Prefrontal cortex and amygdala anatomy in youth with persistent levels of harsh parenting practices and subclinical anxiety symptoms over time during childhood.

Childhood adversity and anxiety have been associated with increased risk for internalizing disorders later in life and with a range of brain structural abnormalities. However, few studies have examined the link between harsh parenting practices and brain anatomy, outside of severe maltreatment or psychopathology. Moreover, to our knowledge, there has been no research on parenting and subclinical anxiety symptoms which remain persistent over time during childhood (i.e., between 2.5 and 9 years old). Here, we examined data in 94 youth, divided into four cells based on their levels of coercive parenting (high / low) and of anxiety (high / low) between 2.5 and 9 years old. Anatomical images were analyzed using voxel-based morphometry (VBM) and FreeSurfer. Smaller gray matter volumes in the prefrontal cortex regions and in the amygdala were observed in youth with high versus low levels of harsh parenting over time. In addition, we observed significant interaction effects between parenting practices and subclinical anxiety symptoms in rostral anterior cingulate cortical thickness and in amygdala volume. These youth should be followed further in time to identify which youth will or will not go on to develop an anxiety disorder, and to understand factors associated with the development of sustained anxiety psychopathology.

Fear conditioning and extinction in anxious youth, offspring at-risk for anxiety and healthy comparisons: An fMRI study.

Dysfunctions in fronto-amygdala circuitry have been linked to anxiety. Questions remain regarding the impact of familial-risk and ongoing anxiety on such circuitry function, especially in youth. Using fMRI fear conditioning and extinction paradigms, we examined these relationships in 10-17 year-olds: 22 youth with an anxiety disorder, 22 healthy youth born to parents with past or current anxiety disorders (at risk), and 32 healthy comparisons. Skin conductance responses and subjective fear ratings were also assessed. During conditioning, healthy comparisons showed differential activation (CS + >CS-) in regions of the fronto-amygdala circuitry. In comparison, the at-risk group showed greater activation to the safety cue (CS - >CS+) in the amygdala and dorsolateral prefrontal cortex. Failure to show differential fear conditioning in the fronto-amygdala circuitry and impairment in extinction learning was specific to anxious youth. These findings expand our ability to track anxiety-related alterations and potential resilience markers to anxiety.

Chronic harsh parenting and anxiety associations with fear circuitry function in healthy adolescents: A preliminary study.

Previous studies have reported altered fear circuitry function during fear conditioning in highly anxious individuals and in adults with a history of severe childhood adversity; less is known regarding younger populations and more common forms of adversity. We investigated fear circuitry functioning in healthy youths with histories of high (HH) or low (LH) chronic harsh parenting and high (HA) or low (LA) anxiety levels. 84 youths aged 13-16 performed an fMRI fear conditioning task. HH displayed decreased selective medial temporal lobe deactivations to CS+> CS- relative to LH. In addition, we found less amygdala-insula connectivity in HH vs LH. Interestingly, we observed distinct patterns of anxiety differences in amygdala-rostral ACC connectivity and subjective fear ratings depending on harsh parenting levels, suggesting a history of harsh parenting is linked with unique neural and behavioral anxious manifestations, which are different from anxiety manifestations in a context of low adversity.

On a continuum to anxiety disorders: Adolescents at parental risk for anxiety show smaller rostral anterior cingulate cortex and insula thickness.

BACKGROUND: Having a parent with an anxiety disorder increases the risk of anxiety symptoms and anxiety disorders during the lifespan. Moreover, childhood and adolescence anxiety disorders and symptoms have been linked to a range of brain structure abnormalities. However, to date, no study has investigated brain anatomy in adolescents at high risk based on parental anxiety disorders and in adolescents with an anxiety disorder but without any treatment or therapy. METHODS: Anatomical images from magnetic resonance imaging of 68 adolescents with anxiety disorders without any treatment (N = 20), at risk for anxiety because of their parents' anxiety disorders (N = 21), and comparison youths (N = 27), were analyzed using Freesurfer. RESULTS: Compared to comparison group, smaller cortical thickness of the rostral anterior cingulate cortex and of the insula was observed in anxious and at-risk groups; smaller amygdala volume was observed in the anxious group only. LIMITATIONS: The age range studied is large (10 to 17 years old). Moreover, this study is cross-sectional. Since adolescence is one of the biggest periods of cerebral reorganization, longitudinal follow-up of these youths would be necessary. CONCLUSIONS: Smaller rostral anterior cingulate cortex and insula cortical thickness appear to be cerebral markers of the risk of developing an anxiety disorder in adolescence. The reduction of the amygdala volume seems to be linked to the onset of the disorder.

