Moving toward reality: Electrocortical reactivity to naturalistic multimodal emotional videos.

While previous research has investigated the effects of emotional videos on peripheral physiological measures and conscious experience, this study extends the research to include electrocortical measures, specifically the steady-state visual-evoked potential (ssVEP). A carefully curated set of 45 videos, designed to represent a wide range of emotional and neutral content, were presented with a flickering border. The videos featured a continuous single-shot perspective, natural soundtrack, and excluded elements associated with professional films, to enhance realism. The results demonstrate a consistent reduction in ssVEP amplitude during emotional videos which strongly correlates with the rated emotional intensity of the clips. This suggests that narrative audiovisual stimuli have the potential to track dynamic emotional processing in the cortex, providing new avenues for research in affective neuroscience. The findings highlight the potential of using realistic video stimuli to investigate how the human brain processes emotional events in a paradigm that increases ecological validity. Future studies can further develop this paradigm by expanding the video set, targeting specific cortical networks, and manipulating narrative predictability. Overall, this study establishes a foundation for investigating emotional perception using realistic video stimuli and has the potential to expand our understanding of real-world emotional processing in the human brain.

A pilot study to investigate the efficacy and tolerability of lesion network guided transcranial electrical stimulation in outpatients with psychosis spectrum illness.

BACKGROUND: Transcranial electrical stimulation (tES) may improve psychosis symptoms, but few investigations have targeted brain regions causally linked to psychosis symptoms. We implemented a novel montage targeting the extrastriate visual cortex (eVC) previously identified by lesion network mapping in the manifestation of visual hallucinations. OBJECTIVE: To determine if lesion network guided High Definition-tES (HD-tES) to the eVC is safe and efficacious in reducing symptoms related to psychosis. METHODS: We conducted a single-blind crossover pilot study (NCT04870710) in patients with psychosis spectrum disorders. Participants first received HD-tDCS (direct current), followed by 4 weeks of wash out, then 2 Hz HD-tACS (alternating current). Participants received 5 days of daily (2×20 min) stimulation bilaterally to the eVC. Primary outcomes included the Positive and Negative Syndrome Scale (PANSS), biological motion task, and Event Related Potentials (ERP) from a steady state visual evoked potential (SSVEP) paradigm. Secondary outcomes included the Montgomery-Asperg Depression Rating Scale, Global Assessment of Functioning (GAF), velocity discrimination and visual working memory task, and emotional ERP. RESULTS: HD-tDCS improved PANSS general psychopathology in the short-term (d=0.47; pfdr=0.03), with long-term improvements in general psychopathology (d=0.62; pfdr=0.05) and GAF (d=-0.56; pfdr=0.04) with HD-tACS. HD-tDCS reduced SSVEP P1 (d=0.25; pfdr=0.005), which correlated with general psychopathology (ß = 0.274, t = 3.59, p = 0.04). No significant differences in safety or tolerability measures were identified. CONCLUSION: Lesion network guided HD-tES to the eVC is a safe, efficacious, and promising approach for reducing general psychopathology via changes in neuroplasticity. These results highlight the need for larger clinical trials implementing novel targeting methodologies for the treatments of psychosis.

Efficacy and Tolerability of Lesion Network Guided Transcranial Electrical Stimulation in Outpatients with Psychosis Spectrum Illness: A Nonrandomized Controlled Trial.

