Comparing Brain Morphometry Across Multiple Childhood Psychiatric Disorders.

OBJECTIVE: In both children and adults, psychiatric illness is associated with structural brain alterations, particularly in the prefrontal cortex (PFC). However, most studies compare gray matter volume (GMV) in healthy volunteers (HVs) to one psychiatric group. We compared GMV among youth with anxiety disorders, bipolar disorder (BD), disruptive mood dysregulation disorder (DMDD), attention-deficit/hyperactivity disorder (ADHD), and HVs. METHOD: 3-Tesla T1-weighted magnetic resonance imaging scans were acquired in 184 youths (39 anxious, 20 BD, 52 DMDD, 20 ADHD, and 53 HV). Voxel-based morphometry analyses were conducted. One-way analysis of variance tested GMV differences with whole-brain familywise error (p < .05) correction; secondary, exploratory whole-brain analyses used a threshold of p < .001, ≥200 voxels. Given recent frameworks advocating dimensional approaches in psychopathology research, we also tested GMV associations with continuous anxiety, irritability, and inattention symptoms. RESULTS: Specificity emerged in the left dorsolateral PFC (dlPFC), which differed among youth with BD, anxiety, and HVs; GMV was increased in youth with anxiety, but decreased in BD, relative to HVs. Secondary analyses revealed BD-specific GMV decreases in the right lateral PFC, right dlPFC, and dorsomedial PFC, and also anxiety-specific GMV increases in the left dlPFC, right ventrolateral PFC, frontal pole, and right parahippocampal gyrus/lingual gyrus. Both BD and DMDD showed decreased GMV relative to HVs in the right dlPFC/superior frontal gyrus. GMV was not associated with dimensional measures of anxiety, irritability, or ADHD symptoms. CONCLUSION: Both disorder-specific and shared GMV differences manifest in pediatric psychopathology. Some differences were specific to anxiety disorders, others specific to BD, and others shared between BD and DMDD. Further developmental research might map commonalities and differences of structure and function in diverse pediatric psychopathologies.

A developmental study on the neural circuitry mediating response flexibility in bipolar disorder.

Cross-sectional neuroimaging studies are an important first step in examining developmental differences in brain function between adults and youth with bipolar disorder (BD). Impaired response flexibility may contribute to reduced ability to modify goal-directed behavior in BD appropriately. We compared neural circuitry mediating this process in child (CBD) vs. adult BD (ABD) and age-matched healthy subjects. fMRI data from 15 CBD, 23 ABD, 20 healthy children, and 27 healthy adults were acquired during a response flexibility paradigm, a task where subjects inhibit a prepotent response and execute an alternative response. When successfully executing an alternate response, CBD showed frontal, parietal, and temporal hyperactivation relative to healthy children and ABD, while ABD hypoactivated these regions relative to healthy adults. Previous studies of response flexibility in healthy volunteers revealed frontal, temporal, and parietal cortex hyperactivation in children and hypoactivation in adults. Relative to age-matched healthy subjects, we found hyperactivation in these regions in CBD and hypoactivation in ABD. This suggests that our findings in patients may represent the extreme extension of the age-related response flexibility activation differences found in healthy subjects. Future studies should use longitudinal fMRI to examine the developmental trajectory of the neural circuitry mediating response flexibility in BD.

Changes in the neural correlates of implicit emotional face processing during antidepressant treatment in major depressive disorder.

