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1.  Neural correlates of social exclusion during adolescence: understanding the distress of peer rejection 
Developmental research has demonstrated the harmful effects of peer rejection during adolescence; however, the neural mechanisms responsible for this salience remain unexplored. In this study, 23 adolescents were excluded during a ball-tossing game in which they believed they were playing with two other adolescents during an fMRI scan; in reality, participants played with a preset computer program. Afterwards, participants reported their exclusion-related distress and rejection sensitivity, and parents reported participants’ interpersonal competence. Similar to findings in adults, during social exclusion adolescents displayed insular activity that was positively related to self-reported distress, and right ventrolateral prefrontal activity that was negatively related to self-reported distress. Findings unique to adolescents indicated that activity in the subgenual anterior cingulate cortex (subACC) related to greater distress, and that activity in the ventral striatum related to less distress and appeared to play a role in regulating activity in the subACC and other regions involved in emotional distress. Finally, adolescents with higher rejection sensitivity and interpersonal competence scores displayed greater neural evidence of emotional distress, and adolescents with higher interpersonal competence scores also displayed greater neural evidence of regulation, perhaps suggesting that adolescents who are vigilant regarding peer acceptance may be most sensitive to rejection experiences.
PMCID: PMC2686232  PMID: 19470528
peer rejection; adolescence; functional magnetic resonance imaging
2.  Are You Being Rejected or Excluded? Insights from Neuroimaging Studies Using Different Rejection Paradigms 
Rejection sensitivity is the heightened tendency to perceive or anxiously expect disengagement from others during social interaction. There has been a recent wave of neuroimaging studies of rejection. The aim of the current review was to determine key brain regions involved in social rejection by selectively reviewing neuroimaging studies that employed one of three paradigms of social rejection, namely social exclusion during a ball-tossing game, evaluating feedback about preference from peers and viewing scenes depicting rejection during social interaction. Across the different paradigms of social rejection, there was concordance in regions for experiencing rejection, namely dorsal anterior cingulate cortex (ACC), subgenual ACC and ventral ACC. Functional dissociation between the regions for experiencing rejection and those for emotion regulation, namely medial prefrontal cortex, ventrolateral prefrontal cortex (VLPFC) and ventral striatum, was evident in the positive association between social distress and regions for experiencing rejection and the inverse association between social distress and the emotion regulation regions. The paradigms of social exclusion and scenes depicting rejection in social interaction were more adept at evoking rejection-specific neural responses. These responses were varyingly influenced by the amount of social distress during the task, social support received, self-esteem and social competence. Presenting rejection cues as scenes of people in social interaction showed high rejection sensitive or schizotypal individuals to under-activate the dorsal ACC and VLPFC, suggesting that such individuals who perceive rejection cues in others down-regulate their response to the perceived rejection by distancing themselves from the scene.
PMCID: PMC3569164  PMID: 23430682
Social distance; Gyrus cinguli; Prefrontal cortex; Social support
3.  An fMRI investigation of responses to peer rejection in adolescents with autism spectrum disorders 
Peer rejection is particularly pervasive among adolescents with autism spectrum disorders (ASD). However, how adolescents with ASD differ from typically developing adolescents in their responses to peer rejection is poorly understood. The goal of the current investigation was to examine neural responses to peer exclusion among adolescents with ASD compared to typically developing adolescents. Nineteen adolescents with ASD and 17 typically developing controls underwent fMRI as they were ostensibly excluded by peers during an online game called Cyberball. Afterwards, participants reported their distress about the exclusion. Compared to typically developing adolescents, those with ASD displayed less activity in regions previously linked with the distressing aspect of peer exclusion, including the subgenual anterior cingulate and anterior insula, as well as less activity in regions previously linked with the regulation of distress responses during peer exclusion, including the ventrolateral prefrontal cortex and ventral striatum. Interestingly, however, both groups self-reported equivalent levels of distress. This suggests that adolescents with ASD may engage in differential processing of social experiences at the neural level, but be equally aware of, and concerned about, peer rejection. Overall, these findings contribute new insights about how this population may differentially experience negative social events in their daily lives.
PMCID: PMC3272329  PMID: 22318914
Autism spectrum disorders; Peer rejection; Social exclusion; Adolescence; Functional magnetic resonance imaging
4.  Self-esteem Modulates Medial Prefrontal Cortical Responses to Evaluative Social Feedback 
Cerebral Cortex (New York, NY)  2010;20(12):3005-3013.
Self-esteem is a facet of personality that influences perception of social standing and modulates the salience of social acceptance and rejection. As such, self-esteem may bias neural responses to positive and negative social feedback across individuals. During functional magnetic resonance imaging scanning, participants (n = 42) engaged in a social evaluation task whereby they ostensibly received feedback from peers indicating they were liked or disliked. Results demonstrated that individuals with low self-esteem believed that they received less positive feedback from others and showed enhanced activity to positive versus negative social feedback in the ventral anterior cingulate cortex/medial prefrontal cortex (vACC/mPFC). By contrast, vACC/mPFC activity was insensitive to positive versus negative feedback in individuals with high self-esteem, and these individuals consistently overestimated the amount of positive feedback received from peers. Voxelwise analyses supported these findings; lower self-esteem predicted a linear increase in vACC/mPFC response to positive versus negative social feedback. Taken together, the present findings propose a functional role for the vACC/mPFC in representing the salience of social feedback and shaping perceptions of relative social standing.