Importance: Transcranial electrical stimulation (tES) may improve psychosis symptoms, but few investigations have targeted brain regions causally linked to psychosis symptoms. We implemented a novel montage targeting the extrastriate visual cortex (eVC) previously identified by lesion network mapping in the manifestation of visual hallucinations. Objective: To determine if lesion network guided HD-tES to the eVC is safe and efficacious in reducing symptoms related to psychosis. Design Setting and Participants: Single-center, nonrandomized, single-blind trial using a crossover design conducted in two 4-week phases beginning November 2020, and ending January 2022. Participants were adults 18-55 years of age with a diagnosis of schizophrenia, schizoaffective or psychotic bipolar disorder as confirmed by the Structured Clinical Interview for DSM-V, without an antipsychotic medication change for at least 4 weeks. A total of 8 participants consented and 6 participants enrolled. Significance threshold set to <0.1 due to small sample size. Interventions: 6 Participants first received HD-tDCS (direct current), followed by 4 weeks of wash out, then 4 received 2Hz HD-tACS (alternating current). Participants received 5 consecutive days of daily (2 × 20min) stimulation applied bilaterally to the eVC. Main Outcomes and Measures: Primary outcomes included the Positive and Negative Syndrome Scale (PANSS) total, positive, negative, and general scores, biological motion task, and Event Related Potential (ERP) measures obtained from a steady state visual evoked potential (SSVEP) task across each 4-week phase. Secondary outcomes included the Montgomery-Asperg Depression Rating Scale (MADRS), Global Assessment of Functioning (GAF), velocity discrimination task, visual working memory task, and emotional ERP across each 4-week phase. Results: HD-tDCS improved general psychopathology in the short-term (d=0.47; p fdr =0.03), with long-term improvements in general psychopathology (d=0.62; p fdr =0.05) and GAF (d=-0.56; p fdr =0.04) with HD-tACS. HD-tDCS reduced SSVEP P1 (d=0.25; p fdr =0.005), which correlated with general psychopathology (ß=0.274, t=3.59, p=0.04). No significant differences in safety or tolerability measures were identified. Conclusions and Relevance: Lesion network guided HD-tES to the eVC is a safe, efficacious, and promising approach for reducing general psychopathology via changes in neuroplasticity. These results highlight the need for larger clinical trials implementing novel targeting methodologies for the treatments of psychosis. Trial Registration: ClinicalTrials.gov Identifier: NCT04870710. Key Points: Question: Is lesion network guided neurostimulation an efficacious, safe, and targeted approach for treating psychosis?Findings: In this single-center, nonrandomized, crossover, single-blind trial of 6 outpatients with psychosis, improvement in general psychopathology was seen in the short-term with HD-tDCS (high-definition transcranial direct current stimulation) and long-term with HD-tACS (alternating current) targeting the extrastriate visual cortex (eVC). HD-tDCS reduced early visual evoked responses which linked to general psychopathology improvements. Overall, both stimulations were well tolerated.Meaning: Study findings suggest that lesion network guided HD-tES to the eVC is a safe, efficacious, and promising approach for reducing general psychopathology via neuroplastic changes.

A 5-min paradigm to evoke robust emotional reactivity in neuroimaging studies.

The advent of the Research Domain Criteria (RDoC) approach to funding translational neuroscience has highlighted a need for research that includes measures across multiple task types. However, the duration of any given experiment is quite limited, particularly in neuroimaging contexts, and therefore robust estimates of multiple behavioral domains are often difficult to achieve. Here we offer a "turn-key" emotion-evoking paradigm suitable for neuroimaging experiments that demonstrates strong effect sizes across widespread cortical and subcortical structures. This short series could be easily added to existing fMRI protocols, and yield a reliable estimate of emotional reactivity to complement research in other behavioral domains. This experimental adjunct could be used to enable an initial comparison of emotional modulation with the primary behavioral focus of an investigator's work, and potentially identify new relationships between domains of behavior that have not previously been recognized.

Emotional Perception: Divergence of Early and Late Event-related Potential Modulation.

The early posterior negativity (EPN) is a mid-latency ERP component that is reliably enhanced by emotional cues, with a deflection beginning between 150 and 200 msec after stimulus onset. The brief, bilateral occipital EPN is followed by the centroparietal late positive potential (LPP), a long duration slow-wave that is strongly associated with emotional arousal ratings of scenes. A recent study suggests that the EPN is particularly sensitive to human bodies in scenes, independent of emotional intensity. Here, we directly investigate the influence of human body features on EPN modulation, using emotional and neutral scenes depicting people across a range of body exposures and orientations, in addition to scenes of pleasant, neutral, and unpleasant animals. The results demonstrate that the EPN is quite sensitive to human body features and weakly related to arousal ratings, whereas the LPP is strongly modulated by scenes that receive high arousal ratings. Based on these results and relevant work on body-specific visual perception, we speculate that modulation of the EPN may strongly reflect the early detection of human bodies, which serves as a predictor of emotional significance, whereas LPP modulation is more closely associated with the extended elaborative processing of scenes that are explicitly judged to be emotionally arousing.

Do rare emotional scenes enhance LPP modulation?