An emerging hypothesis regarding the mechanisms underlying antidepressant pharmacotherapy suggests that these agents benefit depressed patients by reversing negative emotional processing biases (Harmer, 2008). Neuropsychological indices and functional neuroimaging measures of the amygdala response show that antidepressant drugs shift implicit and explicit processing biases away from the negative valence and toward the positive valence. However, few studies have explored such biases in regions extensively connected with the amygdala, such as the pregenual anterior cingulate cortex (pgACC) area, where pre-treatment activity consistently has predicted clinical outcome during antidepressant treatment. We used functional magnetic resonance imaging (fMRI) to investigate changes in haemodynamic response patterns to positive vs. negative stimuli in patients with major depressive disorder (MDD) under antidepressant treatment. Participants with MDD (n = 10) underwent fMRI before and after 8 wk sertraline treatment; healthy controls (n = 10) were imaged across an equivalent interval. A backward masking task was used to elicit non-conscious neural responses to sad, happy and neutral face expressions. Haemodynamic responses to emotional face stimuli were compared between conditions and groups in the pgACC. The response to masked-sad vs. masked-happy faces (SN-HN) in pgACC in the depressed subjects was higher in the pre-treatment condition than in the post-treatment condition and this difference was significantly greater than the corresponding change across time in the controls. The treatment-associated difference was attributable to an attenuated response to sad faces and an enhanced response to happy faces. Pre-treatment pgACC responses to SN-HN correlated positively with clinical improvement during treatment. The pgACC participates with the amygdala in processing the salience of emotional stimuli. Treatment-associated functional changes in this limbic network may influence the non-conscious processing of such stimuli by reversing the negative processing bias extant in MDD.

Abnormal fusiform activation during emotional-face encoding assessed with functional magnetic resonance imaging.

This functional magnetic resonance imaging study shows that children and adults with bipolar disorder (BD), compared with healthy subjects, exhibit impaired memory for emotional faces and abnormal fusiform activation during encoding. Fusiform activation abnormalities in BD were correlated with mania severity and may therefore represent a trait and state BD biomarker.

Nucleus accumbens, thalamus and insula connectivity during incentive anticipation in typical adults and adolescents.

Reward neurocircuitry links motivation with complex behavioral responses. Studies of incentive processing have repeatedly demonstrated activation of nucleus accumbens (NAc), thalamus, and anterior insula, three key components of reward neurocircuitry. The contribution of the thalamus to this circuitry in humans has been relatively ignored, a gap that needs to be filled, given the central role of this structure in processing and filtering information. This study aimed to understand how these three regions function as a network during gain or loss anticipation in adults and youth. Towards this goal, functional magnetic resonance imaging (fMRI) and dynamic causal modeling (DCM) were used to examine effective connectivity among these three nodes in healthy adults and adolescents who performed the monetary incentive delay (MID) task. Seven connectivity models, based on anatomic connections, were tested. They were estimated for incentive anticipation and underwent Bayesian Model Selection (BMS) to determine the best-fit model for each adult and adolescent group. Connection strengths were extracted from the best-fit model and examined for significance in each group. These variables were then entered into a linear mixed model to test between-group effects on effective connectivity in reward neurocircuitry. The best-fit model for both groups included all possible anatomic connections. Three main findings emerged: (1) Across the task, thalamus and insula significantly influenced NAc; (2) A broader set of significant connections was found for the loss-cue condition than the gain-cue condition in both groups; (3) Finally, between-group comparisons of connectivity strength failed to detect statistical differences, suggesting that adults and adolescents use this incentive-processing network in a similar manner. This study demonstrates the way in which the thalamus and insula influence the NAc during incentive processing in humans. Specifically, this is the first study to demonstrate in humans the key role of thalamus projections onto the NAc in support of reward processing. Our results suggest that anticipation of gain/loss involves an 'alerting' signal (thalamus) that converges with interoceptive information (insula) to shape action selection programs in the ventral striatum.

The extended functional neuroanatomy of emotional processing biases for masked faces in major depressive disorder.

BACKGROUND: Major depressive disorder (MDD) is associated with a mood-congruent processing bias in the amygdala toward face stimuli portraying sad expressions that is evident even when such stimuli are presented below the level of conscious awareness. The extended functional anatomical network that maintains this response bias has not been established, however. AIMS: To identify neural network differences in the hemodynamic response to implicitly presented facial expressions between depressed and healthy control participants. METHOD: Unmedicated-depressed participants with MDD (n=22) and healthy controls (HC; n=25) underwent functional MRI as they viewed face stimuli showing sad, happy or neutral face expressions, presented using a backward masking design. The blood-oxygen-level dependent (BOLD) signal was measured to identify regions where the hemodynamic response to the emotionally valenced stimuli differed between groups. RESULTS: The MDD subjects showed greater BOLD responses than the controls to masked-sad versus masked-happy faces in the hippocampus, amygdala and anterior inferotemporal cortex. While viewing both masked-sad and masked-happy faces relative to masked-neutral faces, the depressed subjects showed greater hemodynamic responses than the controls in a network that included the medial and orbital prefrontal cortices and anterior temporal cortex. CONCLUSIONS: Depressed and healthy participants showed distinct hemodynamic responses to masked-sad and masked-happy faces in neural circuits known to support the processing of emotionally valenced stimuli and to integrate the sensory and visceromotor aspects of emotional behavior. Altered function within these networks in MDD may establish and maintain illness-associated differences in the salience of sensory/social stimuli, such that attention is biased toward negative and away from positive stimuli.