PMCID: PMC2978246  PMID: 20351022
anterior cingulate cortex; fMRI; medial prefrontal cortex; self-esteem; social
5.  Resting-State Functional Connectivity of Subgenual Anterior Cingulate Cortex in Depressed Adolescents 
Biological psychiatry  2013;74(12):898-907.
Very few studies have been performed to understand the underlying neural substrates of adolescent major depressive disorder (MDD). Studies in depressed adults have demonstrated that the subgenual anterior cingulate cortex (sgACC) plays a pivotal role in depression and have revealed aberrant patterns of resting-state functional connectivity (RSFC). Here, we examine the RSFC of the sgACC in medication-naïve first-episode adolescents with MDD.
Twenty-three adolescents with MDD and 36 well-matched control subjects underwent functional magnetic resonance imaging to assess the RSFC of the sgACC.
We observed elevated connectivity between the sgACC and the insula and between the sgACC and the amygdala in the MDD group compared with the control subjects. Decreased connectivity between the sgACC and the precuneus was also found in the MDD group relative to the control subjects. Within the MDD group, higher levels of depression significantly correlated with decreased connectivity between the sgACC and left precuneus. Increased rumination was significantly associated with reduced connectivity between sgACC and the middle and inferior frontal gyri in the MDD group.
Our study is the first to examine sgACC connectivity in medication-naïve first-episode adolescents with MDD compared with well-matched control participants. Our results suggest aberrant functional connectivity among the brain networks responsible for salience attribution, executive control, and the resting-state in the MDD group compared with the control participants. Our findings raise the possibility that therapeutic interventions that can restore the functional connectivity among these networks to that typical of healthy adolescents might be a fruitful avenue for future research.
PMCID: PMC4103629  PMID: 23910949
Adolescent major depression; amygdala; default mode network; insula; resting-state; subgenual anterior cingulate
6.  Time spent with friends in adolescence relates to less neural sensitivity to later peer rejection 
Involvement with friends carries many advantages for adolescents, including protection from the detrimental effects of being rejected by peers. However, little is known about the mechanisms through which friendships may serve their protective role at this age, or the potential benefit of these friendships as adolescents transition to adulthood. As such, this investigation tested whether friend involvement during adolescence related to less neural sensitivity to social threats during young adulthood. Twenty-one adolescents reported the amount of time they spent with friends outside of school using a daily diary. Two years later they underwent an fMRI scan, during which they were ostensibly excluded from an online ball-tossing game by two same-age peers. Findings from region of interest and whole brain analyses revealed that spending more time with friends during adolescence related to less activity in the dorsal anterior cingulate cortex and anterior insula—regions previously linked with negative affect and pain processing—during an experience of peer rejection 2 years later. These findings are consistent with the notion that positive relationships during adolescence may relate to individuals being less sensitive to negative social experiences later on.
PMCID: PMC3252626  PMID: 21183457
adolescence; friendship; peer rejection; functional magnetic resonance imaging
7.  Rostral anterior cingulate cortex volume correlates with depressed mood in normal healthy children 
Biological psychiatry  2007;63(4):391-397.
The rostral anterior cingulate cortex (rACC) has been implicated as a structural neural correlate of familial major depressive disorder, raising the possibility that the structure of this region may act as a biologic marker of depression vulnerability. The aim of the current study was to determine whether children and adolescents with depressive symptoms have lower rACC volume relative to those without symptoms and examine how a positive family history of depression affects this relationship.
112 normal healthy children (59 boys, 53 girls), age 7–17, without a current diagnosis or history of depression or other psychiatric illness, were recruited from the community. Mood symptoms were collected using the Pediatric Behavior Scale, a parent- and teacher-reported questionnaire. Volumetric measures of the rACC were generated using structural MRI. The relationship of depressive symptoms and rACC volume was examined.
1) The rACC volume was significantly lower in boys with subclinical depressive symptoms compared to boys with no depressive symptoms, particularly on the left side (14.6% reduction; F = 8.90, p = .005). 2) In comparing the correlation of depressive symptoms and rACC volume in boys with a positive family history of depression to those with no family history there was a more robust negative correlation in subjects with a positive family history. 3) In girls there was not a significant association of depressive symptoms and rACC volume.
These findings lend further support to the notion that rACC structure may act as a biologic marker of vulnerability or trait-marker of depression.
PMCID: PMC2265665  PMID: 17916329
Depression; FreeSurfer; children; anterior cingulate; subgenual
8.  Reduced anterior cingulate gray matter volume in treatment-naïve clinically depressed adolescents☆ 
NeuroImage : Clinical  2014;4:336-342.
