Morphological Biomarkers in the Amygdala and Hippocampus of Children and Adults at High Familial Risk for Depression.

Major Depressive Disorder (MDD) is highly familial, and the hippocampus and amygdala are important in the pathophysiology of MDD. Whether morphological markers of risk for familial depression are present in the hippocampus or amygdala is unknown. We imaged the brains of 148 individuals, aged 6 to 54 years, who were members of a three-generation family cohort study and who were at either high or low familial risk for MDD. We compared surface morphological features of the hippocampus and amygdala across risk groups and assessed their associations with depression severity. High- compared with low-risk individuals had inward deformations of the head of both hippocampi and the medial surface of the left amygdala. The hippocampus findings persisted in analyses that included only those participants who had never had MDD, suggesting that these are true endophenotypic biomarkers for familial MDD. Posterior extension of the inward deformations was associated with more severe depressive symptoms, suggesting that a greater spatial extent of this biomarker may contribute to the transition from risk to the overt expression of symptoms. Significant associations of these biomarkers with corresponding biomarkers for cortical thickness suggest that these markers are components of a distributed cortico-limbic network of familial vulnerability to MDD.

State and Trait Rumination Effects on Overt Attention to Reminders of Errors in a Challenging General Knowledge Retrieval Task.

Rumination is a recurrent and repetitive manner of thinking that can be triggered by blockage of personally relevant goals, creating a temporary state of abstract and evaluative self-focus. Particularly when focused on passive "brooding" over one's problems and feelings, however, rumination can increase negative affect, interfere with problem-solving, and, through a negative feedback cycle, become a chronic trait-like style of responding to personal challenges, particularly in women. Given the pervasiveness of rumination and its potential impact on cognitive processes and emotional states, the present study asks how it impacts attention to feedback that either reminds individuals of goal-state discrepancies (reminders of errors) or could help to remediate them (corrective information). Using eye-tracking, we examined both state and trait rumination effects on overt measures of attention [first fixation duration (FFD) and total fixation duration (TFD)] during simultaneous presentation of these two types of feedback following failed attempts to answer challenging verbal general knowledge questions (average accuracy ∼30%). After a pre-induction baseline, we induced either a state of rumination using a series of writing exercises centered on the description of an unresolved academic concern or a state of distraction by centering writing on the description of a neutral school day. Within our women-only sample, the Rumination condition, which writing analysis showed was dominated by moody brooding, resulted in some evidence for increased initial dwell time (FFD) on reminders of incorrect answers, while the Distraction condition, which did not elicit any rumination during writing, resulted in increased FFD on the correct answer. Trait brooding augmented the expression of the more negative, moody brooding content in the writing samples of both Induction conditions, but only influenced TFD measures of gaze duration and only during the pre-induction baseline, suggesting that once the inductions activated rumination or distraction states, these suppressed the trait effects in this sample. These results provide some support for attentional-bias models of rumination (attentional scope model, impaired disengagement hypothesis) and have implications for how even temporary states of rumination or distraction might impact processing of academic feedback under conditions of challenge and failure.

Rumination and Rebound from Failure as a Function of Gender and Time on Task.

Rumination is a trait response to blocked goals that can have positive or negative outcomes for goal resolution depending on where attention is focused. Whereas "moody brooding" on affective states may be maladaptive, especially for females, "reflective pondering" on concrete strategies for problem solving may be more adaptive. In the context of a challenging general knowledge test, we examined how Brooding and Reflection rumination styles predicted students' subjective and event-related responses (ERPs) to negative feedback, as well as use of this feedback to rebound from failure on a later surprise retest. For females only, Brooding predicted unpleasant feelings after failure as the task progressed. It also predicted enhanced attention to errors through both bottom-up and top-down processes, as indexed by increased early (400-600 ms) and later (600-1000 ms) late positive potentials (LPP), respectively. Reflection, despite increasing females' initial attention to negative feedback (i.e., early LPP), as well as both genders' recurring negative thoughts, did not result in sustained top-down attention (i.e., late LPP) or enhanced negative feelings toward errors. Reflection also facilitated rebound from failure in both genders, although Brooding did not hinder it. Implications of these gender and time-related rumination effects for learning in challenging academic situations are discussed.

Emotion blocks the path to learning under stereotype threat.