Cross-sectional and longitudinal abnormalities in brain structure in children with severe mood dysregulation or bipolar disorder.

BACKGROUND: There is debate as to whether chronic irritability (operationalized as severe mood dysregulation, SMD) is a developmental form of bipolar disorder (BD). Although structural brain abnormalities in BD have been demonstrated, no study compares neuroanatomy among SMD, BD, and healthy volunteers (HV) either cross-sectionally or over time. Furthermore, the developmental trajectories of structural abnormalities in BD or SMD are unknown. This study provides such data in BD, SMD, and HV. METHODS: An optimized, modulated voxel-based morphometry (VBM) analysis was conducted on structural MRI scans from 201 children (78 SMD, 55 BD, and 68 HV). In addition, 92 children (31 SMD, 34 BD, and 27 HV) were rescanned after 2 years (mean interval 1.99 ± 0.94 years), to compare time-related changes among the three groups. RESULTS: Cross-sectionally, the groups differed in gray matter (GM) volume in presupplementary motor area (pre-SMA), dorsolateral prefrontal cortex (DLPFC), insula, and globus pallidus. The cortical differences were driven mainly by increased GM volume in HV compared with BD and SMD. In globus pallidus, there was increased GM in BD compared with HV and SMD. Longitudinally, group-by-time interactions were evident in two clusters in the superior/inferior parietal lobule (R SPL/IPL) and in the precuneus. In both clusters, the interactions were driven by an abnormal increase in volume in BD. CONCLUSIONS: Cross-sectionally, both BD and SMD are associated with structural abnormalities in frontal cortex, insula, and basal ganglia. Although some of these deficits overlap (insula and DLPFC), others differentiate SMD and BD (pre-SMA and globus pallidus). Abnormal developmental trajectories in lateral parietal cortex and precuneus are present in, and unique to, BD. Because of the high proportion of co-occurring ADHD in the SMD subjects, we could not separate effects of ADHD from those of SMD, and future research including a nonirritable ADHD group must address this issue.

A developmental study of the neural circuitry mediating motor inhibition in bipolar disorder.

OBJECTIVE: Despite increased interest in the developmental trajectory of the pathophysiology mediating bipolar disorder, few studies have compared adults and youths with bipolar disorder. Deficits in motor inhibition are thought to play an important role in the pathophysiology of the illness across the age spectrum. The authors compared the neural circuitry mediating this process in bipolar youths relative to bipolar adults and in healthy volunteers. METHOD: Participants were pediatric (N=16) and adult (N=23) patients with bipolar disorder and healthy child (N=21) and adult (N=29) volunteers. Functional MRI (fMRI) data were acquired while participants performed the stop-signal task. RESULTS: During failed inhibition, an age group-by-diagnosis interaction manifested in the anterior cingulate cortex, with bipolar youths exhibiting hypoactivation relative to both healthy youths and bipolar adults, and bipolar adults exhibiting hyperactivation relative to healthy adults. During successful inhibition, a main effect of diagnosis emerged in the right nucleus accumbens and the left ventral prefrontal cortex, with bipolar patients in both age groups showing less activation than healthy subjects. CONCLUSIONS: Anterior cingulate cortex dysfunction during failed motor inhibition was observed in both bipolar youths and adults, although the nature of this dysfunction differed between the two groups. Adults and youths with bipolar disorder exhibited similar deficits in activation of the nucleus accumbens and the ventral prefrontal cortex during successful inhibition. Therefore, while subcortical and ventral prefrontal cortex hypoactivation was present in bipolar patients across the lifespan, anterior cingulate cortex dysfunction varied developmentally, with reduced activation in youths and increased activation in adults during failed inhibition. Longitudinal fMRI studies of the developmental trajectory of the neural circuitry mediating motor inhibition in bipolar disorder are warranted.

