Amygdala and orbitofrontal reactivity to social threat in individuals with impulsive aggression.

BACKGROUND: Converging evidence from animal and human lesion studies implicates the amygdala and orbitofrontal cortex (OFC) in emotional regulation and aggressive behavior. However, it remains unknown if functional deficits exist in these specific brain regions in clinical populations in which the cardinal symptom is impulsive aggression. We have previously shown that subjects diagnosed with intermittent explosive disorder (IED), a psychiatric disorder characterized by reactive aggressive behavior, perform poorly on facial emotion recognition tasks. In this study we employed a social-emotional probe of amygdala-OFC function in individuals with impulsive aggression. METHODS: Ten unmedicated subjects with IED and 10 healthy, matched comparison subjects (HC) underwent functional magnetic resonance imaging while viewing blocks of emotionally salient faces. We compared amygdala and OFC reactivity to faces between IED and HC subjects, and examined the relationship between the extent of activation in these regions and extent of prior history of aggressive behavior. RESULTS: Relative to controls, individuals with IED exhibited exaggerated amygdala reactivity and diminished OFC activation to faces expressing anger. Extent of amygdala and OFC activation to angry faces were differentially related to prior aggressive behavior across subjects. Unlike controls, aggressive subjects failed to demonstrate amygdala-OFC coupling during responses to angry faces. CONCLUSIONS: These findings provide evidence of amygdala-OFC dysfunction in response to an ecologically-valid social threat signal (processing angry faces) in individuals with a history of impulsive aggressive behavior, and further substantiate a link between a dysfunctional cortico-limbic network and aggression.     

The neural substrates of affective processing toward positive and negative affective pictures in patients with major depressive disorder

Previous studies examining neural responses to emotional stimuli in individuals with major depressive disorder (MDD) have indicated increased responses within the left amygdala to sad faces, and increased activity within the visual cortex and striatum to expressions of happiness. Using functional magnetic resonance imaging (fMRI), the current study measured neural responses to neutral, positive and negative pictures of the International Affective Picture System in 15 healthy individuals and 15 patients with MDD. Depressed individuals demonstrated lower activity in the right hippocampus and the right insula to negative affective pictures, whereas they showed lower activity in the right anterior cingulate cortex and the left insula to positive pictures. However, within the MDD group, the severity of depression correlated with the activity of the left amygdala, bilateral inferior orbitofrontal areas, and the left insula to negative pictures, whereas there were no clear indications of association between specific cerebral regions and positive pictures. Our findings indicate that preferential decreases in the left amygdala in response to negative pictures might be involved in the processing of emotional stimuli in depressed individuals. Also, these findings suggest that the bilateral inferior orbitofrontal cortices and left amygdala may be preferentially recruited in MDD patients, but not in healthy individuals.     

Orbito‐frontal cortex mechanism of inhibition of return in current and remitted depression

Deficient inhibition of return (IOR) for emotional materials is an important cognitive biomarker of depression. However, its neural mechanism and role in depression remission remain largely unknown. Using functional magnetic resonance imaging (fMRI), this study observed the neural foundation of inhibition of return in individuals with current (n = 30) and remitted (n = 27) depression and in healthy controls (n = 33), by using a cue‐target task. The results showed that individuals with remitted depression (RMD) possessed a nonavoidant attention model for sad faces, which indicated a cue validity and was correlated with enhanced task‐ and resting‐state activation and function connectivity in orbitofrontal cortex (OFC). The patients with major depressive disorder (MDD), in contrast, displayed an IOR effect for all faces, which indicated a strategy of attention avoidance due to the high cognitive burden in the cue‐target task, and was correlated with decreased resting‐state activation and function connectivity in OFC. Moreover, the hippocampus, a less‐known cortex in IOR, showed a contrary model, that is, lower activation in depression remission and higher task‐ and resting‐state activation in depressive episodes. The results suggest the OFC mechanism of the IOR effect in remitted depression and the hippocampus mechanism of the IOR effect in depressive episodes, which offer potential biomarkers for the clinical treatment of depression.     

Anatomic evaluation of the orbitofrontal cortex in major depressive disorder.

BACKGROUND: The orbitofrontal cortex (OFC) plays a major role in neuropsychologic functioning including exteroceptive and interoceptive information coding, reward-guided behavior, impulse control, and mood regulation. This study examined the OFC and its subdivisions in patients with MDD and matched healthy control subjects. METHODS: Magnetic resonance imaging (MRI) was performed on 31 unmedicated MDD and 34 control subjects matched for age, gender, and race. Gray matter volumes of the OFC and its lateral and medial subdivisions were measured blindly. RESULTS: The MDD patients had smaller gray matter volumes in right medial [two-way analysis of covariance F(1,60) = 4.285; p =.043] and left lateral OFC [F(1,60) = 4.252; p =.044]. Left lateral OFC volume correlated negatively with age in patients but not in control subjects. Male, but not female patients exhibited smaller left and right medial OFC volumes compared with healthy control subjects of the same gender. CONCLUSIONS: These findings suggest that patients with MDD have reduced OFC gray matter volumes. Although this reduction might be important in understanding the pathophysiology of MDD, its functional and psychopathologic consequences are as yet unclear. Future studies examining the relationship between specific symptomatic dimensions of MDD and OFC volumes could be especially informative.     

