A functional anatomic study of emotion in schizophrenia

Using salient pictures with aversive (AV) and non-aversive (NA) content, we probed limbic-emotional function in schizophrenia, testing specific hypotheses that the amygdala would exhibit abnormal activity and a relationship with positive symptoms. Fourteen schizophrenic patients and 13 healthy comparison subjects viewed pictures during [15O] water positron emission tomography (PET). Both groups reported identical subjective experience of the aversive stimuli and both activated right insula (AV-NA). The schizophrenic group showed greater activation of the medial prefrontal cortex (MPFC) for the AV-NA comparison. Control subjects activated bilateral amygdaloid and orbitofrontal regions for NA relative to a blank condition (simple visual fixation, BL), whereas schizophrenic subjects only activated left orbitofrontal cortex. Activity in the left amygdala correlated with positive symptoms in the patients. Both groups activated visual cortex, and the schizophrenic subjects exhibited less modulation throughout visual cortex for NA-BL, as well as more focused deficits in the left fusiform and left mid-occipital gyrus for AV-NA, possibly related to decreased eye movements in the schizophrenic patients. Overall, the data are consistent with a general failure to process salient stimuli in schizophrenia, and the findings support the involvement of the amygdala in the positive symptoms of schizophrenia.     

Activation of the medial prefrontal cortex and extended amygdala by individual ratings of emotional arousal: a fMRI study.

BACKGROUND: Significant differences between individual responses to emotional stimuli can be important for the study of emotion. We investigated whether incorporating individual ratings of emotional arousal in the analysis of functional magnetic resonance imaging (fMRI) data improves the detection of activation in the medial prefrontal cortex (MPFC) and sublenticular extended amygdala (SLEA), areas implicated in the processing of emotional salience. METHODS: Healthy subjects viewed counterbalanced blocks of aversive, nonaversive, and blank images. Outside the scanner, they rated the intensity of emotional arousal (salience) of each presented picture. RESULTS: Incorporating the subject's response to each stimulus by using individualized regressors produced more robust activations within MPFC and SLEA compared with a simple boxcar regressor, identical for all subjects. CONCLUSIONS: Our findings demonstrate that individual behavioral data are useful in improving detection of activation in block-design functional imaging studies.     

Attentional modulation of neuromagnetic evoked responses in early human visual cortex and parietal lobe following a rank-order rule

Top-down voluntary attention modulates the amplitude of magnetic evoked fields in the human visual cortex. Whether such modulation is flexible enough to adapt to the demands of complex tasks in which abstract rules must be applied to select a target in the presence of distracters remains unclear. We recorded brain neuromagnetic activity using whole-head magnetoencephalography in 14 human subjects during a rule-guided target selection task, and applied event-related Synthetic Aperture Magnetometry to image instantaneous changes in neuromagnetic source activity throughout the brain. During the task subjects selected one of two stimuli (the target) and ignored the other (the distracter) based on a color-rank rule (color 1 > color 2 > color 3). Our results revealed that in early visual color-sensitive areas and the parietal cortex visual stimuli evoke activity that scaled following the rank-order rule. This effect was stronger and occurred later in the parietal lobe (~200 ms after target/distracter onset) relative to early visual areas (~180 ms). Moreover, we found that transient changes in the target's motion direction evoked stronger responses relative to similar changes in the distracter at ~180 ms from change onset in contralateral areas hMT+/V5. These results suggest that during target selection and allocation of attention to a stimulus, top-down signals adjust their intensity following complex selection rules according to the organism's priorities, thereby differentially modulating neuromagnetic activity across visual cortical areas.     

Cerebral blood flow changes associated with attribution of emotional valence to pleasant, unpleasant, and neutral visual stimuli in a PET study of normal subjects.