The conditioning and extinction of fear in youths: what's sex got to do with it?

Adult work shows differences in emotional processing influenced by sexes of both the viewer and expresser of facial expressions. We investigated this in 120 healthy youths (57 boys; 10-17 years old) randomly assigned to fear conditioning and extinction tasks using either neutral male or female faces as the conditioned threat and safety cues, and a fearful face paired with a shrieking scream as the unconditioned stimulus. Fear ratings and skin conductance responses (SCRs) were assessed. Male faces triggered increased fear ratings in all participants during conditioning and extinction. Greater differential SCRs were observed in boys viewing male faces and in girls viewing female faces during conditioning. During extinction, differential SCR findings remained significant in boys viewing male faces. Our findings demonstrate how sex of participant and sex of target interact to shape fear responses in youths, and how the type of measure may lead to distinct profiles of fear responses.

Incentive effect on inhibitory control in adolescents with early-life stress: an antisaccade study.

OBJECTIVE: Early-life stress (ES) such as adoption, change of caregiver, or experience of emotional neglect may influence the way in which affected individuals respond to emotional stimuli of positive or negative valence. These modified responses may stem from a direct alteration of how emotional stimuli are coded, and/or the cognitive function implicated in emotion modulation, such as self-regulation or inhibition. These ES effects have been probed on tasks either targeting reward and inhibitory function. Findings revealed deficits in both reward processing and inhibitory control in ES youths. However, no work has yet examined whether incentives can improve automatic response or inhibitory control in ES youths. METHOD: To determine whether incentives would only improve self-regulated voluntary actions or generalize to automated motoric responses, participants were tested on a mixed eye movement task that included reflex-like prosaccades and voluntary controlled antisaccade eye movements. Seventeen adopted children (10 females, mean age 11.3 years) with a documented history of neglect and 29 typical healthy youths (16 females, mean age 11.9 years) performed the mixed prosaccade/antisaccade task during monetary incentive conditions or during no-incentive conditions. RESULTS: Across both saccade types, ES adolescents responded more slowly than controls. As expected, control participants committed fewer errors on antisaccades during the monetary incentive condition relative to the no-incentive condition. By contrast, ES youths failed to show this incentive-related improvement on inhibitory control. No significant incentive effects were found with prepotent prosaccades trials in either group. Finally, co-morbid psychopathology did not modulate the findings. CONCLUSIONS: These data suggest that youths with experience of early stress exhibit deficient modulation of inhibitory control by reward processes, in tandem with a reward-independent deficit in preparation for both automatic and controlled responses. These data may be relevant to interventions in ES youths.

Metyrapone administration reduces the strength of an emotional memory trace in a long-lasting manner.

CONTEXT: It has recently been demonstrated that the process of memory retrieval serves as a reactivation mechanism whereby the memory trace that is reactivated during retrieval is once again sensitive to modifications by environmental or pharmacological manipulations. Recent studies have shown that glucocorticoids (GCs) have the capacity to modulate the process of memory retrieval. This suggests that GCs could be an interesting avenue to investigate with regard to reduction of emotional memory. OBJECTIVE: The current study assessed whether a pharmacological decrease in GC levels, induced by metyrapone, a potent inhibitor of GC secretion, would affect retrieval of emotional and neutral information in an acute and/or long-lasting manner. DESIGN, SETTING, PARTICIPANTS, AND INTERVENTION: To do so, 1 × 750 mg dose of metyrapone, 2 × 750 mg dose of metyrapone, or placebo was administered to young normal participants 3 d after the encoding of a slide show having neutral and emotional segments. The experiment took place in a university and a hospital setting. MAIN OUTCOME MEASURE: Memory performance was assessed after treatment and 4 d later. RESULTS: RESULTS showed that retrieval of emotional information was acutely impaired in the double-dose metyrapone group and that this effect was still present 4 d later, when GC levels were not different between groups. CONCLUSIONS: These results show that decreasing GC levels via metyrapone administration is an efficient way to reduce the strength of an emotional memory in a long-lasting manner.