Serotonin transporter genotype differentially modulates neural responses to emotional words following tryptophan depletion in patients recovered from depression and healthy volunteers.

Previous studies have suggested that polymorphism in the serotonin transporter gene (5-HTTLPR) influences responses to serotonergic manipulation, with opposite effects in patients recovered from depression (rMDD) and controls. Here we sought to clarify the neurocognitive mechanisms underpinning these surprising results. Twenty controls and 23 rMDD subjects completed the study; functional magnetic resonance imaging (fMRI) and genotype data were available for 17 rMDD subjects and 16 controls. Following tryptophan or sham depletion, subjects performed an emotional-processing task during fMRI. Although no genotype effects on mood were identified, significant genotype*diagnosis*depletion interactions were observed in the hippocampus and subgenual cingulate in response to emotionally valenced words. In both regions, tryptophan depletion increased responses to negative words, relative to positive words, in high-expression controls, previously identified as being at low-risk for mood change following this procedure. By contrast, in higher-risk low-expression controls and high-expression rMDD subjects, tryptophan depletion had the opposite effect. Increased neural responses to negative words following tryptophan depletion may reflect an adaptive mechanism promoting resilience to mood change following perturbation of the serotonin system, which is reversed in sub-groups vulnerable to developing depressive symptoms. However, this interpretation is complicated by our failure to replicate previous findings of increased negative mood following tryptophan depletion.

Striatal dysfunction during failed motor inhibition in children at risk for bipolar disorder.

BACKGROUND: A better understanding of the neural underpinnings of bipolar disorder (BD) can be obtained by examining brain activity in symptom-free individuals at risk for BD. This study examined the neural correlates of motor inhibition in a sample of symptom-free youths at familial risk for BD. METHODS: 19 euthymic youths with BD, 13 asymptomatic youths with a first-degree relative with BD, and 21 healthy comparison children completed the stop signal task in a 3 T scanner. RESULTS: Children at familial risk for BD exhibited increased putamen activation during unsuccessful inhibition that distinguished them from both healthy and BD children. Youths with BD exhibited reduced activation of the right nucleus accumbens during unsuccessful inhibition as compared to the other participant groups. CONCLUSIONS: Striatal activation patterns differ between youths at risk for BD and healthy comparison children during a motor inhibition task.

Amygdala hyperactivation during face emotion processing in unaffected youth at risk for bipolar disorder.

OBJECTIVE: Youth at familial risk for bipolar disorder (BD) show deficits in face emotion processing, but the neural correlates of these deficits have not been examined. This preliminary study tests the hypothesis that, relative to healthy comparison (HC) subjects, both BD subjects and youth at risk for BD (i.e., those with a first-degree BD relative) will demonstrate amygdala hyperactivation when viewing fearful and happy faces. The at-risk youth were unaffected, in that they had no history of mood disorder. METHOD: Amygdala activity was examined in 101 unrelated participants, 8 to 18 years old. Age, gender, and IQ-matched groups included BD (N = 32), unaffected at-risk (N = 13), and HC (N = 56). During functional magnetic resonance imaging, participants attended to emotional and nonemotional aspects of fearful and happy faces. RESULTS: While rating their fear of fearful faces, both BD and unaffected at-risk subjects exhibited amygdala hyperactivity versus HC. There were no between-group differences in amygdala activity in response to happy faces. Post-hoc comparisons revealed that, in at-risk youth, familial risk status (offspring versus sibling), presence of Axis I diagnosis (n = 1 attention-deficit/hyperactivity disorder [ADHD], n = 1 social phobia), and history of medication exposure (n = 1) did not influence imaging findings. CONCLUSIONS: We found amygdala hyperactivation in both unaffected at-risk and BD youth while rating their fear of fearful faces. These pilot data suggest that both face emotion labeling deficits and amygdala hyperactivity during face processing should receive further study as potential BD endophenotypes. Longitudinal studies should test whether amygdala hyperactivity to fearful faces predicts conversion to BD in at-risk youth.