Early life trauma and directional brain connectivity within major depression

Objective: Early life trauma (ELT) is a significant risk factor for the onset of depression. Emerging findings indicate ELT is associated with enhanced amygdala reactivity to aversive stimuli in never‐depressed healthy controls as well as those with acute depression but may be absent in non‐ELT exposed depressed. The precise mechanism mediating these differences in amygdala reactivity remains unclear. Method: The authors used Granger causality methods to evaluate task‐based directional connectivity between medial or lateral prefrontal cortex (PFC) and amygdala in 20 unmedicated patients with current major depressive disorder (MDD) and 19 healthy matched controls while participants engaged in an affective variant of the flanker task comparing response to sad and neutral faces. These data were correlated with childhood trauma history. Results: Exposure to ELT was associated with failure of inhibition within the MDD group based on medial PFC–amygdala connectivity. In contrast, non‐ELT exposed MDD was associated with a negative causal pathway from medial prefrontal cortex to amygdala, despite reduced dorsolateral PFC input in comparison to healthy controls. Neither MDD group demonstrated significant lateral PFC–amygdala connectivity in comparison to healthy controls. Conclusions: Failure of the circuit implicated in emotion regulation was associated with a significant history of ELT but not with MDD more broadly. Non‐ELT related depression was associated with intact regulation of emotion despite the absence of difference in severity of illness. These findings indicate opposing system‐level differences within depression relative to ELT are expressed as differential amygdala reactivity. Hum Brain Mapp 35:4815–4826, 2014. © 2014 Wiley Periodicals, Inc .     

Organization of afferents to the orbitofrontal cortex in the rat

The prefrontal cortex (PFC) is usually defined as the frontal cortical area receiving a mediodorsal thalamic (MD) innervation. Certain areas in the medial wall of the rat frontal area receive a MD innervation. A second frontal area that is the target of MD projections is located dorsal to the rhinal sulcus and often referred to as the orbitofrontal cortex (OFC). Both the medial PFC and OFC are comprised of a large number of cytoarchitectonic regions. We assessed the afferent innervation of the different areas of the OFC, with a focus on projections arising from the mediodorsal thalamic nucleus, the basolateral nucleus of the amygdala, and the midbrain dopamine neurons. Although there are specific inputs to various OFC areas, a simplified organizational scheme could be defined, with the medial areas of the OFC receiving thalamic inputs, the lateral areas of the OFC being the recipient of amygdala afferents, and a central zone that was the target of midbrain dopamine neurons. Anterograde tracer data were consistent with this organization of afferents, and revealed that the OFC inputs from these three subcortical sites were largely spatially segregated. This spatial segregation suggests that the central portion of the OFC (pregenual agranular insular cortex) is the only OFC region that is a prefrontal cortical area, analogous to the prelimbic cortex in the medial prefrontal cortex. These findings highlight the heterogeneity of the OFC, and suggest possible functional attributes of the three different OFC areas.     

Beauty in a smile: the role of medial orbitofrontal cortex in facial attractiveness

The attractiveness of a face is a highly salient social signal, influencing mate choice and other social judgements. In this study, we used event-related functional magnetic resonance imaging (fMRI) to investigate brain regions that respond to attractive faces which manifested either a neutral or mildly happy face expression. Attractive faces produced activation of medial orbitofrontal cortex (OFC), a region involved in representing stimulus-reward value. Responses in this region were further enhanced by a smiling facial expression, suggesting that the reward value of an attractive face as indexed by medial OFC activity is modulated by a perceiver directed smile.     

