Anterior pituitary gland volume mediates associations between pubertal hormones and changes in transdiagnostic symptoms in youth.

The pituitary gland (PG) plays a central role in the production and secretion of pubertal hormones, with documented links to the emergence and increase in mental health symptoms known to occur during adolescence. Although much of the literature has focused on examining whole PG volume, recent findings suggest that there are associations among pubertal hormone levels, including dehydroepiandrosterone (DHEA), subregions of the PG, and elevated mental health symptoms (e.g., internalizing symptoms) during adolescence. Surprisingly, studies have not yet examined associations among these factors and increasing transdiagnostic symptomology, despite DHEA being a primary output of the anterior PG. Therefore, the current study sought to fill this gap by examining whether anterior PG volume specifically mediates associations between DHEA levels and changes in dysregulation symptoms in an adolescent sample ( N = 114, 9 - 17 years, M age = 12.87, SD = 1.88). Following manual tracing of the anterior and posterior PG, structural equation modeling revealed that greater anterior, not posterior, PG volume mediated the association between greater DHEA levels and increasing dysregulation symptoms across time, controlling for baseline dysregulation symptom levels. These results suggest specificity in the role of the anterior PG in adrenarcheal processes that may confer risk for psychopathology during adolescence. This work not only highlights the importance of separately tracing the anterior and posterior PG, but also suggests that transdiagnostic factors like dysregulation are useful in parsing hormone-related increases in mental health symptoms in youth.

Dehydroepiandrosterone mediates associations between trauma-related symptoms and anterior pituitary volume in children and adolescents.

INTRODUCTION: The anterior pituitary gland (PG) is a potential locus of hypothalamic-pituitary-adrenal (HPA) axis responsivity to early life stress, with documented associations between dehydroepiandrosterone (DHEA) levels and anterior PG volumes. In adults, elevated anxiety/depressive symptoms are related to diminished DHEA levels, and studies have shown a positive relationship between DHEA and anterior pituitary volumes. However, specific links between responses to stress, DHEA levels, and anterior pituitary volume have not been established in developmental samples. METHODS: High-resolution T1-weighted MRI scans were collected from 137 healthy youth (9-17 years; Mage = 12.99 (SD = 1.87); 49% female; 85% White, 4% Indigenous, 1% Asian, 4% Black, 4% multiracial, 2% not reported). The anterior and posterior PGs were manually traced by trained raters. We examined the mediating effects of salivary DHEA on trauma-related symptoms (i.e., anxiety, depression, and posttraumatic) and PG volumes as well as an alternative model examining mediating effects of PG volume on DHEA and trauma-related symptoms. RESULTS: DHEA mediated the association between anxiety symptoms and anterior PG volume. Specifically, higher anxiety symptoms related to lower DHEA levels, which in turn were related to smaller anterior PG. CONCLUSIONS: These results shed light on the neurobiological sequelae of elevated anxiety in youth and are consistent with adult findings showing suppressed levels of DHEA in those with greater comorbid anxiety and depression. Specifically, adolescents with greater subclinical anxiety may exhibit diminished levels of DHEA during the pubertal window, which may be associated with disruptions in anterior PG growth.

Developmental alterations in the neural oscillatory dynamics underlying attentional reorienting.

The neural and cognitive processes underlying the flexible allocation of attention undergo a protracted developmental course with changes occurring throughout adolescence. Despite documented age-related improvements in attentional reorienting throughout childhood and adolescence, the neural correlates underlying such changes in reorienting remain unclear. Herein, we used magnetoencephalography (MEG) to examine neural dynamics during a Posner attention-reorienting task in 80 healthy youth (6-14 years old). The MEG data were examined in the time-frequency domain and significant oscillatory responses were imaged in anatomical space. During the reorienting of attention, youth recruited a distributed network of regions in the fronto-parietal network, along with higher-order visual regions within the theta (3-7 Hz) and alpha-beta (10-24 Hz) spectral windows. Beyond the expected developmental improvements in behavioral performance, we found stronger theta oscillatory activity as a function of age across a network of prefrontal brain regions irrespective of condition, as well as more limited age- and validity-related effects for alpha-beta responses. Distinct brain-behavior associations between theta oscillations and attention-related symptomology were also uncovered across a network of brain regions. Taken together, these data are the first to demonstrate developmental effects in the spectrally-specific neural oscillations serving the flexible allocation of attention.

Transdiagnostic indicators predict developmental changes in cognitive control resting-state networks.