OBJECTIVE: To assist in the development of a model for the psychopathology of emotions, the present study sought to identify the neural circuits associated with the evaluation of visual stimuli for emotional valence. METHOD: Seventeen healthy individuals were shown three sets of emotionally laden pictures carrying pleasant, unpleasant, and neutral content. While subjects evaluated the picture set for emotional valence, regional cerebral blood flow was measured with the use of [15O] water positron emission tomography. Subjective ratings of the emotional valence of the picture sets were recorded. Data were analyzed by comparing the images acquired during the neutral condition with the unpleasant and pleasant image sets and the unpleasant and pleasant conditions with each other. RESULTS: Processing of pleasant stimuli was associated with increased blood flow in the dorsal-lateral, orbital, and medial frontal cortex relative to the unpleasant condition and in the cingulate, precuneus, and visual cortex relative to the neutral condition. Evaluation of unpleasant stimuli activated the amygdala, visual cortex, and cerebellum relative to the pleasant condition and the nucleus accumbens, precuneus, and visual cortex relative to the neutral condition. CONCLUSIONS: Observing and assigning emotional value to unpleasant stimuli produced activations in subcortical limbic regions, whereas evaluation of pleasant stimuli produced activations in cortical limbic areas. These findings are consistent with the notion of a subcortical and archaic danger recognition system and a system detecting pleasantness in events and situations that is phylogenetically younger, involving primarily the prefrontal cortex.     

Depersonalization disorder: thinking without feeling.

Patients with depersonalization disorder (DP) experience a detachment from their own senses and surrounding events, as if they were outside observers. A particularly common symptom is emotional detachment from the surroundings. Using functional magnetic resonance imaging (fMRI), we compared neural responses to emotionally salient stimuli in DP patients, and in psychiatric and healthy control subjects. Six patients with DP, 10 with obsessive-compulsive disorder (OCD), and six volunteers were scanned whilst viewing standardized pictures of aversive and neutral scenes, matched for visual complexity. Pictures were then rated for emotional content. Both control groups rated aversive pictures as much more emotive, and demonstrated in response to these scenes significantly greater activation in regions important for disgust perception, the insula and occipito-temporal cortex, than DP patients (covarying for age, years of education and total extent of brain activation). In DP patients, aversive scenes activated the right ventral prefrontal cortex. The insula was activated only by neutral scenes in this group. Our findings indicate that a core phenomenon of depersonalization--absent subjective experience of emotion--is associated with reduced neural responses in emotion-sensitive regions, and increased responses in regions associated with emotion regulation.     

Modulation of auditory neural responses by a visual context in human fear conditioning.

Responses to a stimulus signaling danger depend not only on the nature of that stimulus, but also on the context in which it is presented. A large body of work has been conducted in experimental animals investigating the neural correlates of contextual modulation of fear responses. However, much less is known about this process in humans. In this study we used functional MRI in a fear conditioning paradigm to explore this phenomenon. Responses to acoustic conditioned stimuli in auditory cortex were modulated by the presence of a visual context which signaled the likelihood of receiving an aversive unconditioned stimulus. Furthermore, the presence of the aversive visual context was associated with enhanced activity in parietal cortex, which may reflect an increase in attention to the presence of environmental threat stimuli.     

Patients with premenstrual dysphoric disorder have increased startle modulation during anticipation in the late luteal phase period in comparison to control subjects

The acoustic startle response (ASR) is a withdrawal reflex to sudden or noxious auditory stimuli and, most importantly, an unbiased measure of emotional processing of appetitive and aversive stimuli. By exposing subjects to fearful situations, such as aversive pictures, the ASR may be enhanced, suggesting that amygdala modulates the startle circuit during threat situations. As one previous study, investigating affective modulation of the ASR in women with premenstrual dysphoric disorder (PMDD), discovered no difference during picture viewing it is possible that the mood changes observed in PMDD relate to anxious anticipation rather than to direct stimulus responding. Hence we sought to examine the effects of PMDD on picture anticipation and picture response. Sixteen PMDD patients and 16 controls watched slide shows containing pleasant and unpleasant pictures and positive and negative anticipation stimuli during the follicular and luteal phase of the menstrual cycle. Simultaneously, semi-randomized startle probes (105 dB) were delivered and the ASR was assessed with electromyography. Compared with control subjects, PMDD patients displayed an enhanced startle modulation by positive and negative anticipation stimuli in the luteal phase of the menstrual cycle. This finding was mainly driven by increased modulation in the luteal phase in comparison to the follicular phase among PMDD patients but also by an increased modulation in patients compared to controls during luteal phase. This suggests that the neural circuits underlying response to emotional anticipation are more sensitive during this period and emphasize the need of examining the neural correlates of anticipatory processes in women with PMDD.     

