed. The subcortical system is particularly important as it shapes the functional specialization of the face-processing cortex during development. Using functional MRI, we investigated the effect of constraining gaze in the eye-region during dynamic emotional face perception in groups of participants with ASD and typical controls. We computed differences in activation in the subcortical face processing system (superior colliculus, pulvinar nucleus of the thalamus and amygdala) for the same stimuli seen freely or with the gaze constrained in the eye-region. Our results show that when constrained to look in the eyes, individuals with ASD show abnormally high activation in the subcortical system, which may be at the basis of their eye avoidance in daily life.

The effect of constraining eye-contact during dynamic emotional face perception-an fMRI study.

Abstract 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.

Sex-related differences in behavioral and amygdalar responses to compound facial threat cues

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 observers 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 proportionately 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 observers sex.

Hypersensitivity to low intensity fearful faces in autism when fixation is constrained to the eyes

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.

Dedifferentiated face processing in older adults is linked to lower resting state metabolic activity in fusiform face area

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.

Neurodynamics and connectivity during facial fear perception: The role of threat exposure and signal congruity

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 (an approach signal) is incongruent with it. We have previously shown using fMRI that the amygdala is engaged more strongly by fear with averted gaze 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 performed two experiments: one replicating the exposure time by gaze direction interaction in fMRI (N = 23), and another where we confirmed greater early phase locking to averted-gaze fear (congruent threat signal) with MEG (N = 60) in a network of face processing regions, regardless of exposure duration. 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.

Older adults’ neural activation in the reward circuit is sensitive to face trustworthiness

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.