Neural recruitment during failed motor inhibition differentiates youths with bipolar disorder and severe mood dysregulation.

Controversy exists about whether non-episodic irritability (operationalized as severe mood dysregulation, SMD) should be considered a developmental presentation of pediatric bipolar disorder (BD). While assessments of brain function may address this controversy, only one fMRI study has compared BD versus SMD. We compared neural activation in BD, SMD, and controls during a motor inhibition task, since motor disinhibition is an important clinical feature in both BD and SMD. During failed inhibition, BD youths exhibited less activation in the right anterior cingulate cortex (ACC) and right nucleus accumbens relative to both SMD and healthy youths. Exploratory analyses indicate that, in BD youths, reduced activation in the right ACC may be independent of comorbid ADHD. These findings highlight neural distinctions between the phenotypically related BD and SMD populations.

Neural correlates of cognitive flexibility in children at risk for bipolar disorder.

BACKGROUND: Youth with bipolar disorder (BD) show behavioral and neural deficits in cognitive flexibility; however, whether such deficits exist among youths at risk for BD has not been explored. METHODS: The current fMRI study examined the neural basis of cognitive flexibility in BD youth (n = 28), unaffected youth at risk for BD (AR; n = 13), and healthy volunteer youth (HV; n = 21) by comparing brain activation patterns while participants performed the change task. On change trials, subjects must inhibit a prepotent response and execute an alternate one. RESULTS: During successful change trials, both BD and AR youth had increased right ventrolateral prefrontal and inferior parietal activity, compared to HV youth. During failed change trials, both BD and AR youth exhibited increased caudate activation relative to HV youth, but BD youth showed increased activation in the subgenual anterior cingulate cortex (ACC) relative to the other two groups. CONCLUSIONS: Abnormal activity in ventrolateral prefrontal cortex, inferior parietal cortex, and striatum during a cognitive flexibility task may represent a potential BD endophenotype, but subgenual ACC dysfunction may represent a marker of BD illness itself.

Neural correlates of sleepiness induced by catecholamine depletion.

Although extensive indirect evidence exists to suggest that the central dopaminergic system plays a significant role in the modulation of arousal, the functional effect of the dopaminergic influence on the regulation of the sleep-wake cycle remains unclear. Thirteen healthy volunteers and 15 unmedicated subjects with a history of major depressive disorder underwent catecholamine depletion (CD) using oral alpha-methyl-para-tyrosine in a randomized, placebo-controlled, double-blind, crossover study. The main outcome measures in both sessions were sleepiness (Stanford-Sleepiness-Scale), cerebral glucose metabolism (positron emission tomography), and serum prolactin concentration. CD consistently induced clinically relevant sleepiness in both groups. The CD-induced prolactin increase significantly correlated with CD-induced sleepiness but not with CD-induced mood and anxiety symptoms. CD-induced sleepiness correlated with CD-induced increases in metabolism in the medial and orbital frontal cortex, bilateral superior temporal cortex, left insula, cingulate motor area and in the vicinity of the periaqueductal gray. This study suggests that the association between dopamine depletion and sleepiness is independent of the brain reward system and the risk for depression. The visceromotor system, the cingulate motor area, the periaqueductal gray and the caudal hypothalamus may mediate the impact of the dopaminergic system on regulation of wakefulness and sleep.

Preliminary findings: neural responses to feedback regarding betrayal and cooperation in adolescent anxiety disorders.

We compared neural and behavioral responses to feedback received during interpersonal interactions within the Prisoner's Dilemma game between adolescents with anxiety disorders (n = 12) and healthy peers (n = 17). Groups differed significantly in neural activation in the medial prefrontal cortex (mPFC), anterior cingulate cortex (ACC), precuneus, insula, and temporoparietal junction (TPJ). Anxious adolescents were also more likely than controls to cooperate after co-player betrayal. Our findings provide evidence that social behavior and related neural activity differs between anxious and healthy adolescents. These findings constitute a step toward elucidating neural correlates of social impairment in anxious youths.

