Hypoactive medial prefrontal cortex functioning in adults reporting childhood emotional maltreatment

Childhood emotional maltreatment (CEM) has adverse effects on medial prefrontal cortex (mPFC) morphology, a structure that is crucial for cognitive functioning and (emotional) memory and which modulates the limbic system. In addition, CEM has been linked to amygdala hyperactivity during emotional face processing. However, no study has yet investigated the functional neural correlates of neutral and emotional memory in adults reporting CEM. Using functional magnetic resonance imaging, we investigated CEM-related differential activations in mPFC during the encoding and recognition of positive, negative and neutral words. The sample (N = 194) consisted of patients with depression and/or anxiety disorders and healthy controls (HC) reporting CEM (n = 96) and patients and HC reporting no abuse (n = 98). We found a consistent pattern of mPFC hypoactivation during encoding and recognition of positive, negative and neutral words in individuals reporting CEM. These results were not explained by psychopathology or severity of depression or anxiety symptoms, or by gender, level of neuroticism, parental psychopathology, negative life events, antidepressant use or decreased mPFC volume in the CEM group. These findings indicate mPFC hypoactivity in individuals reporting CEM during emotional and neutral memory encoding and recognition. Our findings suggest that CEM may increase individuals’ risk to the development of psychopathology on differential levels of processing in the brain; blunted mPFC activation during higher order processing and enhanced amygdala activation during automatic/lower order emotion processing. These findings are vital in understanding the long-term consequences of CEM.     

Cognitive appraisal and life stress moderate the effects of the 5-HTTLPR polymorphism on amygdala reactivity

The short allele of the serotonin-transporter-linked promoter region (5-HTTLPR) polymorphism is associated with increased amygdala activation in response to emotional stimuli. Although top-down processes may moderate this association, available evidence is conflicting, showing the genotype influence on amygdala reactivity to be either decreased or increased during emotion regulation. Because the effects of the 5-HTTLPR polymorphism on amygdala reactivity are also conditional on self-reported life stress, differences in life stress exposure may account for this apparent discrepancy. Here, we hypothesized that self-reported life stress would moderate the relationships between genotype, cognitive appraisal, and amygdala reactivity. Forty-five healthy never-depressed subjects were presented with emotional stimuli and performed two cognitive tasks: a self-referential task and an emotion-labeling task. Life-stress exposure was measured through a semistructured interview. First, there was a genotype × condition interaction in the right amygdala: short allele carriers displayed increased amygdala activation and decreased functional connectivity with the subgenual anterior cingulate cortex in self-referential processing versus emotion labeling. Second, in line with our hypothesis, there was a genotype × condition × stress interaction in bilateral amygdala the amygdala activation during self-referential processing was negatively correlated with self-reported life stress in short allele carriers and positively in individuals homozygous for the long allele, whereas an opposite pattern was observed during emotion labeling. These results confirm that the influence of the 5-HTTLPR polymorphism on amygdala reactivity is at least partially under cognitive control. Additionally, they suggest that measuring life stress exposure is a critical step when imaging genetics.     

Threat-related amygdala functional connectivity is associated with 5-HTTLPR genotype and neuroticism

Communication between the amygdala and other brain regions critically regulates sensitivity to threat, which has been associated with risk for mood and affective disorders. The extent to which these neural pathways are genetically determined or correlate with risk-related personality measures is not fully understood. Using functional magnetic resonance imaging, we evaluated independent and interactive effects of the 5-HTTLPR genotype and neuroticism on amygdala functional connectivity during an emotional faces paradigm in 76 healthy individuals. Functional connectivity between left amygdala and medial prefrontal cortex (mPFC) and between both amygdalae and a cluster including posterior cingulate cortex, precuneus and visual cortex was significantly increased in 5-HTTLPR S′ allele carriers relative to L_AL_A individuals. Neuroticism was negatively correlated with functional connectivity between right amygdala and mPFC and visual cortex, and between both amygdalae and left lateral orbitofrontal (lOFC) and ventrolateral prefrontal cortex (vlPFC). Notably, 5-HTTLPR moderated the association between neuroticism and functional connectivity between both amygdalae and left lOFC/vlPFC, such that S′ carriers exhibited a more negative association relative to L_AL_A individuals. These findings provide novel evidence for both independent and interactive effects of 5-HTTLPR genotype and neuroticism on amygdala communication, which may mediate effects on risk for mood and affective disorders.     