Gender-based stereotypes undermine females' performance on challenging math tests, but how do they influence their ability to learn from the errors they make? Females under stereotype threat or non-threat were presented with accuracy feedback after each problem on a GRE-like math test, followed by an optional interactive tutorial that provided step-wise problem-solving instruction. Event-related potentials tracked the initial detection of the negative feedback following errors [feedback related negativity (FRN), P3a], as well as any subsequent sustained attention/arousal to that information [late positive potential (LPP)]. Learning was defined as success in applying tutorial information to correction of initial test errors on a surprise retest 24-h later. Under non-threat conditions, emotional responses to negative feedback did not curtail exploration of the tutor, and the amount of tutor exploration predicted learning success. In the stereotype threat condition, however, greater initial salience of the failure (FRN) predicted less exploration of the tutor, and sustained attention to the negative feedback (LPP) predicted poor learning from what was explored. Thus, under stereotype threat, emotional responses to negative feedback predicted both disengagement from learning and interference with learning attempts. We discuss the importance of emotion regulation in successful rebound from failure for stigmatized groups in stereotype-salient environments.

Correlates of intellectual ability with morphology of the hippocampus and amygdala in healthy adults.

Several prior imaging studies of healthy adults have correlated volumes of the hippocampus and amygdala with measures of general intelligence (IQ), with variable results. In this study, we assessed correlations between volumes of the hippocampus and amygdala and full-scale IQ scores (FSIQ) using a method of image analysis that permits detailed regional mapping of this correlation throughout the surface contour of these brain structures. We delineated the hippocampus and amygdala in high-resolution magnetic resonance images of the brain from 34 healthy individuals. We then correlated FSIQ with overall volumes and with the surface morphologies of each of these structures. Hippocampus volumes correlated significantly and inversely with FSIQ independently of gender, age, socioeconomic status, and whole brain volume. Left and right hippocampus volumes correlated respectively with verbal and performance IQ subscales. Higher IQs were significantly associated with large inward deformations of the surface of the anterior hippocampus bilaterally. These findings suggest that a smaller anterior hippocampus contributes to an increased efficiency of neural processing that subserves overall intelligence.

Morphologic features of the amygdala and hippocampus in children and adults with Tourette syndrome.

CONTEXT: Limbic portions of cortical-subcortical circuits are likely involved in the pathogenesis of Tourette syndrome (TS). They are anatomically, developmentally, neurochemically, and functionally related to the basal ganglia, and the basal ganglia are thought to produce the symptoms of tics, obsessive-compulsive disorder, and attention-deficit/hyperactivity disorder that commonly affect persons with TS. OBJECTIVE: To study the morphologic features of the hippocampus and amygdala in children and adults with TS. DESIGN: A cross-sectional, case-control study using anatomical magnetic resonance imaging. SETTING: University research center. PARTICIPANTS: A total of 282 individuals (154 patients with TS and 128 controls) aged 6 to 63 years. MAIN OUTCOME MEASURES: Volumes and measures of surface morphologic features of the hippocampus and amygdala. RESULTS: The overall volumes of the hippocampus and amygdala were significantly larger in the TS group. Surface analyses suggested that the increased volumes in the TS group derived primarily from the head and medial surface of the hippocampus (over the length of the dentate gyrus) and the dorsal and ventral surfaces of the amygdala (over its basolateral and central nuclei). Volumes of these subregions declined with age in the TS group but not in controls, so the subregions were significantly larger in children with TS but significantly smaller in adults with TS than in their control counterparts. In children and adults, volumes in these subregions correlated inversely with the severity of tic, obsessive-compulsive disorder, and attention-deficit/hyperactivity disorder symptoms, suggesting that enlargement of the subregions may have a compensatory and neuromodulatory effect on tic-related symptoms. CONCLUSION: These findings are consistent with the known plasticity of the dentate gyrus and with findings from previous imaging studies suggesting the presence of failed compensatory plasticity in adults with TS who have not experienced the usual decline in symptoms during adolescence.

Hippocampus and amygdala morphology in attention-deficit/hyperactivity disorder.

CONTEXT: Limbic structures are implicated in the genesis of attention-deficit/hyperactivity disorder (ADHD) by the presence of mood and cognitive disturbances in affected individuals and by elevated rates of mood disorders in family members of probands with ADHD. OBJECTIVE: To study the morphology of the hippocampus and amygdala in children with ADHD. DESIGN: A cross-sectional case-control study of the hippocampus and amygdala using anatomical magnetic resonance imaging. SETTINGS: University research institute. PATIENTS: One hundred fourteen individuals aged 6 to 18 years, 51 with combined-type ADHD and 63 healthy controls. MAIN OUTCOME MEASURES: Volumes and measures of surface morphology for the hippocampus and amygdala. RESULTS: The hippocampus was larger bilaterally in the ADHD group than in the control group (t = 3.35; P < .002). Detailed surface analyses of the hippocampus further localized these differences to an enlarged head of the hippocampus in the ADHD group. Although conventional measures did not detect significant differences in amygdalar volumes, surface analyses indicated the presence of reduced size bilaterally over the area of the basolateral complex. Correlations with prefrontal measures suggested abnormal connectivity between the amygdala and prefrontal cortex in the ADHD group. Enlarged subregions of the hippocampus tended to accompany fewer symptoms. CONCLUSIONS: The enlarged hippocampus in children and adolescents with ADHD may represent a compensatory response to the presence of disturbances in the perception of time, temporal processing (eg, delay aversion), and stimulus seeking associated with ADHD. Disrupted connections between the amygdala and orbitofrontal cortex may contribute to behavioral disinhibition. Our findings suggest involvement of the limbic system in the pathophysiology of ADHD.