The slow wave late positive potential (LPP) is one of the most dependable measures of emotional processing in human neuroscience. While LPP positivity shows modest malleability by emotional regulation and competing tasks, its fundamental enhancement by emotional scene perception is extremely reliable. Here we assess the impact of emotional scene frequency (67%, 50% and 17%) on the strength of LPP modulation, across 3 groups of participants, using consistent presentation and analysis methods. The results demonstrate strong consistency in the strength of emotional modulation across frequent, equiprobable, and rare emotion conditions. However, a small enhancement of LPP positivity was found during unpleasant scenes in the rare emotion condition. The LPP thus appears to be largely insensitive to contextual features such as scene frequency and predictability, suggesting that strong emotional cues persistently engage orienting and evaluation processes because this tendency was selected in phylogeny.

Humor and emotion: Quantitative meta analyses of functional neuroimaging studies.

Humor is a ubiquitous aspect of human behavior that is infrequently the focus of neuroscience research. To localize human brain structures associated with the experience of humor, we conducted quantitative activation likelihood estimate (ALE) meta analyses of 57 fMRI studies (n = 1248) reporting enhanced regional brain activity evoked by humorous cues versus matched control cues. We performed separate ALE analyses of studies that employed picture-driven, text-based, and auditory laughter cues to evoke humor. A primary finding was that complex humor activates supramodal areas of the brain strongly associated with emotional processes, including bilateral amygdala and inferior frontal gyrus. Moreover, activation in brain regions associated with language, semantic knowledge, and theory of mind were differentially modulated by text and picture-driven humor cues, while hearing laughter enhances activation in auditory association cortex. The identification of humor-driven brain networks has the potential to expand brain-derived models of human emotion and could provide useful targets in translational research and therapy.

Neural Processing of Repeated Emotional Scenes in Schizophrenia, Schizoaffective Disorder, and Bipolar Disorder.

Impaired emotional processing and cognitive functioning are common in schizophrenia, schizoaffective disorder, and bipolar disorders, causing significant socioemotional disability. While a large body of research demonstrates abnormal cognition/emotion interactions in these disorders, previous studies investigating abnormalities in the emotional scene response using event-related potentials (ERPs) have yielded mixed findings, and few studies compare findings across psychiatric diagnoses. The current study investigates the effects of emotion and repetition on ERPs in a large, well-characterized sample of participants with schizophrenia-bipolar syndromes. Two ERP components that are modulated by emotional content and scene repetition, the early posterior negativity (EPN) and late positive potential (LPP), were recorded in healthy controls and participants with schizophrenia, schizoaffective disorder, bipolar disorder with psychosis, and bipolar disorder without psychosis. Effects of emotion and repetition were compared across groups. Results displayed significant but small effects in schizophrenia and schizoaffective disorder, with diminished EPN amplitudes to neutral and novel scenes, reduced LPP amplitudes to emotional scenes, and attenuated effects of scene repetition. Despite significant findings, small effect sizes indicate that emotional scene processing is predominantly intact in these disorders. Multivariate analyses indicate that these mild ERP abnormalities are related to cognition, psychosocial functioning, and psychosis severity. This relationship suggests that impaired cognition, rather than diagnosis or mood disturbance, may underlie disrupted neural scene processing in schizophrenia-bipolar syndromes.

Repeated noninvasive stimulation of the ventromedial prefrontal cortex reveals cumulative amplification of pleasant compared to unpleasant scene processing: A single subject pilot study.

The ventromedial prefrontal cortex (vmPFC) is a major hub of the reward system and has been shown to activate specifically in response to pleasant / rewarding stimuli. Previous studies demonstrate enhanced pleasant cue reactivity after single applications of transcranial direct current stimulation (tDCS) to the vmPFC. Here we present a pilot case study in which we assess the cumulative impact of multiple consecutive vmPFC-tDCS sessions on the processing of visual emotional stimuli in an event-related MEG recording design. The results point to stable modulation of increased positivity biases (pleasant > unpleasant stimulus signal strength) after excitatory vmPFC stimulation and a reversed pattern (pleasant < unpleasant) after inhibitory stimulation across five consecutive tDCS sessions. Moreover, cumulative effects of these emotional bias modulations were observable for several source-localized spatio-temporal clusters, suggesting an increase in modulatory efficiency by repeated tDCS sessions. This pilot study provides evidence for improvements in the effectiveness and utility of a novel tDCS paradigm in the context of emotional processing.

Emotional and feature-based modulation of the early posterior negativity.