Temporal dynamics of emotional responding: amygdala recovery predicts emotional traits

An individual’s affective style is influenced by many things, including the manner in which an individual responds to an emotional challenge. Emotional response is composed of a number of factors, two of which are the initial reactivity to an emotional stimulus and the subsequent recovery once the stimulus terminates or ceases to be relevant. However, most neuroimaging studies examining emotional processing in humans focus on the magnitude of initial reactivity to a stimulus rather than the prolonged response. In this study, we use functional magnetic resonance imaging to study the time course of amygdala activity in healthy adults in response to presentation of negative images. We split the amygdala time course into an initial reactivity period and a recovery period beginning after the offset of the stimulus. We find that initial reactivity in the amygdala does not predict trait measures of affective style. Conversely, amygdala recovery shows predictive power such that slower amygdala recovery from negative images predicts greater trait neuroticism, in addition to lower levels of likability of a set of social stimuli (neutral faces). These data underscore the importance of taking into account temporal dynamics when studying affective processing using neuroimaging.     

Neural responses to emotional stimuli are associated with childhood family stress.

BACKGROUND: An early family environment marked by harsh parenting has been related to risk for multiple mental disorders in adulthood, risks that may be mediated, in part, by deficits in emotion regulation skills. This study examined neural mechanisms underlying these consequences of "risky" families (RF) by exploring neural activity to tasks involving responses to emotional stimuli. METHODS: Participants completed an assessment of RF and participated in a functional magnetic resonance imaging (fMRI) investigation that examined 1) amygdala reactivity to observation of fearful/angry faces; 2) amygdala and right ventrolateral prefrontal cortex (RVLPFC) reactivity to labeling emotions displayed in these faces; and 3) the relation between RVLPFC and amygdala activity during the labeling task. RESULTS: Offspring from nonrisky families showed expected amygdala reactivity to observing fearful/angry faces and expected activation of RVLPFC while labeling the emotions, which was significantly negatively correlated (-.44) with amygdala activation. Offspring from risky families showed little amygdala activation during the observation task and a strong positive correlation (+.66) between RVLPFC and amygdala activation in the labeling task, suggesting a possible dysregulation in the neural systems involved in responses to emotional stimuli. CONCLUSIONS: Offspring from risky families exhibit atypical responses to emotional stimuli that are evident at the neural level.     

The influence of gender and emotional valence of visual cues on FMRI activation in humans

Emotional neuroscience maps neurocircuits associated with the processing of affective stimuli. To assess gender differences in brain activation elicited by affective stimuli, we used pictures from the International Affective Picture System in a functional magnetic resonance imaging (fMRI) study. Ten male and ten female age-matched healthy volunteers were included and viewed affectively negative versus positive pictures, which were presented in an event related design. There was a significant interaction between valence of emotional stimuli and gender in the sublenticular extended amygdala (SLEA) and the rostral anterior cingulate. fMRI activation in these regions was stronger for negative compared to positive cues in women. In men fMRI activation was independent of stimulus valence. These results suggest to take gender differences into account when emotional paradigms are tested in functional brain imaging.     

Neural correlates of effective and ineffective mood induction

Emotional reactivity and the ability to modulate an emotional state, which are important factors for psychological well-being, are often dysregulated in psychiatric disorders. Neural correlates of emotional states have mostly been studied at the group level, thereby neglecting individual differences in the intensity of emotional experience. This study investigates the relationship between brain activity and interindividual variation in subjective affect ratings. A standardized mood induction (MI) procedure, using positive facial expression and autobiographical memories, was applied to 54 healthy participants (28 female), who rated their subjective affective state before and after the MI. We performed a regression analysis with brain activation during MI and changes in subjective affect ratings. An increase in positive affective ratings correlated with activity in the amygdala, hippocampus and the fusiform gyrus (FFG), whereas reduced positive affect correlated with activity of the subgenual anterior cingulate cortex. Activations in the amygdala, hippocampus and FFG are possibly linked to strategies adopted by the participants to achieve mood changes. Subgenual cingulate cortex activation has been previously shown to relate to rumination. This finding is in line with previous observations of the subgenual cingulate’s role in emotion regulation and its clinical relevance to therapy and prognosis of mood disorders.     