Cortisol levels and hippocampus volumes in healthy preadolescent children.

BACKGROUND: Research in animal models has demonstrated that elevated levels of glucocorticoids can inflict damage within the hippocampus. In adult humans, elevated cortisol levels have been associated with reduced hippocampal volumes; however, normative data in children are not available. The objective of this study was to examine possible associations of serum cortisol levels with hippocampal volumes and morphology in healthy children. METHODS: Morning serum cortisol levels and hippocampus magnetic resonance imaging were measured in 17 healthy children (8 girls, 9 boys) between 7 and 12 years of age. RESULTS: Cortisol levels were not associated with total hippocampal volumes; however, with an analysis of surface morphology, significant associations were found for regionally specific portions of the hippocampus. Positive associations were detected for the anterior segment of the hippocampus and inverse associations along the lateral aspects of the hippocampus. CONCLUSIONS: Associations of cortisol levels with regionally specific variations in hippocampal morphology were detected during early development in healthy preadolescent children.

ROC-based assessments of 3D cortical surface-matching algorithms.

Algorithms for the semi-automated analysis of brain surfaces have recently received considerable attention, and yet, they rarely receive a rigorous assessment of their performance. We present a method for the quantitative assessment of performance across differing surface analysis algorithms and across various modifications of a single algorithm. The sensitivity and specificity of an algorithm for detecting known deformations added synthetically to the brains being studied are assessed using curves for Receiver Operating Characteristics (ROC). We also present a method for the isolation of sources of variance in MRI data sets that can contribute to degradation in performance of surface-matching algorithms. Isolation of these sources of variance allows determination of whether degradation in performance of surface-matching algorithms derives primarily from errors in registration of brains to a common coordinate space, from errors in placement of the known deformation, or from interindividual or between-group variability in morphology of the cortical surface. We apply these methods to the study of surface-matching algorithms that are based on fluid flow (FF) deformation, geodesic (GD) interpolation, or nearest neighbor (NN) proximity. We show that the performances of surface-matching algorithms depend on the presence of interindividual and between-group variability in the surfaces surrounding the cortical deformation. We also show that, in general, the FF algorithm performs as well as or better than the GD and NN algorithms. The large variance in identifying point correspondences across brain surfaces using the GD and the NN algorithms suggests strongly that these point correspondences are less valid than those determined by the FF algorithm. The GD and NN algorithms, moreover, are both vulnerable to detecting false-positive activations at points of high curvature, particularly along large fissures, cisterns, and cortical sulci.

Amygdala and hippocampal volumes in adolescents and adults with bipolar disorder.

BACKGROUND: The purported functions of medial temporal lobe structures suggest their involvement in the pathophysiology of bipolar disorder (BD). Previous reports of abnormalities in the volume of the amygdala and hippocampus in patients with BD have been inconsistent in their findings and limited to adult samples. Appreciation of whether volumetric abnormalities are early features of BD or whether the abnormalities represent neurodegenerative changes associated with illness duration is limited by the paucity of data in juvenile samples. OBJECTIVE: To investigate amygdala and hippocampal volume in adults and adolescents with BD. SETTING AND PARTICIPANTS: Subjects included 36 individuals (14 adolescents and 22 adults) in outpatient treatment for BD type I at a university hospital or Veterans Affairs medical center or in the surrounding community, and 56 healthy comparison subjects (23 adolescents and 33 adults). DESIGN AND MAIN OUTCOME MEASURES: Amygdala and hippocampal volumes were defined and measured on high-resolution anatomic magnetic resonance imaging scans. We used a mixed-model, repeated-measures statistical analysis to compare amygdala and hippocampal volumes across groups while covarying for total brain volume, age, and sex. Potential effects of illness features were explored, including rapid cycling, medication, alcohol or other substance dependence, duration, and mood state. RESULTS: For both the amygdala and hippocampal regions, we found an overall significant volume reduction in the BD compared with the control group (P<.0001). Amygdala volume reductions (15.6%) were highly significant (P<.0001). We observed a nonsignificant trend (P =.054) toward reductions in hippocampal volumes of lesser magnitude (5.3%). Effects of illness features were not detected. CONCLUSIONS: These results suggest that BD is associated with decreased volumes of medial temporal lobe structures, with greater effect sizes in the amygdala than in the hippocampus. These abnormalities are likely manifested early in the course of illness, as they affected adolescent and adult subjects similarly in this sample.