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.

Altered functional activations of prefrontal brain areas during emotional processing of fear in Inuit adolescents exposed to environmental contaminants.

Exposure to mercury, lead and polychlorinated biphenyls (PCBs) have been associated with emotional dysregulation, but their neuronal correlates have yet to be examined. Inuit from Nunavik (Northern Quebec, Canada) face internalizing problems and are among the most exposed individuals to these environmental contaminants in the world. The aim of this study was to examine the link between pre- and postnatal exposure to these contaminants and brain fear-circuitry in Inuit adolescents. Facial expression stimuli were presented to participants (mean age = 18.3 years) in a magnetic resonance imaging (MRI) scanner. Fear conditioning and extinction tasks included neutral faces as the conditioned threat and safety cues and a fearful face paired with a shrieking scream as the unconditioned stimulus. Functional MRI data were gathered at the conditioning phase (n = 71) and at the extinction phase (n = 62). Mercury, lead and PCB 153 concentrations were measured in blood samples at birth (cord blood) and at the time of the adolescent testing to estimate pre- and postnatal exposure, respectively. For each time point, exposures were categorized in tertiles (low, moderate and high exposed groups). Mixed analyses of variance were conducted for each contaminant of interest controlling for sex, age, socioeconomic status, drug/alcohol use, food insecurity and contaminant co-exposure. Results revealed greater differential activation during the conditioning phase in the right orbitofrontal cortex in participants with moderate and high concentrations of cord blood PCB 153 compared to those in the low exposure group. During the extinction phase, the high prenatal mercury exposed group showed a lower differential activation in the right and left anterior cingulate cortex compared to those in the low-exposed group; whereas there was a higher differential activation in right dorsolateral prefrontal cortex in the high postnatal lead exposed group compared to the moderate- and low-exposed groups. Our study is the first to show alterations in the prefrontal brain areas in fear conditioning and extinction tasks in relation to environmental contaminant exposures. The observed brain correlates may advance our understanding of the emotional problems associated with environmental chemical toxicity.

Risk factors associated with developing anxiety in Inuit adolescents from Nunavik.

This study aimed to examine the relation between anxiety among the at-risk population of Inuit adolescents and diverse developmental risk factors including exposure to environmental chemicals, a subject of concern in Nunavik. Anxiety was assessed in 89 Inuit participants (mean age = 18.4 years; range = 16.2-21.9) with the Screen for Child Anxiety Related Emotional Disorders (SCARED) and the State-Trait Anxiety Inventory (STAI). Potential risk factors for anxiety were documented at birth, 11 years of age and 18 years of age, including blood levels of chemicals (mercury, lead, PCBs) and nutrients, as well as age, sex, estimated IQ, drug and alcohol use, bullying, exposure to domestic violence, food insecurity, crowding and socio-economic status. Results showed that participants scored high on both measures of anxiety, particularly the SCARED, for which the mean score was above the clinical threshold. Multiple regression results show that significant risk predictors obtained from the SCARED scores were female sex (ß = 0.32), higher current blood mercury concentration (ß = 0.26), food insecurity (ß = 0.26) and bullying experiences in the last year (ß = 0.21). The significant predictors for the STAI trait anxiety were food insecurity (ß = 0.25) and lower estimated IQ (ß = -0.31), whereas food insecurity (ß = 0.21), lower blood levels of vitamin E (ß = -0.25) and higher cord blood mercury concentrations (ß = 0.25) were found for STAI situational anxiety. Further regression analyses suggested that the adolescent-related variables were the most important risk factors. Our findings show that Inuit adolescents are at risk for anxiety via multiple contributing factors, particularly current exposure to mercury, food insecurity and female sex.

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.

Twenty-year Follow-up of Kangaroo Mother Care Versus Traditional Care.