Over the past decade, transdiagnostic indicators in relation to neurobiological processes have provided extensive insight into youth's risk for psychopathology. During development, exposure to childhood trauma and dysregulation (i.e., so-called AAA symptomology: anxiety, aggression, and attention problems) puts individuals at a disproportionate risk for developing psychopathology and altered network-level neural functioning. Evidence for the latter has emerged from resting-state fMRI studies linking mental health symptoms and aberrations in functional networks (e.g., cognitive control (CCN), default mode networks (DMN)) in youth, although few of these investigations have used longitudinal designs. Herein, we leveraged a three-year longitudinal study to identify whether traumatic exposures and concomitant dysregulation trigger changes in the developmental trajectories of resting-state functional networks involved in cognitive control (N = 190; 91 females; time 1 Mage = 11.81). Findings from latent growth curve analyses revealed that greater trauma exposure predicted increasing connectivity between the CCN and DMN across time. Greater levels of dysregulation predicted reductions in within-network connectivity in the CCN. These findings presented in typically developing youth corroborate connectivity patterns reported in clinical populations, suggesting there is predictive utility in using transdiagnostic indicators to forecast alterations in resting-state networks implicated in psychopathology.

Specialized late cingulo-opercular network activation elucidates the mechanisms underlying decisions about ambiguity.

Cortical task control networks, including the cingulo-opercular (CO) network play a key role in decision-making across a variety of functional domains. In particular, the CO network functions in a performance reporting capacity that supports successful task performance, especially in response to errors and ambiguity. In two studies testing the contribution of the CO network to ambiguity processing, we presented a valence bias task in which masked clearly and ambiguously valenced emotional expressions were slowly revealed over several seconds. This slow reveal task design provides a window into the decision-making mechanisms as they unfold over the course of a trial. In the main study, the slow reveal task was administered to 32 young adults in the fMRI environment and BOLD time courses were extracted from regions of interest in three control networks. In a follow-up study, the task was administered to a larger, online sample (n = 81) using a more extended slow reveal design with additional unmasking frames. Positive judgments of surprised faces were uniquely accompanied by slower response times and strong, late activation in the CO network. These results support the initial negativity hypothesis, which posits that the default response to ambiguity is negative and positive judgments are associated with a more effortful controlled process, and additionally suggest that this controlled process is mediated by the CO network. Moreover, ambiguous trials were characterized by a second CO response at the end of the trial, firmly placing CO function late in the decision-making process.

Developmental differences in functional organization of multispectral networks.

Assessing brain connectivity during rest has become a widely used approach to identify changes in functional brain organization during development. Generally, previous works have demonstrated that brain activity shifts from more local to more distributed processing from childhood into adolescence. However, the majority of those works have been based on functional magnetic resonance imaging measures, whereas multispectral functional connectivity, as measured using magnetoencephalography (MEG), has been far less characterized. In our study, we examined spontaneous cortical activity during eyes-closed rest using MEG in 101 typically developing youth (9-15 years old; 51 females, 50 males). Multispectral MEG images were computed, and connectivity was estimated in the canonical delta, theta, alpha, beta, and gamma bands using the imaginary part of the phase coherence, which was computed between 200 brain regions defined by the Schaefer cortical atlas. Delta and alpha connectivity matrices formed more communities as a function of increasing age. Connectivity weights predominantly decreased with age in both frequency bands; delta-band differences largely implicated limbic cortical regions and alpha band differences in attention and cognitive networks. These results are consistent with previous work, indicating the functional organization of the brain becomes more segregated across development, and highlight spectral specificity across different canonical networks.

Spontaneous cortical dynamics from the first years to the golden years.

In the largest and most expansive lifespan magnetoencephalography (MEG) study to date (n = 434, 6 to 84 y), we provide critical data on the normative trajectory of resting-state spontaneous activity and its temporal dynamics. We perform cutting-edge analyses to examine age and sex effects on whole-brain, spatially-resolved relative and absolute power maps, and find significant age effects in all spectral bands in both types of maps. Specifically, lower frequencies showed a negative correlation with age, while higher frequencies positively correlated with age. These correlations were further probed with hierarchical regressions, which revealed significant nonlinear trajectories in key brain regions. Sex effects were found in absolute but not relative power maps, highlighting key differences between outcome indices that are generally used interchangeably. Our rigorous and innovative approach provides multispectral maps indicating the unique trajectory of spontaneous neural activity across the lifespan, and illuminates key methodological considerations with the widely used relative/absolute power maps of spontaneous cortical dynamics.