Adolescent depression is associated with increased risk for suicidality, social and educational impairment, smoking, substance use, obesity, and depression in adulthood. It is of relevance to further our insight in the neurobiological mechanisms underlying this disorder in the developing brain, as this may be essential to optimize treatment and prevention of adolescent depression and its negative clinical trajectories. The equivocal findings of the limited number of studies on neural abnormalities in depressed youth stress the need for further neurobiological investigation of adolescent depression. We therefore performed a voxel-based morphometry study of the hippocampus, amygdala, superior temporal gyrus, and anterior cingulate cortex (ACC) in 26 treatment-naïve, clinically depressed adolescents and 26 pair-wise matched healthy controls. Additionally, an exploratory whole-brain analysis was performed. Clinically depressed adolescents showed a volume reduction of the bilateral dorsal ACC compared to healthy controls. However, no association was found between gray matter volume of the ACC and clinical severity scores for depression or anxiety. Our finding of a smaller ACC in clinically depressed adolescents is consistent with literature on depressed adults. Future research is needed to investigate if gray matter abnormalities precede or follow clinical depression in adolescents.
•Voxel-based morphometry ROI and exploratory whole-brain analyses were performed•Depressed adolescents showed a smaller anterior cingulate cortex compared to healthy controls•No association found between gray matter volume of the effect and clinical scores for depression
PMCID: PMC3913835  PMID: 24501702
Depression; Anxiety; Adolescents; MRI; Voxel-based morphometry; Anterior cingulate cortex
9.  Depressed adolescents demonstrate greater subgenual anterior cingulate activity 
Neuroreport  2009;20(4):440-444.
Neuroimaging studies implicate the subgenual anterior cingulate cortex (sgACC) as a critical brain region in adult depression. However, unlike adult depression, little is known about the underlying neural substrates of adolescent depression, and there are no published data examining differences in sgACC activation between depressed and healthy adolescents. This study used functional magnetic resonance imaging to examine sgACC activity in twenty-six depressed and normal 13- to 17-year olds during the performance of a stop-signal task. Significantly greater sgACC activation was found in the depressed adolescents relative to controls. These results establish for the first time abnormal functioning of the sgACC in depressed adolescents and have important implications for understanding the underlying neural correlates and potential treatments of adolescent depression.
PMCID: PMC2672880  PMID: 19218875
adolescent; depression; FMRI; subgenual anterior cingulate cortex; prefrontal cortex; major depressive disorder; functional neuroimaging; functional MRI; pediatrics; mood disorder
10.  Altered functional connectivity in posttraumatic stress disorder with versus without comorbid major depressive disorder: a resting state fMRI study 
F1000Research  2014;2:289.
Posttraumatic stress disorder (PTSD) is an anxiety disorder that is often diagnosed with comorbid depressive disorder. Therefore, neuroimaging studies investigating PTSD typically include both patients with and without comorbid depression. Differences in activity of the anterior cingulate cortex (ACC) and insula have been shown to differentiate PTSD patients with and without major depressive disorder (MDD). Whether or not comorbid MDD affects resting state functional connectivity of PTSD patients has not been investigated to our knowledge. Here, resting state functional connectivity of PTSD patients with (PTSD+MDD; n=27) and without (PTSD-MDD; n=23) comorbid MDD was investigated. The subgenual ACC and insula were investigated as seed regions. Connectivity between the subgenual ACC and perigenual parts of the ACC was increased in PTSD+MDD versus PTSD-MDD, which may reflect the presence of depressive specific symptoms such as rumination. Functional connectivity of the subgenual ACC with the thalamus was reduced, potentially related to more severe deficits in executive functioning in the PTSD+MDD group versus the PTSD-MDD group. In addition, the PTSD+MDD group showed reduced functional connectivity of the insula with the hippocampus compared to the PTSD-MDD group. However, this cluster was no longer significantly different when PTSD patients that were using medication were excluded from analyses. Thus, resting state functional connectivity of the subgenual ACC can distinguish PTSD+MDD from PTSD-MDD, and this may therefore be used as a neurobiological marker for comorbid MDD in the presence of PTSD. As PTSD+MDD are more treatment resistant, these findings can also guide treatment development, for example by targeting the subgenual ACC network with treatment.
PMCID: PMC4184309  PMID: 25309726
11.  The Subgenual Anterior Cingulate Cortex in Mood Disorders 
CNS spectrums  2008;13(8):663-681.
In the latest edition of our series of neuroanatomical areas of importance for neuropsychiatry, Wayne Drevets, MD, and Jonathan Savitz, PhD, have outlined the clinical importance of the ventral anterior cingulate structures for the regulation of mood. This area was an early target for interventional neurosurgery for depression some half a century ago, and today has become one of the key sites of deep brain stimulation for affective disorders. The anterior cingulate cortex was a part of the initial circuit of Papez thought to be related to the regulation of emotion. However, since then, much experimental work has outlined different cingulate regions with differing anatomical connectivity and functions. Drevets and Savitz draw attention to the subgenual area and describe the local and distant anatomical connectivities that emphasize its relevance for several neuropsychiatric disorders.