Relationship between amygdala responses to masked faces and mood state and treatment in major depressive disorder.

CONTEXT: Major depressive disorder (MDD) is associated with behavioral and neurophysiological evidence of mood-congruent processing biases toward explicitly presented, emotionally valenced stimuli. However, few studies have investigated such biases toward implicitly presented stimuli. OBJECTIVE: To investigate differential amygdala responses to sad, happy, and neutral faces presented below the level of explicit conscious awareness using a backward masking task in unmedicated participants with MDD and healthy controls (HCs). DESIGN: Initial cross-sectional design followed by a longitudinal treatment trial using functional magnetic resonance imaging. SETTING: Psychiatric outpatient clinic at the National Institute of Mental Health. PARTICIPANTS: We studied 22 unmedicated, currently depressed people with MDD (dMDD), 16 unmedicated individuals with MDD in full remission (rMDD), and 25 HCs. INTERVENTION: Ten dMDD participants underwent 8 weeks of antidepressant treatment with the selective serotonin reuptake inhibitor sertraline hydrochloride. MAIN OUTCOME MEASURES: Amygdala region-of-interest and whole-brain analyses evaluated the hemodynamic response during exposure to masked sad vs masked happy faces, to masked sad vs neutral faces, and to masked happy vs neutral faces. RESULTS: The dMDD participants showed greater amygdala responses than HCs to masked sad faces, whereas HCs showed greater amygdala responses to masked happy faces. The bias toward sad faces also was evident in rMDD participants relative to HCs and did not differ between dMDD and rMDD participants. This processing bias reversed toward the normative pattern in dMDD participants after sertraline treatment. CONCLUSIONS: Emotional-processing biases occur in amygdala responses to sad faces presented below the level of conscious awareness in dMDD or rMDD individuals and to happy faces in HCs. By influencing the salience of social stimuli, mood-congruent processing biases in the amygdala may contribute to dysfunction in conscious perceptions and social interactions in MDD. Our data suggest, however, that the negative bias resolves and a positive bias develops in patients with MDD during selective serotonin reuptake inhibitor treatment.

Amygdala activation during emotion processing of neutral faces in children with severe mood dysregulation versus ADHD or bipolar disorder.

OBJECTIVE: To understand disorder-unique and common pathophysiology, studies in multiple patient groups with overlapping symptoms are needed. Deficits in emotion processing and hyperarousal symptoms are prominent features of bipolar disorder, attention deficit hyperactivity disorder (ADHD), and severe mood dysregulation. The authors compared amygdala response during emotional and nonemotional ratings of neutral faces in youths with these disorders as well as a group of healthy comparison youths. METHOD: Blood-oxygen-level-dependent (BOLD) signal in the amygdala was examined in children with bipolar disorder (N=43), ADHD (N=18), and severe mood dysregulation (N=29) and healthy comparison subjects (N=37). During functional magnetic resonance imaging (fMRI), participants attended to emotional and nonemotional aspects of neutral faces. RESULTS: While rating subjective fear of neutral faces, youths with ADHD demonstrated left amygdala hyperactivity relative to the other three groups, whereas youths with severe mood dysregulation demonstrated hypoactivity. CONCLUSIONS: These findings support the role of unique neural correlates in face-emotion processing among youths with bipolar disorder, ADHD, and severe mood dysregulation.

The effects of tryptophan depletion on neural responses to emotional words in remitted depression.

BACKGROUND: Major depressive disorder (MDD) has been associated with both dysfunction of the central serotonergic system and abnormal responses to emotional stimuli. We used acute tryptophan depletion (ATD) to investigate the effect of temporarily reducing brain serotonin synthesis on neural and behavioral responses to emotional stimuli in remitted MDD subjects (rMDD) and healthy control subjects. METHODS: Twenty control subjects and 23 rMDD subjects who had been unmedicated and in remission for > or =3 months completed the study. Following tryptophan or sham depletion, participants performed an emotional-processing task during functional magnetic resonance imaging. In addition, resting state regional blood flow was measured using arterial spin labeling. RESULTS: Neither group exhibited significant mood change following ATD. However, tryptophan depletion differentially affected the groups in terms of hemodynamic responses to emotional words in a number of structures implicated in the pathophysiology of MDD, including medial thalamus and caudate. These interactions were driven by increased responses to emotional words in the control subjects, with little effect in the patients under the ATD condition. Following ATD, habenula blood flow increased significantly in the rMDD subjects relative to the control subjects, and increasing amygdala blood flow was associated with more negative emotional bias score across both groups. CONCLUSIONS: These data provide evidence for elevated habenula blood flow and alterations in the neural processing of emotional stimuli following ATD in rMDD subjects, even in the absence of overt mood change. However, further studies are required to determine whether these findings represent mechanisms of resilience or vulnerability to MDD.