Depersonalization disorder: thinking without feeling

Patients with depersonalization disorder (DP) experience a detachment from their own senses and surrounding events, as if they were outside observers. A particularly common symptom is emotional detachment from the surroundings. Using functional magnetic resonance imaging (fMRI), we compared neural responses to emotionally salient stimuli in DP patients, and in psychiatric and healthy control subjects. Six patients with DP, 10 with obsessive–compulsive disorder (OCD), and six volunteers were scanned whilst viewing standardized pictures of aversive and neutral scenes, matched for visual complexity. Pictures were then rated for emotional content. Both control groups rated aversive pictures as much more emotive, and demonstrated in response to these scenes significantly greater activation in regions important for disgust perception, the insula and occipito-temporal cortex, than DP patients (covarying for age, years of education and total extent of brain activation). In DP patients, aversive scenes activated the right ventral prefrontal cortex. The insula was activated only by neutral scenes in this group. Our findings indicate that a core phenomenon of depersonalization — absent subjective experience of emotion — is associated with reduced neural responses in emotion-sensitive regions, and increased responses in regions associated with emotion regulation.     

Anticipation of aversive visual stimuli is associated with increased insula activation in anxiety-prone subjects.

BACKGROUND: Anticipation is a critical component of affective processing in general and for anxiety in particular. Prior research suggests that the right insula plays an important role in anticipation of affective processing during aversive images. This study aimed to test the hypothesis that individuals with increased anxiety-related temperamental traits (anxiety-prone [AP]) relative to anxiety-normative (AN) subjects would show an exaggerated insula response during anticipation of an aversive image. METHODS: 16 AP and 16 AN individuals performed a task in the functional magnetic resonance imaging scanner, during which they viewed pictures of spiders and snakes. Subjects were prompted 4-6 sec before the onset of each aversive image. Blood oxygenation level-dependent signal was contrasted during cued anticipation of images versus non-anticipatory task performance as well as viewing images. RESULTS: As hypothesized, AP subjects showed greater response than AN subjects in the bilateral insula during anticipation. In addition, these individuals had lower activity within the superior/medial frontal gyrus. During the image presentation phase, AN subjects showed greater activation than AP subjects in the bilateral temporal lobes and left superior frontal gyrus. Moreover, bilateral temporal lobe activation during image presentation was inversely correlated with bilateral insula activation during anticipation both within groups and in the combined group. CONCLUSIONS: These data suggest that greater activation of the insula during visual anticipation is associated with visual processing of aversive stimuli in AP individuals. Insula hyperactivity might be a common feature in persons with elevated trait anxiety and, as such, might be a neuroimaging marker for anxiety proneness.     

Neural correlates of using distancing to regulate emotional responses to social situations

Cognitive reappraisal is a commonly used and highly adaptive strategy for emotion regulation that has been studied in healthy volunteers. Most studies to date have focused on forms of reappraisal that involve reinterpreting the meaning of stimuli and have intermixed social and non-social emotional stimuli. Here we examined the neural correlates of the regulation of negative emotion elicited by social situations using a less studied form of reappraisal known as distancing. Whole brain fMRI data were obtained as participants viewed aversive and neutral social scenes with instructions to either simply look at and respond naturally to the images or to downregulate their emotional responses by distancing. Three key findings were obtained accompanied with the reduced aversive response behaviorally. First, across both instruction types, aversive social images activated the amygdala. Second, across both image types, distancing activated the precuneus and posterior cingulate cortex (PCC), intraparietal sulci (IPS), and middle/superior temporal gyrus (M/STG). Third, when distancing one's self from aversive images, activity increased in dorsal anterior cingulate (dACC), medial prefrontal cortex (mPFC), lateral prefrontal cortex, precuneus and PCC, IPS, and M/STG, meanwhile, and decreased in the amygdala. These findings demonstrate that distancing from aversive social cues modulates amygdala activity via engagement of networks implicated in social perception, perspective-taking, and attentional allocation.     