The anterior cingulate cortex (ACC) ventral to the genu of the corpus callosum has been implicated in the modulation of emotional behavior on the basis of neuroimaging studies in humans and lesion analyses in experimental animals. In a combined positron emission tomography/magnetic resonance imaging study of mood disorders, we demonstrated that the mean gray matter volume of this “subgenual” ACC (sgACC) cortex is abnormally reduced in subjects with major depressive disorder (MDD) and bipolar disorder, irrespective of mood state. Neuropathological assessments of sgACC tissue acquired postmortem from subjects with MDD or bipolar disorder confirmed the decrement in gray matter volume, and revealed that this abnormality was associated with a reduction in glia, with no equivalent loss of neurons. In positron emission tomography studies, the metabolic activity was elevated in this region in the depressed relative to the remitted phases of the same MDD subjects, and effective antidepressant treatment was associated with a reduction in sgACC activity. Other laboratories replicated and extended these findings, and the clinical importance of this treatment effect was underscored by a study showing that deep brain stimulation of the sgACC ameliorates depressive symptoms in treatment-resistant MDD. This article discusses the functional significance of these findings within the context of the preclinical literature that implicates the putative homologue of this region in the regulation of emotional behavior and stress response. In experimental animals, this region participates in an extended “visceromotor network” of structures that modulates autonomic/neuroendocrine responses and neurotransmitter transmission during the neural processing of reward, fear, and stress. These data thus hold important implications for the development of neural models of depression that can account for the abnormal motivational, neuroendocrine, autonomic, and emotional manifestations evident in human mood disorders.
PMCID: PMC2729429  PMID: 18704022
12.  Neural circuitry underlying affective response to peer feedback in adolescence 
Peer feedback affects adolescents’ behaviors, cognitions and emotions. We examined neural circuitry underlying adolescents’ emotional response to peer feedback using a functional neuroimaging paradigm whereby, 36 adolescents (aged 9–17 years) believed they would interact with unknown peers postscan. Neural activity was expected to vary based on adolescents’ perceptions of peers and feedback type. Ventrolateral prefrontal cortex (vlPFC) activity was found when adolescents indicated how they felt following feedback (acceptance or rejection) from peers of low vs high interest. Greater activation in both cortical (e.g. superior temporal gyrus, insula, anterior cingulate) and subcortical (e.g. striatum, thalamus) regions emerged in response to acceptance vs rejection feedback. Response to acceptance also varied by age and gender in similar regions (e.g. superior temporal gyrus, fusiform, insula), with greater age-related increases in activation to acceptance vs rejection for females than males. Affective response to rejection vs acceptance did not yield significantly greater neural activity in any region. vlPFC response suggests cognitive flexibility in reappraising initial perceptions of peers following feedback. Striatal response suggests that acceptance is a potent social reward for adolescents, an interpretation supported by more positive self-reported affective response to acceptance than rejection from high- but not low-interest peers.
PMCID: PMC3252630  PMID: 21828112
adolescence; cognitive flexibility; peer feedback; social reward
13.  Gene expression in the anterior cingulate cortex and amygdala of adolescent marmoset monkeys following parental separations in infancy 
Early life adversities are risk factors for later mood and emotional disorders. Repeated separation of infant marmosets from their parents provides a validated primate model of depression vulnerability, producing in vivo biochemical and behavioural effects indicative of persistently altered stress reactivity and mild anhedonia. Here we report the long-term effect (in adolescence) of this intervention on the expression of synaptophysin, GAP-43, VGluT1, VGAT, MAP-2, spinophilin, and 5-HT1A and 5-HT2A receptors, in the anterior cingulate cortex (ACC; supragenual and subgenual areas) and amygdala (lateral, basal and central nuclei). These genes and regions are implicated in the response to stress or in mood disorder. The profile of 5-HT1A receptor binding in ACC was affected by early deprivation, notably in the subgenual region, with a decrease in deep laminae but an increase in superficial laminae. Following early deprivation, spinophilin was reduced in the subgenual ACC. In the amygdala, no significant effects of the manipulation were seen, but expression of several transcripts was sexually dimorphic. There were correlations between expression of some transcripts and in vivo measurements. The results show that early deprivation in a non-human primate has a selective long-term effect on expression of genes in the ACC, particularly the subgenual area. The results differ from those reported in the hippocampus of the same animals, indicating the presence of limbic region-specific long-term molecular responses to early life stress.
PMCID: PMC2695425  PMID: 19102816
Subgenual area; serotonin 1A receptor; Depression; Mood disorder; Sexual dimorphism
14.  Response to learned threat: an fMRI study in adolescent and adult anxiety 
The American journal of psychiatry  2013;170(10):1195-1204.
Poor threat-safety discrimination reflects prefrontal cortex dysfunction in adult anxiety disorders. While adolescent anxiety disorders are impairing and predict high risk for adult anxiety disorders, no prior study examines neural correlates of threat-safety discrimination in this group. The current study compares prefrontal cortex function in anxious and healthy adolescents and adults following conditioning and extinction, processes requiring threat-safety learning.
Anxious and healthy adolescents and adults (n=114) completed fear conditioning and extinction in the clinic. Conditioned stimuli (CS+) were neutral faces, paired with an aversive scream. Physiological and subjective data were acquired. Several weeks later, 82 participants viewed the CS+ and morphed images resembling the CS+ in a magnetic resonance imaging (MRI) scanner. During scanning, participants made difficult threat-safety discriminations while appraising threat and explicit memory of the CS+.
During conditioning and extinction, anxious groups reported more fear than healthy groups, but patient groups did not differ on physiology. During imaging, both anxious adolescents and adults exhibited lower sub-genual anterior cingulate (sgACC) activation than healthy peers, specifically when appraising threat. In ventromedial prefrontal cortex (vmPFC), relative to their age-matched peer groups, anxious adults exhibited reduced activation when appraising threat, whereas anxious adolescents exhibited a U-shaped pattern of activation, with greater activation to the most extreme CS and CS−.