Task-irrelevant emotional faces impact BOLD responses more for prosaccades than antisaccades in a mixed saccade fMRI task.

Cognitive control allows individuals to flexibly and efficiently perform tasks by attending to relevant stimuli while inhibiting distraction from irrelevant stimuli. The antisaccade task assesses cognitive control by requiring participants to inhibit a prepotent glance towards a peripheral stimulus and generate an eye movement to the mirror image location. This task can be administered with various contextual manipulations to investigate how factors such as trial timing or emotional content interact with cognitive control. In the current study, 26 healthy adults completed a mixed antisaccade and prosaccade fMRI task that included task irrelevant emotional faces and gap/overlap timing. The results showed typical antisaccade and gap behavioral effects with greater BOLD activation in frontal and parietal brain regions for antisaccade and overlap trials. Conversely, there were no differences in behavior based on the emotion of the task irrelevant face, but trials with neutral faces had greater activation in widespread visual regions than trials with angry faces, particularly for prosaccade and overlap trials. Together, these effects suggest that a high level of cognitive control and inhibition was required throughout the task, minimizing the impact of the face presentation on saccade behavior, but leading to increased attention to the neutral faces on overlap prosaccade trials when both the task cue (look towards) and emotion stimulus (neutral, non-threatening) facilitated disinhibition of visual processing.

Abnormal Visual Evoked Responses to Emotional Cues Correspond to Diagnosis and Disease Severity in Fibromyalgia.

Background: Chronic pain disorders are often associated with cognitive-emotional dysregulation. However, the relations between such dysregulation, underlying brain processes, and clinical symptom constellations, remain unclear. Here, we aimed to characterize the abnormalities in cognitive-emotional processing involved in fibromyalgia syndrome (FMS) and their relation to disease severity. Methods: Fifty-eight participants, 39 FMS patients (35F), and 19 healthy control subjects (16F) performed an EEG-based paradigm assessing attention allocation by extracting steady-state visually evoked potentials (ssVEP) in response to affective distractors presented during a cognitive task. Patients were also evaluated for pain severity, sleep quality, depression, and anxiety. Results: EEG ssVEP measurement indicated that, compared to healthy controls, FMS patients displayed impaired affective discrimination, and sustained attention to negative distractors. Moreover, patients displayed decreased task-related fronto-occipital EEG connectivity. Lack of adaptive attentional discrimination, measured via EEG, was predictive of pain severity, while impairments in fronto-occipital connectivity were predictive of impaired sleep. Conclusions: FMS patients display maladaptive affective attention modulation, which predicts disease symptoms. These findings support the centrality of cognitive-emotional dysregulation in the pathophysiology of chronic pain.

Eyes-closed versus eyes-open differences in spontaneous neural dynamics during development.

BACKGROUND: Assessing brain activity during rest has become a widely used approach in developmental neuroscience. Extant literature has measured resting brain activity both during eyes-open and eyes-closed conditions, but the difference between these conditions has not yet been well characterized. Studies, limited to fMRI and EEG, have suggested that eyes-open versus -closed conditions may differentially impact neural activity, especially in visual cortices. METHODS: Spontaneous cortical activity was recorded using MEG from 108 typically developing youth (9-15 years-old; 55 female) during separate sessions of eyes-open and eyes-closed rest. MEG source images were computed, and the strength of spontaneous neural activity was estimated in the canonical delta, theta, alpha, beta, and gamma bands, respectively. Power spectral density maps for eyes-open were subtracted from eyes-closed rest, and then submitted to vertex-wise regression models to identify spatially specific differences between conditions and as a function of age and sex. RESULTS: Relative alpha power was weaker in the eyes-open compared to -closed condition, but otherwise eyes-open was stronger in all frequency bands, with differences concentrated in the occipital cortex. Relative theta power became stronger in the eyes-open compared to the eyes-closed condition with increasing age in frontal cortex. No differences were observed between males and females. CONCLUSIONS: The differences in relative power from eyes-closed to -open conditions are consistent with changes observed in task-based visual sensory responses. Age differences occurred in relatively late developing frontal regions, consistent with canonical attention regions, suggesting that these differences could be reflective of developmental changes in attention processes during puberty. Taken together, resting-state paradigms using eyes-open versus -closed produce distinct results and, in fact, can help pinpoint sensory related brain activity.