Serotonin transporter genotype modulates cognitive reappraisal of negative emotions: a functional magnetic resonance imaging study

A functional polymorphism within the serotonin transporter gene (5-HTTLPR) has been reported to modulate emotionality and risk for affective disorders. The short (S) allele has less functional efficacy than the long (L) allele and has been associated with enhanced emotional reactivity. One possible contributing factor to the high emotionality in S carriers may be inefficient use of cognitive strategies such as reappraisal to regulate emotional responses. The aim of the present study was to test whether the 5-HTTLPR genotype modulates the neural correlates of emotion regulation. To determine neural differences between S and L allele carriers during reappraisal of negative emotions, 15 homozygous S (S′/S′) and 15 homozygous L (L′/L′) carriers underwent functional magnetic resonance imaging (fMRI), while performing an instructed emotion regulation task including downregulation, upregulation and passive viewing of negative emotional pictures. Compared to L′/L′ allele carriers, subjects who carry the S′/S′ allele responded with lower posterior insula and prefrontal brain activation during passive perception of negative emotional information but showed greater prefrontal activation and anterior insula activation during down- and upregulation of negative emotional responses. The current results support and extend previous findings of enhanced emotionality in S carriers by providing additional evidence of 5-HTTLPR modulation of volitional emotion regulation.     

Decoding of affective facial expressions in the context of emotional situations

The ability to recognize other persons' affective states and to link these with aspects of the current situation arises early in development and is precursor functions of a Theory of Mind (ToM). Until now, studies investigated either the processing of affective faces or affective pictures. In the present study, we tried to realize a scenario more similar to every day situations. We employed fMRI and used a picture matching task to explore the neural correlates associated with the integration and decoding of facial affective expressions in the context of affective situations. In the emotion condition, the participants judged an emotional facial expression with respect to the content of an emotional picture. In the two other conditions, participants indicated colour matches on the background of either affective or scrambled pictures. In contrast to colour matching on scrambled pictures, colour matching on emotional pictures resulted in longer reaction times and increased activation of the bilateral fusiform and occipital gyrus. These results indicated that, although task irrelevant, participants may attend to the emotional background of the pictures. The emotion task was associated with higher reaction times and with activation of the bilateral fusiform and occipital gyrus. Additionally, emotion attribution induced left amygdala activity. Possibly, attention processes and amygdala projections modulated the activation found in the occipital and fusiform areas. Furthermore, the involvement of the amygdala in the ToM precursor ability to link facial expressions with an emotional situation may indicate that the amygdala is involved in the development of stable ToM abilities.     

Amygdala and nucleus accumbens activation to emotional facial expressions in children and adolescents at risk for major depression

OBJECTIVE: Offspring of parents with major depressive disorder face a threefold higher risk for major depression than offspring without such family histories. Although major depression is a significant cause of morbidity and mortality, neural correlates of risk for major depression remain poorly understood. This study compares amygdala and nucleus accumbens activation in children and adolescents at high and low risk for major depression under varying attentional and emotional conditions. METHOD: Thirty-nine juveniles, 17 offspring of parents with major depression (high-risk group) and 22 offspring of parents without histories of major depression, anxiety, or psychotic disorders (low-risk group) completed a functional magnetic resonance imaging study. During imaging, subjects viewed faces that varied in intensity of emotional expressions across blocks of trials while attention was unconstrained (passive viewing) and constrained (rate nose width on face, rate subjective fear while viewing face). RESULTS: When attention was unconstrained, high-risk subjects showed greater amygdala and nucleus accumbens activation to fearful faces and lower nucleus accumbens activation to happy faces (small volume corrected for the amygdala and nucleus accumbens). No group differences emerged in amygdala or nucleus accumbens activation during constrained attention. Exploratory analysis showed that constraining attention was associated with greater medial prefrontal cortex activation in the high-risk than in the low-risk group. CONCLUSIONS: Amygdala and nucleus accumbens responses to affective stimuli may reflect vulnerability for major depression. Constraining attention may normalize emotion-related neural function possibly by engagement of the medial prefrontal cortex; face-viewing with unconstrained attention may engage aberrant processes associated with risk for major depression.     