Deficient inhibition of return for emotional faces in depression

Depression is a commonly-occurred mental disorder. Researchers have highlighted the attentional bias of depressive disorders, although results have been mixed. The cue-target task has often been used to explore attentional bias; a particular phenomenon revealed by such studies is the inhibition of return (IOR). However, cue-target task has seldom been used so far in the study of depressed patients. The aim of the present study was to investigate the IOR phenomenon in depressed individuals in cue-target task using emotional faces as cues.Control participants who had never suffered depression (NC), participants who had experienced at least two depressive episodes in their lives but were currently remitted (RMD), and participants diagnosed with a current major depressive disorder (MDD), were recruited using BDI, BAI, HDRS and DSM-IV as tools. Seventeen participants in each group completed a cue-target task in a behavioral experiment that comprised three kinds of experimental condition, two cue types and four face types. Each participant also completed a simpler cue-target task in an event-related potential (ERP) experiment. In cue-target task, a target appeared after a cue and the participant responded to its location.In the behavioral experiment, it was found that when the stimulus onset asynchrony (SOA) was 14 ms, the NC and RMD participants had IOR effects for all faces and MDD participants for angry and sad faces. When the SOA was 250 ms, all three groups all had cue validity for sad faces but the effect was much more marked for the MDD group. When the SOA was 750 ms, the NC participants had an IOR effect for sad faces, the RMD participants had cue validity for angry, happy and sad faces, and the MDD participants had cue validity for sad faces and an IOR effect for angry faces. In the ERP experiment, the NC participants showed bigger P3 amplitude for happy cue compared with the other groups, smaller P1 amplitude for happy faces in the invalid cue condition than for other faces, smaller P1 amplitude for sad faces in the valid cue condition than for happy faces, bigger P3 amplitude for happy faces in the valid cue condition compared with MDD participants, and bigger P3 amplitude for sad faces in the invalid cue condition compared with other groups. The RMD participants had larger P3 amplitude for sad cue than for other faces, larger P3 amplitude for happy faces in the valid cue condition compared with MDD participants, and smaller P3 amplitude for sad faces in the invalid cue condition compared with NC participants. The MDD participants had larger P1 amplitude for sad cue compared with other groups, larger P3 amplitude for sad cue than for other face cues, smaller P3 amplitude for sad faces in the invalid cue condition compared with NC participants, and smaller P3 amplitude for happy faces in the valid cue condition compared with other groups.It can be concluded that the MDD participants had cue validity and deficient IOR for negative stimuli. The deficient inhibition of negative stimuli renders them unable to eliminate the interference of negative stimuli and causes the maintenance and development of depression. The RMD participants had cue validity and deficient IOR for both positive and negative stimuli, which enables them to perceive positive and negative stimuli sufficiently and to maintain emotional balance.     

Preferential responses to faces in superior temporal and medial prefrontal cortex in three-year-old children

Perceiving faces and understanding emotions are key components of human social cognition. Prior research with adults and infants suggests that these social cognitive functions are supported by superior temporal cortex (STC) and medial prefrontal cortex (MPFC). We used functional near-infrared spectroscopy (fNIRS) to characterize functional responses in these cortical regions to faces in early childhood. Three-year-old children (n = 88, M(SD) = 3.15(.16) years) passively viewed faces that varied in emotional content and valence (happy, angry, fearful, neutral) and, for fearful and angry faces, intensity (100%, 40%), while undergoing fNIRS. Bilateral STC and MPFC showed greater oxygenated hemoglobin concentration values to all faces relative to objects. MPFC additionally responded preferentially to happy faces relative to neutral faces. We did not detect preferential responses to angry or fearful faces, or overall differences in response magnitude by emotional valence (100% happy vs. fearful and angry) or intensity (100% vs. 40% fearful and angry). In exploratory analyses, preferential responses to faces in MPFC were not robustly correlated with performance on tasks of early social cognition. These results link and extend adult and infant research on functional responses to faces in STC and MPFC and contribute to the characterization of the neural correlates of early social cognition.     

Reduced activation in the mirror neuron system during a virtual social cognition task in euthymic bipolar disorder

Social cognition entails both cognitive and affective processing, and impairments in both have accounted for residual symptoms of bipolar disorder (BD). However, there has been a lack of studies identifying neural substrates responsible for social cognitive difficulties in BD patients. Fourteen euthymic BD patients and 14 healthy normal controls underwent functional MRI while performing a virtual reality social cognition task, which incorporated both cognitive and emotional dimensions, simulating real-world social situations. During the scanning, subjects tried to guess (attribute) possible reasons for expressed emotion of virtual humans (avatars) while viewing their facial expressions, just after observing their verbal and nonverbal (facial) expressions which were emotionally valenced (happy, angry and neutral). BD patients compared to normal controls showed delayed reaction times in emotional conditions, with comparable response accuracy. Healthy normal controls activated the right anterior cingulate cortex, inferior frontal, and insular cortex in emotional conditions contrasted with neutral control conditions, that is, the regions that have been related to empathic processes during viewing others' emotional expression. Relative to normal controls, BD patients showed reduced activations in the ‘mirror neuron system’, including the right inferior frontal cortex, premotor cortex, and insula, mainly in angry or happy condition. These results may suggest that, even during euthymic state, BD patients have difficulties in recruiting brain regions for the utilization of emotional cues as a means for understanding others. Clinical attention should be paid to emotion-related residual symptoms to help improve social outcomes in these patients.