Amygdala and hippocampal subregions mediate outcomes following trauma during typical development: Evidence from high-resolution structural MRI.

The vast majority of individuals experience trauma within their lifetime. Yet, most people do not go on to develop clinical levels of psychopathology. Recently, studies have highlighted the potential protective effects of having larger amygdala and hippocampal volumes, such that larger volumes may promote adaptive functioning following trauma. However, research has not yet elucidated whether certain subregions of these stress-sensitive structures have specific protective effects. Herein, we examined the mediating effects of amygdala and hippocampal subregions on the relationship between traumatic exposure and concurrent or longitudinal changes in psychiatric symptom levels in typically developing youth (9-15 years of age). Using high-resolution T1-and T2-weighted structural MRI scans, we found that the volume of the right basolateral complex of the amygdala mediated associations between trauma exposure and internalizing symptoms. Specifically, greater levels of childhood trauma related to larger volumes, and larger volumes were associated with fewer internalizing symptoms. The volume of the right CA4/dentate gyrus (DG) of the hippocampus yielded similar mediation results, such that greater trauma was related to larger volumes, which in turn were associated with decreases in internalizing symptoms across time. These findings provide initial support for potentially protective effects of larger right amygdala and hippocampal subregion volumes against internalizing symptomology concurrently and longitudinally during adolescence.

Positivity effect in aging: evidence for the primacy of positive responses to emotional ambiguity.

Older compared to younger adults show greater amygdala activity to positive emotions, and are more likely to interpret emotionally ambiguous stimuli (e.g., surprised faces) as positive. While some evidence suggests this positivity effect results from a top-down, effortful mechanism, others suggest it may emerge as the default or initial response. The amygdala is a key node in rapid, bottom-up processing and patterns of amygdala activity over time (e.g., habituation) can shed light on the mechanisms underlying the positivity effect. Younger and older adults passively viewed neutral and surprised faces in an MRI. Only in older adults, amygdala habituation was associated with the tendency to interpret surprised faces as positive or negative (valence bias), where a more positive bias was associated with greater habituation. Interestingly, although a positive bias in younger adults was associated with slower responses, consistent with an initial negativity hypothesis in younger adults, older adults showed faster categorizations of positivity. Together, we propose that there may be a switch to a primacy of positivity in aging.

Exploring valence bias as a metric for frontoamygdalar connectivity and depressive symptoms in childhood.

Negativity bias is a core feature of depression that is associated with dysfunctional frontoamygdalar connectivity; this pathway is associated with emotion regulation and sensitive to neurobiological change during puberty. We used a valence bias task (ratings of emotional ambiguity) as a potential early indicator of depression risk and differences in frontoamygdalar connectivity. Previous work using this task demonstrated that children normatively have a negative bias that attenuates with maturation. Here, we test the hypothesis that persistence of this negativity bias as maturation ensues may reveal differences in emotion regulation development, and may be associated with increased risk for depression. In children aged 6-13 years, we tested the moderating role of puberty on relationships between valence bias, depressive symptoms, and frontoamygdalar connectivity. A negative bias was associated with increased depressive symptoms for those at more advanced pubertal stages (within this sample) and less regulatory frontoamygdalar connectivity, whereas a more positive bias was associated with more regulatory connectivity patterns. These data suggest that with maturation, individual differences in positivity biases and associated emotion regulation circuitry confer a differential risk for depression. Longitudinal work is necessary to determine the directionality of these effects and explore the influence of early life events.

Selection of Visual Objects in Perception and Working Memory One at a Time.

How does the content of visual working memory influence the way we process the visual environment? We addressed this question using the steady-state visual evoked potential (SSVEP), which provides a discernible measure of visuocortical activation to multiple stimuli simultaneously. Fifty-six adults were asked to remember a set of two oriented gratings. During the retention interval, two frequency-tagged oriented gratings were presented to probe the visuocortical processing of matching versus mismatching orientations relative to the memory set. Matching probes prompted an increased visuocortical response, whereas mismatching stimuli were suppressed. This suggests that the visual cortex prioritizes attentional selection of memory-relevant features at the expense of non-memory-relevant features. When two memory items were probed simultaneously, visuocortical amplification alternated between the two stimuli at a rate of 3 Hz to 4 Hz, consistent with the rate of attentional sampling of sensory events from the external world. These results suggest a serial, single-item attentional sampling of remembered features.