Association between amygdala response to emotional faces and social anxiety in autism spectrum disorders

Difficulty interpreting facial expressions has been reported in autism spectrum disorders (ASD) and is thought to be associated with amygdala abnormalities. To further explore the neural basis of abnormal emotional face processing in ASD, we conducted an fMRI study of emotional face matching in high-functioning adults with ASD and age, IQ, and gender matched controls. In addition, we investigated whether there was a relationship between self-reported social anxiety and fMRI activation. During fMRI scanning, study participants were instructed to match facial expressions depicting fear or anger. The control condition was a comparable shape-matching task. The control group evidenced significantly increased left prefrontal activation and decreased activation in the occipital lobes compared to the ASD group during emotional face matching. Further, within the ASD group, greater social anxiety was associated with increased activation in right amygdala and left middle temporal gyrus, and decreased activation in the fusiform face area. These results indicate that level of social anxiety mediates the neural response to emotional face perception in ASD.     

Amygdala and insula response to emotional images in patients with generalized social anxiety disorder

Background

Functional brain imaging studies have demonstrated amygdala and insula hyper-reactivity to probes of social threat in participants with generalized social anxiety disorder (gSAD). The amygdala and insula are known to serve broad functions in emotional processing, including integration of affective information. However, few studies have examined brain responses in socially anxious participants during general emotional processing. We examined brain response to emotionally evocative images in patients with gSAD and matched healthy controls.

Methods

Eleven patients with gSAD who were not taking psychotropic medications and did not have psychiatric comorbidities and 11 matched healthy controls underwent functional magnetic resonance imaging while viewing blocks of emotionally salient (positive, negative, neutral) pictures.

Results

Participants with gSAD exhibited enhanced bilateral amygdala and insula reactivity to negative (v. neutral) images compared with healthy controls who did not exhibit enhanced reactivity. Within the gSAD group, the extent of amygdala activation was correlated with social anxiety severity, whereas the extent of insula activation was correlated with trait anxiety.

Limitations

The small sample size may have limited our ability to detect group differences in other relevant brain regions and in behavioural measures.

Conclusion

In addition to prior findings of probes of social information processing, our findings suggest that the amygdala and insula responses are hyper-reactive to general emotional images with negative emotional content and that these brain regions may play divergent roles in their representation of different phenotypes.     

FMRI activations of amygdala, cingulate cortex, and auditory cortex by infant laughing and crying

One of the functions of emotional vocalizations is the regulation of social relationships like those between adults and children. Listening to infant vocalizations is known to engage amygdala as well as anterior and posterior cingulate cortices. But, the functional relationships between these structures still need further clarification. Here, nonparental women and men listened to laughing and crying of preverbal infants and to vocalization-derived control stimuli, while performing a pure tone detection task during low-noise functional magnetic resonance imaging. Infant vocalizations elicited stronger activation in amygdala and anterior cingulate cortex (ACC) of women, whereas the alienated control stimuli elicited stronger activation in men. Independent of listeners' gender, auditory cortex (AC) and posterior cingulate cortex (PCC) were more strongly activated by the control stimuli than by infant laughing or crying. The gender-dependent correlates of neural activity in amygdala and ACC may reflect neural predispositions in women for responses to preverbal infant vocalizations, whereas the gender-independent similarity of activation patterns in PCC and AC may reflect more sensory-based and cognitive levels of neural processing. In comparison to our previous work on adult laughing and crying, the infant vocalizations elicited manifold higher amygdala activation.     