Two regions of the prefrontal cortex are involved in anxiety disorders. Reduced sgACC engagement is a shared feature in adult and adolescent anxiety disorders, but vmPFC dysfunction is age-specific. The unique U-shaped pattern of vmPFC activation in many anxious adolescents could reflect heightened sensitivity to threat and safety conditions. How variations in the pattern relate to later risk for adult illness remains to be determined.
PMCID: PMC3790858  PMID: 23929092
15.  Adolescent subgenual anterior cingulate activity is related to harm avoidance 
Neuroreport  2009;20(1):19-23.
Recent adult studies suggest that the subgenual anterior cingulate cortex (sgACC) is involved in fundamental mental operations such as affective processing and inhibitory control. However, little is known about inhibition-associated sgACC function in adolescents, and there are no published data regarding whether personality characteristics are related to inhibition-associated sgACC brain activity in adolescents. This study examined the relationship between personality and inhibition-associated sgACC response in healthy adolescents. Seventeen adolescents of 13–17 years of age underwent functional magnetic resonance imaging while performing a parametric stop-signal task. Greater harm avoidance levels were significantly associated with increased inhibition-related sgACC activity. These results establish, for the first time, a link between personality and differential sgACC activation in adolescents.
PMCID: PMC2852645  PMID: 19034055
adolescents; emotion; functional MRI; harm avoidance; personality; subgenual anterior cingulate; temperament and character inventory
16.  Stress Response Circuitry Hypoactivation Related to Hormonal Dysfunction in Women with Major Depression 
Journal of affective disorders  2010;131(1-3):379-387.
Women have approximately twice the risk of major depressive disorder (MDD) than men, yet this difference remains largely unexplained. Previous MDD research suggests high rates of endocrine dysfunction, which may be related to deficits in brain activity in stress response circuitry [hypothalamus, amygdala, hippocampus, anterior cingulate cortex (ACC), orbitofrontal cortex (OFC)]. This functional magnetic resonance imaging (fMRI) study investigated the relationship between hypothalamic-pituitary-gonadal (HPG)-axis hormones and stress response circuitry dysfunction in MDD in women.
During the late follicular/midcycle phase of the menstrual cycle, female participants (10 with extensive histories of MDD, in remission, 10 healthy controls) were scanned while viewing negative and neutral arousal pictures. Group differences in blood oxygen-level dependent (BOLD) signal changes were analyzed using SPM2. Baseline gonadal hormones included estradiol, progesterone, and testosterone.
fMRI results showed greater BOLD signal intensity changes in controls versus MDD in hypothalamus, amygdala, hippocampus, OFC, ACC, and subgenual ACC, findings unrelated to medication status. MDD women had a lower serum estradiol and higher serum progesterone compared to controls. Hypoactivations in hypothalamus, subgenual ACC, amygdala and OFC in MDD were associated with low estradiol and high progesterone.
Generalizability of our findings is limited by small sample size and restriction to females, although this did not affect the internal validity of the results.
Hypoactivation of the stress response circuitry in MDD women is associated with dysregulation of the HPG-axis. Associations between brain activity deficits and hormonal disruption in MDD may ultimately contribute to understanding sex differences in MDD.
PMCID: PMC3073153  PMID: 21183223
Depression; stress; hormones; fMRI; HPG; women’s mental health; mood; HPA
17.  Serotonin Transporter Genotype Modulates Subgenual Response to Fearful Faces Using an Incidental Task 
Journal of cognitive neuroscience  2011;23(11):3681-3693.
This study assessed the impact of serotonin transporter genotype (5-HTTLPR) on regional responses to emotional faces in the amygdala and subgenual cingulate cortex (sgACC), while subjects performed a gender discrimination task. Although we found no evidence for greater amygdala reactivity or reduced amygdala–sgACC coupling in short variant 5-HTTLPR homozygotes (s/s), we observed an interaction between genotype and emotion in sgACC. Only long variant homozygotes (la/la) exhibited subgenual deactivation to fearful versus neutral faces, whereas the effect in s/s subjects was in the other direction. This absence of subgenual deactivation in s/s subjects parallels a recent finding in depressed subjects [Grimm, S., Boesiger, P., Beck, J., Schuepbach, D., Bermpohl, F., Walter, M., et al. Altered negative BOLD responses in the default-mode network during emotion processing in depressed subjects. Neuropsychopharmacology, 34, 932–943, 2009]. Taken together, the findings suggest that subgenual cingulate activity may play an important role in regulating the impact of aversive stimuli, potentially conferring greater resilience to the effects of aversive stimuli in la/la subjects. Using dynamic causal modeling of functional magnetic resonance imaging data, we explored the effects of genotype on effective connectivity and emotion-specific changes in coupling across a network of regions implicated in social processing. Viewing fearful faces enhanced bidirectional excitatory coupling between the amygdala and the fusiform gyrus, and increased the inhibitory influence of the amygdala over the sgACC, although this modulation of coupling did not differ between the genotype groups. The findings are discussed in relation to the role of sgACC and serotonin in moderating responses to aversive stimuli [Dayan, P., & Huys, Q. J., Serotonin, inhibition, and negative mood. PLoS Comput Biol, 4, e4, 2008; Mayberg, H. S., Liotti, M., Brannan, S. K., McGinnis, S., Mahurin, R. K., Jerabek, P. A., et al. Reciprocal limbic–cortical function and negative mood: Converging PET findings in depression and normal sadness. Am J Psychiatry, 156, 675–682, 1999].