Functional Source Separation for EEG-fMRI Fusion: Application to Steady-State Visual Evoked Potentials.

Neurorobotics is one of the most ambitious fields in robotics, driving integration of interdisciplinary data and knowledge. One of the most productive areas of interdisciplinary research in this area has been the implementation of biologically-inspired mechanisms in the development of autonomous systems. Specifically, enabling such systems to display adaptive behavior such as learning from good and bad outcomes, has been achieved by quantifying and understanding the neural mechanisms of the brain networks mediating adaptive behaviors in humans and animals. For example, associative learning from aversive or dangerous outcomes is crucial for an autonomous system, to avoid dangerous situations in the future. A body of neuroscience research has suggested that the neurocomputations in the human brain during associative learning involve re-shaping of sensory responses. The nature of these adaptive changes in sensory processing during learning however are not yet well enough understood to be readily implemented into on-board algorithms for robotics application. Toward this overall goal, we record the simultaneous electroencephalogram (EEG) and functional magnetic resonance imaging (fMRI), characterizing one candidate mechanism, i.e., large-scale brain oscillations. The present report examines the use of Functional Source Separation (FSS) as an optimization step in EEG-fMRI fusion that harnesses timing information to constrain the solutions that satisfy physiological assumptions. We applied this approach to the voxel-wise correlation of steady-state visual evoked potential (ssVEP) amplitude and blood oxygen level-dependent imaging (BOLD), across both time series. The results showed the benefit of FSS for the extraction of robust ssVEP signals during simultaneous EEG-fMRI recordings. Applied to data from a 3-phase aversive conditioning paradigm, the correlation maps across the three phases (habituation, acquisition, extinction) show converging results, notably major overlapping areas in both primary and extended visual cortical regions, including calcarine sulcus, lingual cortex, and cuneus. In addition, during the acquisition phase when aversive learning occurs, we observed additional correlations between ssVEP and BOLD in the anterior cingulate cortex (ACC) as well as the precuneus and superior temporal gyrus.

Pre-target alpha power predicts the speed of cued target discrimination.

The human visual system selects information from dense and complex streams of spatiotemporal input. This selection process is aided by prior knowledge of the features, location, and temporal proximity of an upcoming stimulus. In the laboratory, this knowledge is often conveyed by cues, preceding a task-relevant target stimulus. Response speed in cued selection tasks varies within and across participants and is often thought to index efficient selection of a cued feature, location, or moment in time. The present study used a reverse correlation approach to identify neural predictors of efficient target discrimination: Participants identified the orientation of a sinusoidal grating, which was presented in one hemifield following the presentation of bilateral visual cues that carried temporal but not spatial information about the target. Across different analytic approaches, faster target responses were predicted by larger alpha power preceding the target. These results suggest that heightened pre-target alpha power during a cue period may index a state that is beneficial for subsequent target processing. Our findings are broadly consistent with models that emphasize capacity sharing across time, as well as models that link alpha oscillations to temporal predictions regarding upcoming events.

Individual differences in valence bias: fMRI evidence of the initial negativity hypothesis.

Facial expressions offer an ecologically valid model for examining individual differences in affective decision-making. They convey an emotional signal from a social agent and provide important predictive information about one's environment (presence of potential rewards or threats). Although some expressions provide clear predictive information (angry, happy), others (surprised) are ambiguous in that they predict both positive and negative outcomes. Thus, surprised faces can delineate an individual's valence bias, or the tendency to interpret ambiguity as positive or negative. Our initial negativity hypothesis suggests that the initial response to ambiguity is negative, and that positivity relies on emotion regulation. We tested this hypothesis by comparing brain activity during explicit emotion regulation (reappraisal) and while freely viewing facial expressions, and measuring the relationship between brain activity and valence bias. Brain regions recruited during reappraisal showed greater activity for surprise in individuals with an increasingly positive valence bias. Additionally, we linked amygdala activity with an initial negativity, revealing a pattern similarity in individuals with negative bias between viewing surprised faces and maintaining negativity. Finally, these individuals failed to show normal habituation to clear negativity. These results support the initial negativity hypothesis, and are consistent with emotion research in both children and adult populations.

Amygdala Adaptation and Temporal Dynamics of the Salience Network in Conditioned Fear: A Single-Trial fMRI Study.