Cumulative activation during positive and negative events and state anxiety predicts subsequent inertia of amygdala reactivity

Inertia, together with intensity and valence, is an important component of emotion. We tested whether positive and negative events generate lingering changes in subsequent brain responses to unrelated threat stimuli and investigated the impact of individual anxiety. We acquired fMRI data while participants watched positive or negative movie-clips and subsequently performed an unrelated task with fearful and neutral faces. We quantified changes in amygdala reactivity to fearful faces as a function of the valence of preceding movies and cumulative neural activity evoked during them. We demonstrate that amygdala responses to emotional movies spill over to subsequent processing of threat information in a valence-specific manner: negative movies enhance later amygdala activation whereas positive movies attenuate it. Critically, the magnitude of such changes is predicted by a measure of cumulative amygdala responses to the preceding positive or negative movies. These effects appear independent of overt attention, are regionally limited to amygdala, with no changes in functional connectivity. Finally, individuals with higher state anxiety displayed stronger modulation of amygdala reactivity by positive movies. These results suggest that intensity and valence of emotional events as well as anxiety levels promote local changes in amygdala sensitivity to threat, highlighting the importance of past experience in shaping future affective reactivity.     

Sex differences in brain activation to emotional stimuli: a meta-analysis of neuroimaging studies

Substantial sex differences in emotional responses and perception have been reported in previous psychological and psychophysiological studies. For example, women have been found to respond more strongly to negative emotional stimuli, a sex difference that has been linked to an increased risk of depression and anxiety disorders. The extent to which such sex differences are reflected in corresponding differences in regional brain activation remains a largely unresolved issue, however, in part because relatively few neuroimaging studies have addressed this issue. Here, by conducting a quantitative meta-analysis of neuroimaging studies, we were able to substantially increase statistical power to detect sex differences relative to prior studies, by combining emotion studies which explicitly examined sex differences with the much larger number of studies that examined only women or men. We used an activation likelihood estimation approach to characterize sex differences in the likelihood of regional brain activation elicited by emotional stimuli relative to non-emotional stimuli. We examined sex differences separately for negative and positive emotions, in addition to examining all emotions combined. Sex differences varied markedly between negative and positive emotion studies. The majority of sex differences favoring women were observed for negative emotion, whereas the majority of the sex differences favoring men were observed for positive emotion. This valence-specificity was particularly evident for the amygdala. For negative emotion, women exhibited greater activation than men in the left amygdala, as well as in other regions including the left thalamus, hypothalamus, mammillary bodies, left caudate, and medial prefrontal cortex. In contrast, for positive emotion, men exhibited greater activation than women in the left amygdala, as well as greater activation in other regions including the bilateral inferior frontal gyrus and right fusiform gyrus. These meta-analysis findings indicate that the amygdala, a key region for emotion processing, exhibits valence-dependent sex differences in activation to emotional stimuli. The greater left amygdala response to negative emotion for women accords with previous reports that women respond more strongly to negative emotional stimuli, as well as with hypothesized links between increased neurobiological reactivity to negative emotion and increased prevalence of depression and anxiety disorders in women. The finding of greater left amygdala activation for positive emotional stimuli in men suggests that greater amygdala responses reported previously for men for specific types of positive stimuli may also extend to positive stimuli more generally. In summary, this study extends efforts to characterize sex differences in brain activation during emotion processing by providing the largest and most comprehensive quantitative meta-analysis to date, and for the first time examining sex differences as a function of positive vs. negative emotional valence. The current findings highlight the importance of considering sex as a potential factor modulating emotional processing and its underlying neural mechanisms, and more broadly, the need to consider individual differences in understanding the neurobiology of emotion.     