Enhanced right amygdala activity in adolescents during encoding of positively valenced pictures.

While studies among adults implicate the amygdala and interconnecting brain regions in encoding emotional stimuli, few studies have examined whether developmental changes occur within this emotional-memory network during adolescence. The present study examined whether adolescents and adults differentially engaged the amygdala and hippocampus during successful encoding of emotional pictures, with either positive or negative valence. Eighteen adults and twelve adolescents underwent event-related fMRI while encoding emotional pictures. Approximately 30 min later, outside the scanner, subjects were asked to recall the pictures seen during the scan. Age group differences in brain activity in the amygdala and hippocampus during encoding of the pictures that were later successfully and unsuccessfully recalled were separately compared for the positive and negative pictures. Adolescents, relative to adults, demonstrated enhanced activity in the right amygdala during encoding of positive pictures that were later recalled compared to not recalled. There were no age group differences in amygdala or hippocampal activity during successful encoding of negative pictures. The findings of preferential activity within the adolescent right amygdala during successful encoding of positive pictures may have implications for the increased reward and novelty seeking behavior, as well as elevated rates of psychopathology, observed during this distinct developmental period.

Early-life stress is associated with impairment in cognitive control in adolescence: an fMRI study.

Early-life stress (ES) has been associated with diverse forms of psychopathology. Some investigators suggest that these associations reflect the effects of stress on the neural circuits that support cognitive control. However, very few prior studies have examined the associations between ES, cognitive control, and underlying neural architecture. The present study compares adolescents with a documented history of ES to typical adolescents on a cognitive control task using functional magnetic resonance imaging (fMRI). Twelve ES adolescents who were adopted because of early caregiver deprivation (9 females, age=13 years+/-2.58) and 21 healthy control adolescents without a history of ES (10 females, age=13 years+/-1.96) who resided with their biological parents performed the change task (Nelson, Vinton et al., 2007)--a variant of the stop task--during fMRI. Behaviourally, ES adolescents took longer to switch from a prepotent response ("go") to an alternative response ("change") than control adolescents. During correct "change" responses vs. correct "go" responses, this behavioural group difference was accompanied by higher activation in ES subjects than controls. These differences were noted in regions involved in primary sensorimotor processes (pre- and postcentral gyri), conflict monitoring (dorsal anterior cingulate gyrus), inhibitory and response control (inferior prefrontal cortex and striatum), and somatic representations (posterior insula). Furthermore, correct "change" responses vs. incorrect "change" responses recruited the inferior prefrontal cortex (BA 44/46) more strongly in ES subjects than controls. These data suggest impaired cognitive control in youth who experienced ES.

A preliminary study of medial temporal lobe function in youths with a history of caregiver deprivation and emotional neglect.

Previous research findings have linked caregiver deprivation and emotional neglect with sensitivity to threatening cues. The present preliminary study investigated whether dysfunctions of the medial temporal lobe could underlie these associations. Using fMRI, we measured medial temporal lobe responses to emotional faces (angry, fearful, happy, neutral) among 30 youths. Eleven of the youths had a history of caregiver deprivation and emotional neglect. Attention states (i.e., attention to anger, fear, or physical attributes, or passive viewing) were systematically manipulated. Relative to comparison youths, youths with a history of caregiver deprivation and emotional neglect showed significantly greater left amygdala and left anterior hippocampus activation during the processing of threatening information. To our knowledge, these findings are the first to demonstrate altered medial temporal lobe function during the processing of threat cues in youths with a history of caregiver deprivation and emotional neglect.