The early posterior negativity (EPN) has been shown to be enhanced by emotional relative to neutral scene perception. A subset of studies has also reported a bias in the EPN toward pleasant relative to unpleasant scenes. Functional MRI research has also identified a region in lateral occipital cortex that shows a sensitivity to the visual perception of body parts, which may contribute to the EPN. Here, we assess the roles of rated scene pleasantness and the depiction of body parts on modulation of the EPN in two studies, using scenes that are chosen to be of equivalent perceptual complexity. In Study 1, we presented two distinct highly pleasant and arousing scene contents (erotic couples and moments of jubilant victory) as well as neutral people, threat, and mutilation scenes. As in prior research, the EPN was enhanced by emotionally arousing scenes, with the greatest modulation evoked by erotic scenes, although victory scenes elicited stronger ratings of pleasantness and equivalent ratings of arousal. This result suggests that the EPN may be sensitive to distinct features found in erotic scenes. To determine the extent to which body part perception modulates the EPN, Study 2 compared EPN modulation evoked by erotic scenes with nonerotic nudist scenes. Ratings of pleasantness and arousal were reduced, yet nudist scenes led to stronger modulation of the EPN compared to erotic scenes. These data indicate that, in addition to the emotional intensity of scenes, modulation of the EPN may in part reflect the discrimination of unclothed body parts.

Electrophysiological correlates of emotional scene processing in bipolar disorder.

Emotional dysfunction is a core feature of bipolar I disorder (BD). Behavioral data suggest that emotional processing may differ based on history of psychosis, but physiological studies frequently disregard this differentiating feature. Face processing studies indicate that emotion-related components of event-related potentials (ERPs) are abnormal in BD, but fMRI data using emotional scenes are mixed. The current study used ERPs to examine emotional scene perception in BD with and without a history of psychosis (BDP, BDNP). 386 participants from the PARDIP consortium (HC = 181, BDP = 130, BDNP = 75) viewed neutral, pleasant, and unpleasant scenes from the International Affective Picture System (IAPS) during continuous EEG recording. The early posterior negativity (EPN) and late positive potential (LPP) were examined for group and stimulus effects. Analyses were conducted for groups on and off medications to examine associations between medication status, psychosis, and ERP response. Group differences were found between HC and BD in emotional modulation of the EPN and between HC and BDP in the LPP to pleasant images. There was a significant interaction between psychosis history and anticonvulsant status in the EPN, but no other medication associations were found. The relationship between neural/self-reported emotional responses and clinical symptoms were examined with canonical correlations, but no significant associations were found. Results from this large well characterized sample indicate mild deviations in neural reactivity related to medication, mood, and psychosis history. However, processing of emotional scenes appears mostly intact in individuals with BD regardless of symptom severity.

Noninvasive Stimulation of the Ventromedial Prefrontal Cortex Indicates Valence Ambiguity in Sad Compared to Happy and Fearful Face Processing.

The ventromedial prefrontal cortex (vmPFC) is known to be specifically involved in the processing of stimuli with pleasant, rewarding meaning to the observer. By the use of non-invasive transcranial direct current stimulation (tDCS), it was previously possible to show evidence for this valence specificity and to modulate the impact of the vmPFC on emotional network processing. Prior results showed increased neural activation during pleasant relative to unpleasant stimulus processing after excitatory compared to inhibitory vmPFC-tDCS. As dysfunctional vmPFC activation patterns are associated with major depressive disorder (MDD), tDCS of this region could render an attractive application in future therapy. Here, we investigated vmPFC-tDCS effects on sad compared to happy face processing, as sad faces are often used in the study of mood disorders. After counterbalanced inhibitory or excitatory tDCS, respectively, healthy participants viewed happy and sad faces during magnetoencephalography (MEG) recording. In addition, tDCS effects on an interpretational bias of ambiguous happy-sad face morphs and an attentional bias of a dot-probe task with happy and sad faces as emotional primes were investigated. Finally, in conjoint analyses with data from a previous sibling study (happy and fearful faces) we examined whether excitatory vmPFC-tDCS would reveal a general increase in processing of pleasant stimuli independent of the type of unpleasant stimuli applied (sad vs. fearful faces). MEG and behavioral results showed that happy faces promoted a relative positivity bias after excitatory compared to inhibitory tDCS, visible in left orbitofrontal cortex and in the emotion-primed dot-probe task. A converse pattern in the MEG data during sad face processing suggests the possible involvement of an empathy network and thus significantly differed from neuronal processing of fearful face processing. Implications for the bearing of vmPFC modulation on emotional face processing and the impact of specific unpleasant face expressions are discussed.