The serotonin transporter gene polymorphism and the effect of baseline on amygdala response to emotional faces

Previous research has found that a common polymorphism in the serotonin transporter gene (5-HTTLPR) is an important mediator of individual differences in brain responses associated with emotional behaviour. In particular, relative to individuals homozygous for the l-allele, carriers of the s-allele display heightened amygdala activation to emotional compared to non-emotional stimuli. However, there is some debate as to whether this difference is driven by increased activation to emotional stimuli, resting baseline differences between the groups, or decreased activation to neutral stimuli. We performed functional imaging during an implicit facial expression processing task in which participants viewed angry, sad and neutral faces. In addition to neutral faces, we included two further baseline conditions, houses and fixation. We found increased amygdala activation in s-allele carriers relative to l-homozygotes in response to angry faces compared to neutral faces, houses and fixation. When comparing neutral faces to houses or fixation, we found no significant difference in amygdala response between the two groups. In addition, there was no significant difference between the groups in response to fixation when compared with a houses baseline. Overall, these results suggest that the increased amygdala response observed in s-allele carriers to emotional faces is primarily driven by an increased response to emotional faces rather than a decreased response to neutral faces or an increased resting baseline. The results are discussed in relation to the tonic and phasic hypotheses of 5-HTTLPR-mediated modulation of amygdala activity.     

Piccolo genotype modulates neural correlates of emotion processing but not executive functioning

Major depressive disorder (MDD) is characterized by affective symptoms and cognitive impairments, which have been associated with changes in limbic and prefrontal activity as well as with monoaminergic neurotransmission. A genome-wide association study implicated the polymorphism rs2522833 in the piccolo (PCLO) gene—involved in monoaminergic neurotransmission—as a risk factor for MDD. However, the role of the PCLO risk allele in emotion processing and executive function or its effect on their neural substrate has never been studied. We used functional magnetic resonance imaging (fMRI) to investigate PCLO risk allele carriers vs noncarriers during an emotional face processing task and a visuospatial planning task in 159 current MDD patients and healthy controls. In PCLO risk allele carriers, we found increased activity in the left amygdala during processing of angry and sad faces compared with noncarriers, independent of psychopathological status. During processing of fearful faces, the PCLO risk allele was associated with increased amygdala activation in MDD patients only. During the visuospatial planning task, we found no genotype effect on performance or on BOLD signal in our predefined areas as a function of increasing task load. The PCLO risk allele was found to be specifically associated with altered emotion processing, but not with executive dysfunction. Moreover, the PCLO risk allele appears to modulate amygdala function during fearful facial processing in MDD and may constitute a possible link between genotype and susceptibility for depression via altered processing of fearful stimuli. The current results may therefore aid in better understanding underlying neurobiological mechanisms in MDD.     

A process-specific functional dissociation of the amygdala in emotional memory

Converging evidence highlights the important role of the amygdala in the enhanced memory for emotional material. However, it is unknown whether any regional and/or hemispheric specificity exists regarding its involvement in the different memory stages, such as encoding and retrieval. We directly addressed this issue by conducting an event-related functional magnetic resonance imaging study of memory for faces with different emotional expressions, in which both encoding and recognition were scanned. We found significant amygdala activation associated with both successful encoding and retrieval of fearful faces. Critically, a direct comparison between both stages revealed that whereas the right amygdala was involved in emotional memory formation, the retrieval of those memories relied on the left amygdala. Thus, this study demonstrates a hemispheric dissociation of amygdala involvement in different stages of emotional memory in humans.     

Predictors of amygdala activation during the processing of emotional stimuli: a meta-analysis of 385 PET and fMRI studies

Although amygdala activity has been purported to be modulated by affective and non-affective factors, considerable controversy remains on its precise functional nature. We conducted a meta-analysis of 385 functional neuroimaging studies of emotional processing, examining the effects of experimental characteristics on the probability of detecting amygdala activity. All emotional stimuli were associated with higher probability of amygdala activity than neutral stimuli. Comparable effects were observed for most negative and positive emotions, however there was a higher probability of activation for fear and disgust relative to happiness. The level of attentional processing affected amygdala activity, as passive processing was associated with a higher probability of activation than active task instructions. Gustatory-olfactory and visual stimulus modalities increased the probability of activation relative to internal stimuli. Aversive learning increased the probability of amygdala activation as well. There was some evidence of hemispheric specialization with a relative left-lateralization for stimuli containing language and a relative right-lateralization for masked stimuli. Methodological variables, such as type of analysis and magnet strength, were also independent predictors of amygdala activation.