Altered amygdala and hippocampus function in adolescents with hypercortisolemia: a functional magnetic resonance imaging study of Cushing syndrome.

Chronic elevations of endogenous cortisol levels have been shown to alter medial temporal cortical structures and to be accompanied by declarative memory impairments and depressive symptoms in human adults. These effects of elevated endogenous levels of cortisol have not been directly studied in adolescents. Because adolescents with Cushing syndrome show endogenous elevations in cortisol, they represent a unique natural model to study the effects of prolonged hypercortisolemia on brain function, and memory and affective processes during this developmental stage. Using functional magnetic resonance imaging (fMRI), we compared 12 adolescents with Cushing syndrome with 22 healthy control adolescents on amygdala and anterior hippocampus activation during an emotional faces encoding task. None of these adolescents manifested depressive symptoms. Encoding success was assessed using a memory recognition test performed after the scan. The fMRI analyses followed an event-related design and were conducted using the SPM99 platform. Compared to healthy adolescents, patients with Cushing syndrome showed greater left amygdala and right anterior hippocampus activation during successful face encoding. Memory performance for faces recognition did not differ between groups. This first study of cerebral function in adolescents with chronic endogenous hypercortisolemia due to Cushing syndrome demonstrates the presence of functional alterations in amygdala and hippocampus, which are not associated with affective or memory impairments. Such findings need to be followed by work examining the role of age and related brain maturational stage on these effects, as well as the identification of possible protective factors conferring resilience to affective and cognitive consequences in this disease and/or during this stage of cerebral development.

Steroid abnormalities and the developing brain: declarative memory for emotionally arousing and neutral material in children with congenital adrenal hyperplasia.

Steroid hormones modulate memory in animals and human adults. Little is known on the developmental effects of these hormones on the neural networks underlying memory. Using Congenital adrenal hyperplasia (CAH) as a naturalistic model of early steroid abnormalities, this study examines the consequences of CAH on memory and its neural correlates for emotionally arousing and neutral material in children. Seventeen patients with CAH and 17 age- and sex-matched healthy children (ages 12-14 years) completed the study. Subjects were presented positive, negative and neutral pictures. Memory recall occurred about 30min after viewing the pictures. Children with CAH showed memory deficits for negative pictures compared to healthy children (p<0.01). There were no group differences on memory performance for either positive or neutral pictures (p>0.1). In patients, 24h urinary-free cortisol levels (reflecting glucocorticoid replacement therapy) and testosterone levels were not associated with memory performance. These findings suggest that early steroid imbalances affect memory for negative material in children with CAH. Such memory impairments may result from abnormal brain organization and function following hormonal dysfunction during critical periods of development.

Amygdala function in adolescents with congenital adrenal hyperplasia: a model for the study of early steroid abnormalities.

Early disruption of steroids affects the development of mammalian neural circuits underlying affective processes. In humans, patients with classic congenital adrenal hyperplasia (CAH) can serve as a natural model to study early hormonal alterations on functional brain development. CAH is characterized by congenital glucocorticoid insufficiency, leading to altered hypothalamic-pituitary-adrenal (HPA) function, and hyperandrogenism. Using fMRI, we compared fourteen adolescents with CAH to 14 healthy controls on amygdala response to a face viewing task. In response to negative facial emotions, CAH females activated the amygdala significantly more than healthy females, whereas CAH males did not differ from control males. Furthermore, females with CAH showed a similar pattern of amygdala activation to control males, suggesting virilized amygdala function in females with CAH. These findings suggest a prominent effect of early hyperandrogenism on the development and function of the amygdala in females with CAH, whereas no effects were detected in males with CAH. This study provides data that can be further tested in a model of the neurobiological mechanisms underlying early androgen organizational effects on amygdala function.

The perfect time to be stressed: a differential modulation of human memory by stress applied in the morning or in the afternoon.