Common and distinct amygdala-function perturbations in depressed vs anxious adolescents.

CONTEXT: Few studies directly compare amygdala function in depressive and anxiety disorders. Data from longitudinal research emphasize the need for such studies in adolescents. OBJECTIVE: To compare amygdala response to varying attention and emotion conditions among adolescents with major depressive disorder (MDD) or anxiety disorders, relative to adolescents with no psychopathology. DESIGN: Case-control study. SETTING: Government clinical research institute. PARTICIPANTS: Eighty-seven adolescents matched on age, sex, intelligence, and social class: 26 with MDD (14 with and 12 without anxiety disorders), 16 with anxiety disorders but no depression, and 45 without psychopathology. MAIN OUTCOME MEASURES: Blood oxygen level-dependent signal in the amygdala, measured by means of event-related functional magnetic resonance imaging. During imaging, participants viewed facial expressions (neutral, fearful, angry, and happy) while attention was constrained (afraid, hostility, and nose-width ratings) or unconstrained (passive viewing). RESULTS: Left and right amygdala activation differed as a function of diagnosis, facial expression, and attention condition both when patients with comorbid MDD and anxiety were included and when they were excluded (group x emotion x attention interactions, P < or = .03). Focusing on fearful face-viewing events, patients with anxiety and those with MDD both differed in amygdala responses from healthy participants and from each other during passive viewing. However, both MDD and anxiety groups, relative to healthy participants, exhibited similar signs of amygdala hyperactivation to fearful faces when subjectively experienced fear was rated. CONCLUSIONS: Adolescent MDD and anxiety disorders exhibit common and distinct functional neural correlates during face processing. Attention modulates the degree to which common or distinct amygdala perturbations manifest in these patient groups, relative to healthy peers.

Amygdala function and 5-HTT gene variants in adolescent anxiety and major depressive disorder.

BACKGROUND: Associations between a functional polymorphism in the serotonin transporter gene and amygdala activation have been found in healthy, depressed, and anxious adults. This study explored these gene-brain associations in adolescents by examining predictive effects of serotonin transporter gene variants (S and L(G) allele carriers vs. L(A) allele homozygotes) and their interaction with diagnosis (healthy vs. patients) on amygdala responses to emotional faces. METHODS: Functional magnetic resonance data were collected from 33 healthy adolescents (mean age: 13.71, 55% female) and 31 medication-free adolescents with current anxiety or depressive disorders (or both; mean age: 13.58, 56% female) while viewing fearful, angry, happy, and neutral facial expressions under varying attention states. RESULTS: A significant three-way genotype-by-diagnosis-by-face-emotion interaction characterized right amygdala activity while subjects monitored internal fear levels. This interaction was decomposed to map differential gene-brain associations in healthy and affected adolescents. First, consistent with healthy adult data, healthy adolescents with at least one copy of the S or L(G) allele showed stronger amygdala responses to fearful faces than healthy adolescents without these alleles. Second, patients with two copies of the L(A) allele exhibited greater amygdala responses to fearful faces relative to patients with S or L(G) alleles. Third, although weaker, genotype differences on amygdala responses in patients extended to happy faces. All effects were restricted to the fear-monitoring attention state. CONCLUSIONS: S/L(G) alleles in healthy adolescents, as in healthy adults, predict enhanced amygdala activation to fearful faces. Contrary findings of increased activation in patients with L(A)L(A) relative to the S or L(G) alleles require further exploration.