PMCID: PMC3435845  PMID: 21568644
18.  Striatum-Based Circuitry of Adolescent Depression and Anhedonia 
Striatum-based circuits have been implicated in both major depressive disorder (MDD) and anhedonia, a symptom that reflects deficits of reward processing. Yet adolescents with MDD often exhibit a wide range of anhedonia severity. Addressing this clinical phenomenon, we aimed to use intrinsic functional connectivity (iFC) to study striatum-based circuitry in relation to categorical diagnosis of MDD and anhedonia severity.
A total of 21 psychotropic medication–free adolescents with MDD and 21 healthy controls (HC), group-matched for age and sex, underwent resting-state functional magnetic resonance imagining (fMRI) scans. Voxelwise maps indicating correlation strengths of spontaneous blood-oxygenation-level–dependent (BOLD) signals among 6 bilateral striatal seeds (dorsal caudate, ventral caudate, nucleus accumbens, dorsal-rostral putamen, dorsal-caudal putamen, ventral-rostral putamen) and the remaining brain regions were compared between groups. Relationships between striatal iFC and severity of MDD and anhedonia were examined in the MDD group. Analyses were corrected for multiple comparisons.
Adolescents with MDD manifested increased iFC between all striatal regions bilaterally and the dorsomedial prefrontal cortex (dmPFC), as well as between the right ventral caudate and the anterior cingulate cortex (ACC). MDD severity was associated with iFC between the striatum and midline structures including the precuneus, posterior cingulate cortex, and dmPFC. However, distinct striatal iFC patterns involving the pregenual ACC, subgenual ACC, supplementary motor area, and supramarginal gyrus were associated with anhedonia severity.
Although MDD diagnosis and severity were related to striatal networks involving midline cortical structures, distinct circuits within the reward system were associated with anhedonia.
PMCID: PMC3762469  PMID: 23702452
depression; functional connectivity; functional magnetic resonance imagining (fMRI); intrinsic functional connectivity (iFC)
19.  Severe depression is associated with increased microglial quinolinic acid in subregions of the anterior cingulate gyrus: Evidence for an immune-modulated glutamatergic neurotransmission? 
Immune dysfunction, including monocytosis and increased blood levels of interleukin-1, interleukin-6 and tumour necrosis factor α has been observed during acute episodes of major depression. These peripheral immune processes may be accompanied by microglial activation in subregions of the anterior cingulate cortex where depression-associated alterations of glutamatergic neurotransmission have been described.
Microglial immunoreactivity of the N-methyl-D-aspartate (NMDA) glutamate receptor agonist quinolinic acid (QUIN) in the subgenual anterior cingulate cortex (sACC), anterior midcingulate cortex (aMCC) and pregenual anterior cingulate cortex (pACC) of 12 acutely depressed suicidal patients (major depressive disorder/MDD, n = 7; bipolar disorder/BD, n = 5) was analyzed using immunohistochemistry and compared with its expression in 10 healthy control subjects.
Depressed patients had a significantly increased density of QUIN-positive cells in the sACC (P = 0.003) and the aMCC (P = 0.015) compared to controls. In contrast, counts of QUIN-positive cells in the pACC did not differ between the groups (P = 0.558). Post-hoc tests showed that significant findings were attributed to MDD and were absent in BD.
These results add a novel link to the immune hypothesis of depression by providing evidence for an upregulation of microglial QUIN in brain regions known to be responsive to infusion of NMDA antagonists such as ketamine. Further work in this area could lead to a greater understanding of the pathophysiology of depressive disorders and pave the way for novel NMDA receptor therapies or immune-modulating strategies.
PMCID: PMC3177898  PMID: 21831269
20.  Frontolimbic structural changes in borderline personality disorder 
Journal of psychiatric research  2007;42(9):727-733.
Frontolimbic dysfunction is observed in borderline personality disorder (BPD), with responses to emotional stimuli that are exaggerated in the amygdala and impaired in the anterior cingulate cortex (ACC). This pattern of altered function is consistent with animal models of stress responses and depression, where hypertrophic changes in the amygdala and atrophic changes in the ACC are observed. We tested the hypothesis that BPD patients exhibit gross structural changes that parallel the respective increases in amygdala activation and impairment of rostral/subgenual ACC activation.
12 unmedicated outpatients with BPD by DSM-IV and 12 normal control (NC) subjects underwent a high-resolution T1-weighted structural MRI scan. Relative gray matter concentration (GMC) in spatially-normalized images was evaluated by standard voxel-based morphometry, with voxel-wise subject group comparisons by t test constrained to amygdala and rostral/subgenual ACC.
The BPD group was significantly higher than NC in GMC in the amygdala. In contrast, the BPD group showed significantly lower GMC than the NC group in left rostral/subgenual ACC.