Re-entrant projections modulate visual cortex in affective perception: evidence from Granger causality analysis

Re-entrant modulation of visual cortex has been suggested as a critical process for enhancing perception of emotionally arousing visual stimuli. This study explores how the time information inherent in large-scale electrocortical measures can be used to examine the functional relationships among the structures involved in emotional perception. Granger causality analysis was conducted on steady-state visual evoked potentials elicited by emotionally arousing pictures flickering at a rate of 10 Hz. This procedure allows one to examine the direction of neural connections. Participants viewed pictures that varied in emotional content, depicting people in neutral contexts, erotica, or interpersonal attack scenes. Results demonstrated increased coupling between visual and cortical areas when viewing emotionally arousing content. Specifically, intraparietal to inferotemporal and precuneus to calcarine connections were stronger for emotionally arousing picture content. Thus, we provide evidence for re-entrant signal flow during emotional perception, which originates from higher tiers and enters lower tiers of visual cortex.     

Corticolimbic blood flow during nontraumatic emotional processing in posttraumatic stress disorder

CONTEXT: Recent brain imaging studies implicate dysfunction of limbic and paralimbic circuitry, including the amygdala and medial prefrontal cortex (MPFC), in the pathogenesis of posttraumatic stress disorder (PTSD) during traumatic recollection and imagery. However, the relationship between activity in these regions and general emotional processing unrelated to traumatic experience has not been fully examined. OBJECTIVE: To investigate activity in the limbic and paralimbic brain regions in PTSD in response to a challenge with emotionally salient generic visual images. DESIGN: Cross-sectional, case-control study. SETTING: Academic medical center. PARTICIPANTS: Sixteen Vietnam veterans with combat-related PTSD (PTSD group), 15 combat-exposed Vietnam veterans without PTSD (combat control group), and 15 age- and sex-matched healthy controls (normal control group). MAIN OUTCOME MEASURES: We used positron emission tomography to study regional cerebral blood flow while participants viewed complex visual pictures with negatively valenced/aversive, nonaversive ("neutral"), and blank pictures. Psychophysiologic and emotional self-report data were also recorded. RESULTS: All 3 groups activated the dorsal MPFC to general salient content. Controls without PTSD activated the left amygdala in response to aversive stimuli. Normal controls activated the ventral MPFC and combat-exposed non-PTSD and PTSD participants exhibited either no response or deactivation in these regions, respectively, during negative emotional experience. CONCLUSIONS: Consistent with current functional neuroanatomic models, patients with PTSD exhibited altered neural responses in the amygdala and ventral MPFC during the processing of emotionally salient but trauma-unrelated stimuli, potentially reflecting disorder-specific changes. Activation of the amygdala and lack of ventral MPFC deactivation to negatively valenced images in combat controls may reflect compensatory changes after trauma exposure that are not associated with PTSD.     

Behavioral activation system modulation on brain activation during appetitive and aversive stimulus processing

The reinforcement sensitivity theory (RST) proposed the behavioral activation system (BAS) as a neurobehavioral system that is dependent on dopamine-irrigated structures and that mediates the individual differences in sensitivity and reactivity to appetitive stimuli associated with BAS-related personality traits. Theoretical developments propose that high BAS sensitivity is associated with both enhanced appetitive stimuli processing and the diminished processing of aversive stimuli. The objective of this study was to analyze how individual differences in BAS functioning were associated with brain activation during erotic and aversive picture processing while subjects were involved in a simple goal-directed task. Forty-five male participants took part in this study. The task activation results confirm the activation of the reward and punishment brain-related structures while viewing erotic and aversive pictures, respectively. The SR scores show a positive correlation with activation of the left lateral prefrontal cortex, the mesial prefrontal cortex and the right occipital cortex while viewing erotic pictures, and a negative correlation with the right lateral prefrontal cortex and the left occipital cortex while viewing aversive pictures. In summary, the SR scores modulate the activity of the cortical areas in the prefrontal and the occipital cortices that are proposed to modulate the BAS and the BIS-FFFS.     