We measured the effects of a stressful experience on memory for emotionally arousing and neutral material learned after exposure to a stressor which induces a significant increase in corticosteroid stress hormones. Because memory performance can be influenced by circadian changes in corticosteroid levels, subjects were tested either in the morning or in the afternoon. Nineteen healthy men (9 in the morning group and 10 in the afternoon group) were submitted to a psychological stress task before viewing a story composed of emotionally negative and neutral segments, while another 20 healthy males (10 in the morning group and 10 in the afternoon group) viewed the story without being exposed to the psychological stressor. Salivary cortisol levels were measured before and after the stressor. Memory performance was assessed by a one week post learning delayed recall. Results show that stress-induced increases in salivary cortisol levels impaired delayed free recall of emotionally arousing material in the morning group, but not in the afternoon group. There was no effect of stress on memory for neutral material. Altogether, these findings suggest that stressing participants in the morning, at a time of high circulating levels of corticosteroids, over stimulated the corticosteroid receptors in the brain, impairing declarative memory for emotionally arousing material unrelated to the stressor. These findings suggest that the experimental context, i.e., time of day at which the experiment occurs, the nature of the to-be-remembered material (remembering the stressful event itself or material unrelated to the stressor) and the valence of the to-be-remembered material (emotionally arousing vs. neutral), modulates the effects of stress on human declarative memory.

Declarative memory after stress in humans: differential involvement of the beta-adrenergic and corticosteroid systems.

To determine the role played by the beta-adrenergic and corticosteroid systems in the modulatory effects of stress on declarative memory function, 42 young men were administered a placebo, propranolol (beta-adrenergic blocker), or metyrapone (corticosteroid synthesis inhibitor) before being submitted to a psychological stress protocol. Immediately after stress, subjects viewed a neutral story, unrelated to the stressor. Short- (5 min post learning) and long-term (1 wk post learning) recall of the story was assessed. Placebo and propranolol groups showed significant stress-related increases in corticosteroid levels, whereas metyrapone prevented corticosteroid reactivity to the stressor. Stress triggered significant elevations in cardiac activity (heart rate, systolic and diastolic blood pressure levels) in all three groups, with the metyrapone group showing the strongest elevation in heart rate levels in response to stress. Compared with placebo, propranolol had no effect on short- and long-term recall of the story learned after stress, whereas metyrapone impaired short-term recall of the story, with no further effects on long-term declarative memory. These results suggest that, contrary to the beta-adrenergic system, the corticosteroid system is implicated in declarative memory function after stress in humans.

Differential effects of adrenergic and corticosteroid hormonal systems on human short- and long-term declarative memory for emotionally arousing material.

The effects of adrenergic and corticosteroid hormonal systems on emotional memory were measured in 64 young men. Placebo, propranolol (40 or 80 mg; beta blocker), or metyiapone (corticosteroid synthesis inhibitor) was administered before the viewing of a story composed of emotional and neutral segments. Short- and long-term declarative memory for the story was assessed. Propranolol 40 mg had no effects on declarative memory. Propranolol 80 mg impaired short- and long-term declarative memory for emotionally arousing material. Metyrapone did not impair short-term declarative memory but impaired long-term declarative memory for emotionally arousing and neutral material. Results demonstrate that adrenergic and corticosteroid hormonal systems differentially affect declarative memory for emotionally arousing and neutral material, and suggest that interactions between adrenal hormonal systems modulate emotionally arousing declarative memory in humans.

[Memory in the grip of emotions and stress: a necessarily harmful impact?]. / La mémoire aux prises avec les émotions et le stress: un impact nécessairement dommageable?

While intense negative events are vividly recalled, information learned during stressful situations is poorly remembered. These differential effects of emotions and stress on memory have been attributed to the physiological manifestations generated during those affective states. Intense emotional and stressful events trigger the secretion of catecholamines and of glucocorticoids, in particular. These hormones would be modulatory agents of memory functions. In the first part of this paper, we review the specific effects emotions and stress have on memory. We then summarize the psychological and biological determinants responsible for these effects. Finally, we discuss different methodological issues that could explain the discrepancy found between the impact of emotions and stress on memory. Defining more precisely the effects emotion and stress have on memory will lead to a better comprehension of the cognitive problems that characterize patients dealing with emotional turmoil, such as patients suffering from depression or post-traumatic stress disorder.