BACKGROUND AND OBJECTIVES: Kangaroo mother care (KMC) is a multifaceted intervention for preterm and low birth weight infants and their parents. Short- and mid-term benefits of KMC on survival, neurodevelopment, breastfeeding, and the quality of mother-infant bonding were documented in a randomized controlled trial (RCT) conducted in Colombia from 1993 to 1996. The aim of the present study was to evaluate the persistence of these results in young adulthood. METHODS: From 2012 to 2014, a total of 494 (69%) of the 716 participants of the original RCT known to be alive were identified; 441 (62% of the participants in the original RCT) were re-enrolled, and results for the 264 participants weighing ≤1800 g at birth were analyzed. The KMC and control groups were compared for health status and neurologic, cognitive, and social functioning with the use of neuroimaging, neurophysiological, and behavioral tests. RESULTS: The effects of KMC at 1 year on IQ and home environment were still present 20 years later in the most fragile individuals, and KMC parents were more protective and nurturing, reflected by reduced school absenteeism and reduced hyperactivity, aggressiveness, externalization, and socio-deviant conduct of young adults. Neuroimaging showed larger volume of the left caudate nucleus in the KMC group. CONCLUSIONS: This study indicates that KMC had significant, long-lasting social and behavioral protective effects 20 years after the intervention. Coverage with this efficient and scientifically based health care intervention should be extended to the 18 million infants born each year who are candidates for the method.

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.

Emotional memory in early steroid abnormalities: an FMRI study of adolescents with congenital adrenal hyperplasia.

Hormonal imbalances during development may have long-lasting effects. Using functional magnetic resonance imaging (fMRI), we compared 14 youths with Congenital Adrenal Hyperplasia (CAH), a genetic disorder of hormonal dysfunction, with 22 healthy controls on memory encoding of emotional faces. Patients remembered fewer faces than controls, particularly fearful faces. FMRI data to successfully encoded fearful faces revealed that males with CAH showed significant activations in amygdala, hippocampus, and anterior cingulate relative to unaffected males, while females with CAH demonstrated deactivations relative to unaffected females in these regions. Findings indicate that steroid abnormalities during development can have important effects on neural correlates of emotional memory.

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.

Hormetic influence of glucocorticoids on human memory.

In this paper, we discuss the effects of glucocorticoids on human learning and memory using the recent model of hormesis proposed by Calabrese and collaborators. Although acute increases in glucocorticoids have been shown to impair memory function in humans, other studies report no such impairments or, in contrast, beneficial effects of acute glucocorticoid increases on human memory function. We summarize these studies and assess whether the wealth of data obtained in humans with regard to the effects of acute increase of glucocorticoids on human cognition are in line with a hormetic function. We then discuss several factors that will have to be taken into account in order to confirm the presence of a hormetic function between glucocorticoids and human cognitive performance.

Stress hormones and human memory function across the lifespan.

In this paper, we summarize the data obtained in our laboratory showing the effects of glucocorticoids on human cognitive function in older adults, young adults and children. We first present data obtained in the aged human population which showed that long-term exposure to high endogenous levels of glucocorticoids is associated with both memory impairments and a 14% smaller volume of the hippocampus. We then report on studies showing that in older adults with moderate levels of glucocorticoids, memory performance can be acutely modulated by pharmacological manipulations of glucocorticoids. In young adults, we present data obtained in our laboratory showing that cognitive processing sustained by the frontal lobes is also sensitive to acute increases of glucocorticoids. We also summarize studies showing that just as in older adults, memory performance in young adults can be acutely modulated by pharmacological manipulations of glucocorticoids. We then present a study in which we showed a differential involvement of adrenergic and glucocorticoid hormones for short- and long-term memory of neutral and emotional information. In the last section of the paper, we present data obtained in a population of young children and teenagers from low and high socioeconomic status (SES), where we showed that children from low SES present significantly higher levels of basal cortisol when compared to children from high SES. We then present new data obtained in this population showing that children and teenagers from low and high SES do not process the plausibility of positive and negative attributes in the same way. Children from low SES tended to process positive and negative attributes on a more negative note than children from high SES, and this type of processing was significantly related to basal cortisol at age 10, 12 and 14. Altogether, the results of these studies show that both bottom-up (effects of glucocorticoids on cognitive function), and top-down (effects of cognitive processing on glucocorticoid secretion) effects exist in the human population.