Analysis of single-unit responses to emotional scenes in human ventromedial prefrontal cortex

Lesion and functional imaging studies in humans have shown that the ventral and medial prefrontal cortex is critically involved in the processing of emotional stimuli, but both of these methods have limited spatiotemporal resolution. Conversely, neurophysiological studies of emotion in nonhuman primates typically rely on stimuli that do not require elaborate cognitive processing. To begin bridging this gap, we recorded from a total of 267 neurons in the left and right orbital and anterior cingulate cortices of four patients who had chronically implanted depth electrodes for monitoring epilepsy. Peristimulus activity was recorded to standardized, complex visual scenes depicting neutral, pleasant, or aversive content. Recording locations were verified with postoperative magnetic resonance imaging. Using a conservative, multistep statistical evaluation, we found significant responses in 56 neurons; 16 of these were selective for only one emotion class, most often aversive. The findings suggest sparse and widely distributed processing of emotional value in the prefrontal cortex, with a predominance of responses to aversive stimuli.     

Preferences for visual stimuli following amygdala damage

Bilateral damage to the human amygdala impairs retrieval of emotional and social information from faces. An important unanswered question concerns the specificity of the impairment for faces. To address this question, we examined preferences for a broad class of visual stimuli in two subjects with complete bilateral amygdala damage, both of whom were impaired in judgments of faces. Relative to controls, the subjects showed a positive bias for simple nonsense figures, color patterns, three-dimensional-looking objects and landscapes. The impairment was most pronounced in regard to those stimuli that are normally liked the least. The human amygdala thus appears to play a general role in guiding preferences for visual stimuli that are normally judged to be aversive.     

Behavioral and electrophysiological evidence of a right hemisphere bias for the influence of negative emotion on higher cognition

We examined how responses to aversive pictures affected performance and stimulus-locked event-related potentials (ERPs) recorded during a demanding cognitive task. Numeric Stroop stimuli were brief ly presented to either left or right visual hemifield (LVF and RVF, respectively) after a centrally presented aversive or neutral picture from the International Affective Picture System. Subjects indicated whether a quantity value from each Stroop stimulus matched the preceding Stroop stimulus while passively viewing the pictures. After aversive pictures, responses were more accurate for LVF Stroops and less accurate for RVF Stroops. Early-latency extrastriate attention-dependent visual ERPs were enhanced for LVF Stroops. The N2 ERP was enhanced for LVF Stroops over the right frontal and parietal scalp sites. Slow potentials (300-800 msec) recorded over the frontal and parietal regions showed enhanced picture related modulation and amplitude for LVF Stroops. These results suggest that emotional responses to aversive pictures selectively facilitated right hemisphere processing during higher cognitive task performance.     

Silent speechreading in the absence of scanner noise: an event-related fMRI study

In a previous study we used functional magnetic resonance imaging (fMRI) to demonstrate activation in auditory cortex during silent speechreading. Since image acquisition during fMRI generates acoustic noise, this pattern of activation could have reflected an interaction between background scanner noise and the visual lip-read stimuli. In this study we employed an event-related fMRI design which allowed us to measure activation during speechreading in the absence of acoustic scanner noise. In the experimental condition, hearing subjects were required to speechread random numbers from a silent speaker. In the control condition subjects watched a static image of the same speaker with mouth closed and were required to subvocally count an intermittent visual cue. A single volume of images was collected to coincide with the estimated peak of the blood oxygen level dependent (BOLD) response to these stimuli across multiple baseline and experimental trials. Silent speechreading led to greater activation in lateral temporal cortex relative to the control condition. This indicates that activation of auditory areas during silent speechreading is not a function of acoustic scanner noise and confirms that silent speechreading engages similar regions of auditory cortex as listening to speech.     