Research in rodents has established the role of the amygdaloid complex in defensive responses to conditioned threat. In human imaging studies, however, activation of the amygdala by conditioned threat cues is often not observed. One hypothesis states that this finding reflects adaptation of amygdaloid responses over time. We tested this hypothesis by estimating single-trial neural responses over a large number of conditioning trials. Functional MRI (fMRI) was recorded from 18 participants during classical differential fear conditioning: Participants viewed oriented grayscale grating stimuli (45° or 135°) presented centrally in random order. In the acquisition block, one grating (the CS+) was paired with a noxious noise, the unconditioned stimulus (US), on 25% of trials. The other grating, denoted CS-, was never paired with the US. Consistent with previous reports, BOLD in dorsal anterior cingulate cortex (dACC) and insula, but not the amygdala, was heightened when viewing CS+ stimuli that were not paired with US compared to CS- stimuli. Trial-by-trial analysis showed that over the course of acquisition, activity in the amygdala attenuated. Interestingly, activity in the dACC and insula also declined. Representational similarity analysis (RSA) corroborated these results, indicating that the voxel patterns evoked by CS+ and CS- in these brain regions became less distinguishable over time. Together, the present findings support the hypothesis that the lack of BOLD differences in the amygdaloid complex in many studies of classical conditioning is due to adaptation, and the adaptation effects may reflect changes in large-scale networks mediating aversive conditioning, particularly the salience network.

Cross multivariate correlation coefficients as screening tool for analysis of concurrent EEG-fMRI recordings.

Over the past decade, the simultaneous recording of electroencephalogram (EEG) and functional magnetic resonance imaging (fMRI) data has garnered growing interest because it may provide an avenue towards combining the strengths of both imaging modalities. Given their pronounced differences in temporal and spatial statistics, the combination of EEG and fMRI data is however methodologically challenging. Here, we propose a novel screening approach that relies on a Cross Multivariate Correlation Coefficient (xMCC) framework. This approach accomplishes three tasks: (1) It provides a measure for testing multivariate correlation and multivariate uncorrelation of the two modalities; (2) it provides criterion for the selection of EEG features; (3) it performs a screening of relevant EEG information by grouping the EEG channels into clusters to improve efficiency and to reduce computational load when searching for the best predictors of the BOLD signal. The present report applies this approach to a data set with concurrent recordings of steady-state-visual evoked potentials (ssVEPs) and fMRI, recorded while observers viewed phase-reversing Gabor patches. We test the hypothesis that fluctuations in visuo-cortical mass potentials systematically covary with BOLD fluctuations not only in visual cortical, but also in anterior temporal and prefrontal areas. Results supported the hypothesis and showed that the xMCC-based analysis provides straightforward identification of neurophysiological plausible brain regions with EEG-fMRI covariance. Furthermore xMCC converged with other extant methods for EEG-fMRI analysis.

Multimodal Imaging Evidence for a Frontoparietal Modulation of Visual Cortex during the Selective Processing of Conditioned Threat.

Emotionally salient cues are detected more readily, remembered better, and evoke greater visual cortical responses compared with neutral stimuli. The current study used concurrent EEG-fMRI recordings to identify large-scale network interactions involved in the amplification of visual cortical activity when viewing aversively conditioned cues. To generate a continuous neural signal from pericalcarine visual cortex, we presented rhythmic (10/sec) phase-reversing gratings, the orientation of which predicted the presence (CS+) or absence (CS-) of a cutaneous electric shock (i.e., the unconditioned stimulus). The resulting single trial steady-state visual evoked potential (ssVEP) amplitude was regressed against the whole-brain BOLD signal, resulting in a measure of ssVEP-BOLD coupling. Across all trial types, ssVEP-BOLD coupling was observed in both primary and extended visual cortical regions, the rolandic operculum, as well as the thalamus and bilateral hippocampus. For CS+ relative to CS- trials during the conditioning phase, BOLD-alone analyses showed CS+ enhancement at the occipital pole, superior temporal sulci, and the anterior insula bilaterally, whereas ssVEP-BOLD coupling was greater in the pericalcarine cortex, inferior parietal cortex, and middle frontal gyrus. Dynamic causal modeling analyses supported connectivity models in which heightened activity in pericalcarine cortex for threat (CS+) arises from cortico-cortical top-down modulation, specifically from the middle frontal gyrus. No evidence was observed for selective pericalcarine modulation by deep cortical structures such as the amygdala or anterior insula, suggesting that the heightened engagement of pericalcarine cortex for threat stimuli is mediated by cortical structures that constitute key nodes of canonical attention networks.