This sample of BPD patients exhibits gross structural changes in gray matter in cortical and subcortical limbic regions that parallel the regional distribution of altered functional activation to emotional stimuli among these same subjects. While the histological basis for GMC changes in adult clinical populations is poorly-known at present, the observed pattern is consistent with the direction of change, in animal models of anxiety and depression, of neuronal number and/or morphological complexity in both the amygdala (where it is increased) and ACC (where it is decreased).
PMCID: PMC2708084  PMID: 17825840
borderline personality disorder; frontolimbic; amygdala; anterior cingulate cortex; gray matter; voxel-based morphometry
21.  PTSD symptom severity is associated with increased recruitment of top-down attentional control in a trauma-exposed sample☆ 
NeuroImage : Clinical  2014;7:19-27.
Recent neuroimaging work suggests that increased amygdala responses to emotional stimuli and dysfunction within regions mediating top down attentional control (dorsomedial frontal, lateral frontal and parietal cortices) may be associated with the emergence of anxiety disorders, including posttraumatic stress disorder (PTSD). This report examines amygdala responsiveness to emotional stimuli and the recruitment of top down attention systems as a function of task demands in a population of U.S. military service members who had recently returned from combat deployment in Afghanistan/Iraq. Given current interest in dimensional aspects of pathophysiology, it is worthwhile examining patients who, while not meeting full PTSD criteria, show clinically significant functional impairment.
Fifty-seven participants with sub-threshold levels of PTSD symptoms completed the affective Stroop task while undergoing fMRI. Participants with PTSD or depression at baseline were excluded.
Greater PTSD symptom severity scores were associated with increased amygdala activation to emotional, particularly positive, stimuli relative to neutral stimuli. Furthermore, greater PTSD symptom severity was associated with increased superior/middle frontal cortex response during task conditions relative to passive viewing conditions. In addition, greater PTSD symptom severity scores were associated with: (i) increased activation in the dorsolateral prefrontal, lateral frontal, inferior parietal cortices and dorsomedial frontal cortex/dorsal anterior cingulate cortex (dmFC/dACC) in response to emotional relative to neutral stimuli; and (ii) increased functional connectivity during emotional trials, particularly positive trials, relative to neutral trials between the right amygdala and dmFC/dACC, left caudate/anterior insula cortex, right lentiform nucleus/caudate, bilateral inferior parietal cortex and left middle temporal cortex.
We suggest that these data may reflect two phenomena associated with increased PTSD symptomatology in combat-exposed, but PTSD negative, armed services members. First, these data indicate increased emotional responsiveness by: (i) the positive relationship between PTSD symptom severity and amygdala responsiveness to emotional relative to neutral stimuli; (ii) greater BOLD response as a function of PTSD symptom severity in regions implicated in emotion (striatum) and representation (occipital and temporal cortices) during emotional relative to neutral conditions; and (iii) increased connectivity between the amygdala and regions implicated in emotion (insula/caudate) and representation (middle temporal cortex) as a function of PTSD symptom severity during emotional relative to neutral trials. Second, these data indicate a greater need for the recruitment of regions implicated in top down attention as indicated by (i) greater BOLD response in superior/middle frontal gyrus as a function of PTSD symptom severity in task relative to view conditions; (ii) greater BOLD response in dmFC/dACC, lateral frontal and inferior parietal cortices as a function of PTSD symptom severity in emotional relative to neutral conditions and (iii) greater functional connectivity between the amygdala and inferior parietal cortex as a function of PTSD symptom severity during emotional relative to neutral conditions.
•Greater PTSD symptoms associated with increased amygdala activation to emotional stimuli•PTSD symptoms associated with greater top down attention response in task and emotion conditions•PTSD symptoms were associated with slower reaction times.•Increased top down attention recruitment may compensate for heightened emotional responses.
PMCID: PMC4299952  PMID: 25610763
Post-traumatic stress disorder; Emotion attention; Amygdala; Top down attention
22.  The Pathology of Social Phobia is Independent of Developmental Changes in Face Processing 
The American journal of psychiatry  2011;168(11):1202-1209.
While social phobia (SP) in adolescence predicts risk for SP in adulthood, no work has directly compared neural responses in SP adults and adolescents. The current study examines neural response to facial expressions in adult and adolescent SP to determine whether the neural correlates of adult SP during face processing also manifest in adolescent SP.
Blood oxygen level-dependent (BOLD) was compared in 39 medication-free individuals with SP (25 adults and 14 adolescents), and 39 healthy comparison individuals (23 adult and 16 adolescent) matched on age, IQ, and gender using functional magnetic resonance imaging (fMRI). During fMRI scans, individuals saw angry, fearful, and neutral expression stimuli while making a gender judgment.
Hypothesized significant diagnosis-by-emotion interactions were observed within the amygdala and rostral anterior cingulate cortex (rACC). In these regions, the adolescent and adult SP patients both showed significantly increased BOLD responses, relative to their respective age-matched comparison groups, with no evidence of age-related modulation of between-group differences. These enhanced responses occurred specifically to angry (rACC) and fearful (amygdala and rACC) but not neutral expressions. In addition, SP severity correlated significantly with this enhanced rACC response in the adults.
The neural correlates of adult SP during face processing also manifest in adolescents. As such, neural correlates observed in adult SP may represent the persistence of profiles established earlier in life, rather than adaptive responses to such earlier perturbations or maturational changes. These cross-sectional observations might encourage longitudinal fMRI studies of adolescent SP.