Aversive Conditioning of Spatial Position Sharpens Neural Population-Level Tuning in Visual Cortex and Selectively Alters Alpha-Band Activity

Processing capabilities for many low-level visual features are experientially malleable, aiding sighted organisms in adapting to dynamic environments. Explicit instructions to attend a specific visual field location influence retinotopic visuocortical activity, amplifying responses to stimuli appearing at cued spatial positions. It remains undetermined both how such prioritization affects surrounding nonprioritized locations, and if a given retinotopic spatial position can attain enhanced cortical representation through experience rather than instruction. The current report examined visuocortical response changes as human observers (N = 51, 19 male) learned, through differential classical conditioning, to associate specific screen locations with aversive outcomes. Using dense-array EEG and pupillometry, we tested the preregistered hypotheses of either sharpening or generalization around an aversively associated location following a single conditioning session. Competing hypotheses tested whether mean response changes would take the form of a Gaussian (generalization) or difference-of-Gaussian (sharpening) distribution over spatial positions, peaking at the viewing location paired with a noxious noise. Occipital 15 Hz steady-state visual evoked potential responses were selectively heightened when viewing aversively paired locations and displayed a nonlinear, difference-of-Gaussian profile across neighboring locations, consistent with suppressive surround modulation of nonprioritized positions. Measures of alpha-band (8–12 Hz) activity were differentially altered in anterior versus posterior locations, while pupil diameter exhibited selectively heightened responses to noise-paired locations but did not evince differences across the nonpaired locations. These results indicate that visuocortical spatial representations are sharpened in response to location-specific aversive conditioning, while top-down influences indexed by alpha-power reduction exhibit posterior generalization and anterior sharpening.SIGNIFICANCE STATEMENT It is increasingly recognized that early visual cortex is not a static processor of physical features, but is instead constantly shaped by perceptual experience. It remains unclear, however, to what extent the cortical representation of many fundamental features, including visual field location, is malleable by experience. Using EEG and an aversive classical conditioning paradigm, we observed sharpening of visuocortical responses to stimuli appearing at aversively associated locations along with location-selective facilitation of response systems indexed by pupil diameter and EEG alpha power. These findings highlight the experience-dependent flexibility of retinotopic spatial representations in visual cortex, opening avenues toward novel treatment targets in disorders of attention and spatial cognition.     

Anticipation of emotionally aversive visual stimuli activates right insula

Understanding the neural substrates of anticipation is required for a comprehensive model of the ways in which anxiety influences information processing. While it is apparent that the insula and medial frontal cortex are involved in processing anticipation of physical (i.e., painful) stimuli, their role in processing anticipation of aversive affective stimuli has yet to be determined. Twenty-eight healthy non-phobic volunteers observed aversive affective images (spiders and snakes) that were preceded by an auditory signal. The insula, dorsolateral prefrontal cortex, and parahippocampal gyrus activated during anticipation of aversive affective images. These findings indicate that common neural circuitry is involved in the anticipation of (and, perhaps, the subjective experience of anticipating) aversive affective and noxious physical stimuli.     

Strong correspondence between prefrontal and visual representations during emotional perception

Emotion is thought to cause focal enhancement or distortion of certain components of memory, indicating a complex property of emotional modulation on memory rather than simple enhancement. However, the neural basis for detailed modulation of emotional memory contents has remained unclear. Here has been shown that the information processing of the prefrontal cortex differentially affects sensory representations during experience of emotional information compared with neutral information, using functional magnetic resonance imaging (fMRI). It was found that during perception of emotional pictures, information representation in primary visual cortex (V1) significantly corresponded with the representations in dorsolateral prefrontal cortex (dlPFC). This correspondence was not observed for neutral pictures. Furthermore, participants with greater correspondence between visual and prefrontal representations showed better memory for high‐level semantic components but not for low‐level visual components of emotional stimuli. These results suggest that sensory representation during experience of emotional stimuli, compared with neutral stimuli, is more directly influenced by internally generated higher‐order information from the prefrontal cortex.