Directional interconnectivity of the human amygdala, fusiform gyrus, and orbitofrontal cortex in emotional scene perception.

The perception of emotionally arousing scenes modulates neural activity in ventral visual areas via reentrant signals from the amygdala. The orbitofrontal cortex (OFC) shares dense interconnections with amygdala and has been strongly implicated in emotional stimulus processing in primates, but our understanding of the functional contribution of this region to emotional perception in humans is poorly defined. In this study we acquired targeted rapid functional imaging from lateral OFC, amygdala, and fusiform gyrus (FG) over multiple scanning sessions (resulting in over 1,000 trials per participant) in an effort to define the activation amplitude and directional connectivity among these regions during naturalistic scene perception. All regions of interest showed enhanced activation during emotionally arousing, compared with neutral scenes. In addition, we identified bidirectional connectivity between amygdala, FG, and OFC in the great majority of individual subjects, suggesting that human emotional perception is implemented in part via nonhierarchical causal interactions across these three regions.NEW & NOTEWORTHY Due to the practical limitations of noninvasive recording methodologies, there is a scarcity of data regarding the interactions of human amygdala and orbitofrontal cortex (OFC). Using rapid functional MRI sampling and directional connectivity, we found that the human amygdala influences emotional perception via distinct interactions with late-stage ventral visual cortex and OFC, in addition to distinct interactions between OFC and fusiform gyrus. Future efforts may leverage these patterns of directional connectivity to noninvasively distinguish clinical groups from controls with respect to network causal hierarchy.

Assessing the Primacy of Human Amygdala-Inferotemporal Emotional Scene Discrimination with Rapid Whole-Brain fMRI.

The comparative roles of the human amygdala and orbitofrontal cortex in emotional processing are under substantial debate, supported prominently by invasive primate studies. Noninvasive studies in humans are restricted by the limitations of electro- and magneto-encephalographic methods, which are hampered by the closed-field architecture and deep location of these structures. Here we employ whole-brain functional magnetic resonance imaging at an effective sampling rate of 300 ms to define the latency of enhanced blood oxygen level dependent (BOLD) contrast within structures activated by emotionally evocative relative to neutral scenes, in an effort to assess the hypothesized primacy of amygdala-inferotemporal co-activity in human emotional perception, relative to orbitofrontal cortex. Consistent with much prior work, we identified heightened BOLD signal during pleasant and unpleasant scene presentations in extrastriate occipital, ventral temporal, and posterior parietal visual system, as well as enhanced activation in cortical regions including the dorsal frontoparietal network, insula, and orbitofrontal cortex. Subcortical structures including the amygdala, locus coeruleus, and basal forebrain also showed reliably increased activity during emotional scene perception. The latency at which emotional BOLD signal enhancement varied considerably across structures, ranging from 2 to 6 seconds after scene onset. Though coarse, the spatiotemporal pattern of emotion-enhanced activity identified here is consistent with the idea that the amygdala and inferior temporal fusiform gyrus are the first regions to discriminate scene emotionality, which may then distribute this categorical information to other cortical and subcortical structures.

Hemodynamic and electrocortical reactivity to specific scene contents in emotional perception.

Emotional scene perception is characterized by enhanced neural activity across broad regions of visual cortex, the frontoparietal network, and anterior corticolimbic structures. In human fMRI and electrocortical experiments, activation enhancement is strongly related to self-reported emotional arousal evoked by scene stimuli. However, an additional bias in reaction to pleasant scenes has been reported in a subset of emotion-enhanced brain regions. Human fMRI and primate electrophysiological studies show biased frontoparietal network activity in response to rewarding cues. In addition, activation in lateral occipital regions may show a bias in pleasant scene perception, as shown in fMRI and in the early posterior negativity (EPN) ERP component. To define this potential pleasure bias, we presented a balanced set of naturalistic scenes to participants during separate fMRI and ERP recording sessions. Consistent with past work, the amplitude of the slow-wave late positive potential (LPP), as well as hemodynamic activity in fusiform gyrus and amygdala, showed equivalent enhancement across highly arousing pleasant and unpleasant, relative to neutral scenes. In addition to this emotional enhancement, the EPN component, as well as hemodynamic activity in lateral occipital cortex and frontoparietal network, showed greater reactivity during highly arousing pleasant relative to unpleasant scenes, consistent with a pleasure bias. The interpretation of this pattern of reactivity is discussed with respect to selective and evolved attention mechanisms.