PMCID: PMC3248999  PMID: 21632650
23.  The optimal calibration hypothesis: how life history modulates the brain's social pain network 
A growing body of work demonstrates that the brain responds similarly to physical and social injury. Both experiences are associated with activity in the dorsal anterior cingulate cortex (dACC) and anterior insula. This dual functionality of the dACC and anterior insula underscores the evolutionary importance of maintaining interpersonal bonds. Despite the weight that evolution has placed on social injury, the pain response to social rejection varies substantially across individuals. For example, work from our lab demonstrated that the brain's social pain response is moderated by attachment style: anxious-attachment was associated with greater intensity and avoidant-attachment was associated with less intensity in dACC and insula activation. In an attempt to explain these divergent responses in the social pain network, we propose the optimal calibration hypothesis, which posits variation in social rejection in early life history stages shifts the threshold of an individual's social pain network such that the resulting pain sensitivity will be increased by volatile social rejection and reduced by chronic social rejection. Furthermore, the social pain response may be exacerbated when individuals are rejected by others of particular importance to a given life history stage (e.g., potential mates during young adulthood, parents during infancy and childhood).
PMCID: PMC3389670  PMID: 22783189
social pain; social rejection; life history; attachment style; anterior cingulate cortex; anterior insula
24.  Inflammation Causes Mood Changes Through Alterations in Subgenual Cingulate Activity and Mesolimbic Connectivity 
Biological Psychiatry  2009;66(5):407-414.
Inflammatory cytokines are implicated in the pathophysiology of depression. In rodents, systemically administered inflammatory cytokines induce depression-like behavior. Similarly in humans, therapeutic interferon-α induces clinical depression in a third of patients. Conversely, patients with depression also show elevated pro-inflammatory cytokines.
To determine the neural mechanisms underlying inflammation-associated mood change and modulatory effects on circuits involved in mood homeostasis and affective processing.
In a double-blind, randomized crossover study, 16 healthy male volunteers received typhoid vaccination or saline (placebo) injection in two experimental sessions. Mood questionnaires were completed at baseline and at 2 and 3 hours. Two hours after injection, participants performed an implicit emotional face perception task during functional magnetic resonance imaging. Analyses focused on neurobiological correlates of inflammation-associated mood change and affective processing within regions responsive to emotional expressions and implicated in the etiology of depression.
Typhoid but not placebo injection produced an inflammatory response indexed by increased circulating interleukin-6 and significant mood reduction at 3 hours. Inflammation-associated mood deterioration correlated with enhanced activity within subgenual anterior cingulate cortex (sACC) (a region implicated in the etiology of depression) during emotional face processing. Furthermore, inflammation-associated mood change reduced connectivity of sACC to amygdala, medial prefrontal cortex, nucleus accumbens, and superior temporal sulcus, which was modulated by peripheral interleukin-6.
Inflammation-associated mood deterioration is reflected in changes in sACC activity and functional connectivity during evoked responses to emotional stimuli. Peripheral cytokines modulate this mood-dependent sACC connectivity, suggesting a common pathophysiological basis for major depressive disorder and sickness-associated mood change and depression.
PMCID: PMC2885494  PMID: 19423079
Cytokines; depression; fMRI; mood; peripheral inflammation; subgenual cingulate
25.  Diagnosis of depression by MRI scans with the use of VSRAD – a promising auxiliary means of diagnosis: a report of 10 years research 
This study was designed to evaluate the usefulness of assessing subgenual anterior cingulate cortex (sACC) volume reduction by magnetic resonance imaging (MRI) as an objective auxiliary means of diagnosis of depression. The study was additionally designed to analyze the association of sACC volume reduction with the effectiveness of treatments for depression and other diseases presenting with similar symptoms, and to examine the possibility of using sACC volume reduction in the distinction between depression and bipolar disorder and determining optimum medication for these conditions.
Three-dimensional T1-weighted sagittal images, taken with Achieva 1.5T NOVA (Philips), were analyzed with VSRAD plus® to evaluate a reduction in sACC volume. The finding from this analysis was compared with the clinical data, including the longitudinal course follow-up data based on the treatment algorithm.
The study involved 88 patients aged over 54 who received MRI during 2010, ie, 71 patients with major depressive disorder (MDD), 11 patients bipolar disorder, and 6 patients in whom the initial diagnosis (MDD) was later modified. Thirty-three normal individuals served as controls.
sACC volume reduction was noted in 66 of the 71 patients receiving treatment of MDD, with sensitivity of 93%, specificity of 85%, and accuracy of 90%. In the 66 patients diagnosed as having MDD and exhibiting sACC volume reduction, the disease showed remission in response to treatment with antidepressants, but medication needed to be continued after achievement of remission. In cases initially diagnosed as having MDD but not exhibiting sACC volume reduction, the necessity of modifying the diagnosis was considered. Typical cases of bipolar disorder did not exhibit sACC volume reduction.
That patients receiving treatment of MDD often showed reduction in sACC volume suggests the usefulness of this parameter as an objective auxiliary means of diagnosis for MDD.
PMCID: PMC3100220  PMID: 21625414
depression; subgenual anterior cingulate cortex (sACC); MRI; VSRAD; neuroimaging

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