Noninvasive stimulation of the ventromedial prefrontal cortex modulates emotional face processing.

The ventromedial prefrontal cortex (vmPFC) is associated with emotional states that can be characterized as positive affect. Moreover, a variety of psychiatric disorders that are associated with disturbed reactions toward reward- or safety-signaling stimuli reveal functional or structural anomalies within this area. Thus, neuromodulation of this region via transcranial direct current stimulation (tDCS) offers an attractive opportunity to noninvasively influence pleasant emotional and reward processing. Recent experiments revealed hemodynamic and electrophysiological evidence for valence specific modulations of emotional scene processing after excitatory and inhibitory tDCS of the vmPFC. Here, we identified that tDCS modulation of vmPFC during emotional face processing results in effects convergent with scene processing, in that excitatory tDCS increased neural reactivity during happy compared to fearful face perception, whereas inhibitory stimulation led to a converse effect. In addition, behavioral data (affect identification of ambiguous expressive faces) revealed a bias toward preferential processing of happy compared to fearful faces after excitatory compared to after inhibitory stimulation. These results further support the vmPFC as an appropriate target for noninvasive neuromodulation of an appetitive processing network in patients suffering from disturbed cognition of reward- and safety-signaling stimuli. It should however be noted that electrophysiological pre-tDCS differences at earlier time intervals of emotional face and scene processing appeared amplified by tDCS, which remains to be investigated.

Noninvasive Stimulation of the Ventromedial Prefrontal Cortex Enhances Pleasant Scene Processing.

Depressive patients typically show biased attention towards unpleasant and away from pleasant emotional material. Imaging studies suggest that dysfunctions in a distributed neural network, including the ventromedial prefrontal cortex (vmPFC), are associated with this processing bias. Accordingly, changes in vmPFC activation should mediate changes in processing of emotional stimuli. Here, we investigated the effect of inhibitory and excitatory transcranial direct current stimulation (tDCS) of the vmPFC on emotional scene processing in two within-subject experiments using functional magnetic resonance imaging (fMRI) and magnetoencephalography (MEG). Both studies showed that excitatory relative to inhibitory tDCS amplifies processing of pleasant compared to unpleasant scenes in healthy participants. This modulatory effect occurred in a distributed network including sensory and prefrontal cortex regions and was visible during very early to late processing stages. Findings are discussed with regard to neurophysiological models of emotional processing. The convergence of stimulation effects across independent groups of healthy participants and complementary neuroimaging methods (fMRI, MEG) provides a basis for further investigation of a potentially therapeutic use of this novel stimulation approach in patients with depression or other affective disorders.

Primate Visual Perception: Motivated Attention in Naturalistic Scenes.

Research has consistently revealed enhanced neural activation corresponding to attended cues coupled with suppression to unattended cues. This attention effect depends both on the spatial features of stimuli and internal task goals. However, a large majority of research supporting this effect involves circumscribed tasks that possess few ecologically relevant characteristics. By comparison, natural scenes have the potential to engage an evolved attention system, which may be characterized by supplemental neural processing and integration compared to mechanisms engaged during reduced experimental paradigms. Here, we describe recent animal and human studies of naturalistic scene viewing to highlight the specific impact of social and affective processes on the neural mechanisms of attention modulation.

Sex differences in emotional perception: Meta analysis of divergent activation.

Behavioral and physiological sex differences in emotional reactivity are well documented, yet comparatively few neural differences have been identified. Here we apply quantitative activation likelihood estimation (ALE) meta-analysis across functional brain imaging studies that each reported clusters of activity differentiating men and women as they participated in emotion-evoking tasks in the visual modality. This approach requires the experimental paradigm to be balanced across the sexes, and thus may provide greater clarity than previous efforts. Results across 56 emotion-eliciting studies (n=1907) reveal distinct activation in the medial prefrontal cortex, anterior cingulate cortex, frontal pole, and mediodorsal nucleus of the thalamus in men relative to women. Women show distinct activation in bilateral amygdala, hippocampus, and regions of the dorsal midbrain including the periaqueductal gray/superior colliculus and locus coeruleus. While some clusters are consistent with prevailing perspectives on the foundations of sex differences in emotional reactivity, thalamic and brainstem regions have not previously been highlighted as sexually divergent. These data strongly support the need to include sex as a factor in functional brain imaging studies of emotion, and to extend our investigative focus beyond the cortex.