Frontostriatal dysfunction during response inhibition in Williams syndrome.

BACKGROUND: Williams syndrome (WS) has provided researchers with an exciting opportunity to understand the complex interplay among genes, neurobiological and cognitive functions. However, despite a well-characterized cognitive and behavioral phenotype, little attention has been paid to the marked deficits in social and behavioral inhibition. Here we explore the neural systems that mediate response inhibition in WS. METHODS: We used functional MRI (fMRI) to obtain blood oxygenation level dependence (BOLD) signal maps during the performance of a Go/NoGo response inhibition task from 11 clinically and genetically diagnosed WS patients and 11 age- and gender-matched typically developing (TD) control subjects. Correlations between behavioral, neuropsychological measures, and BOLD signal were also conducted. RESULTS: Although TD control subjects showed significantly faster response times, no group differences in behavioral accuracy were observed. Compared with control subjects, WS participants demonstrated significantly reduced activity in the striatum, dorsolateral prefrontal, and dorsal anterior cingulate cortices. These findings support the hypothesis that persons with WS fail to activate critical cortical and subcortical structures involved in behavioral inhibition. CONCLUSIONS: Our results provide important evidence for reduced engagement of the frontostriatal circuits in WS and provide putative biological markers for the deficits in response inhibition and the unusual social phenotype.     

Heritability and genetic correlation of hair cortisol in vervet monkeys in low and higher stress environments

Chronic activation of the hypothalamic-pituitary adrenal (HPA) system is a risk factor for a variety of physical and mental disorders, and yet the complexity of the system has made it difficult to define the role of genetic and environmental factors in producing long-term individual differences in HPA activity. Cortisol levels in hair have been suggested as a marker of total HPA activation over a period of several months. This study takes advantage of a pedigreed nonhuman primate colony to investigate genetic and environmental influences on hair cortisol levels before and after an environmental change. A sample of 226 adult female vervet monkeys (age 3-18) living in multigenerational, matrilineal social groups at the Vervet Research Colony were sampled in a stable low stress baseline environment and 6 months after the entire colony was moved to a new facility with more frequent handling and group disturbances (higher stress environment). Variance components analysis using the extended colony pedigree was applied to determine heritability of hair cortisol levels in the two environments. Bivariate genetic correlation assessed degree of overlap in genes influencing hair cortisol levels in the low and higher stress environments. The results showed that levels of cortisol in hair of female vervets increased significantly from the baseline to the post-move environment. Hair cortisol levels were heritable in both environments (h(2)=0.31), and there was a high genetic correlation across environments (rhoG=0.79), indicating substantial overlap in the genes affecting HPA activity in low and higher stress environments. This is the first study to demonstrate that the level of cortisol in hair is a heritable trait. It shows the utility of hair cortisol as a marker for HPA activation, and a useful tool for identifying genetic influences on long term individual differences in HPA activity. The results provide support for an additive model of the effects of genes and environment on this measure of long term HPA activity.     

Early life stress affects cerebral glucose metabolism in adult rhesus monkeys (Macaca mulatta)

Early life stress (ELS) is a risk factor for anxiety, mood disorders and alterations in stress responses. Less is known about the long-term neurobiological impact of ELS. We used [(18)F]-fluorodeoxyglucose Positron Emission Tomography (FDG-PET) to assess neural responses to a moderate stress test in adult monkeys that experienced ELS as infants. Both groups of monkeys showed hypothalamic-pituitary-adrenal (HPA) axis stress-induced activations and cardiac arousal in response to the stressor. A whole brain analysis detected significantly greater regional cerebral glucose metabolism (rCGM) in superior temporal sulcus, putamen, thalamus, and inferotemporal cortex of ELS animals compared to controls. Region of interest (ROI) analyses performed in areas identified as vulnerable to ELS showed greater activity in the orbitofrontal cortex of ELS compared to control monkeys, but greater hippocampal activity in the control compared to ELS monkeys. Together, these results suggest hyperactivity in emotional and sensory processing regions of adult monkeys with ELS, and greater activity in stress-regulatory areas in the controls. Despite these neural responses, no group differences were detected in neuroendocrine, autonomic or behavioral responses, except for a trend towards increased stillness in the ELS monkeys. Together, these data suggest hypervigilance in the ELS monkeys in the absence of immediate danger.     

Preliminary evidence that hippocampal volumes in monkeys predict stress levels of adrenocorticotropic hormone.

BACKGROUND: Hippocampal volumes previously determined in monkeys by magnetic resonance imaging are used to test the hypothesis that small hippocampi predict increased stress levels of adrenocorticotropic hormone (ACTH). METHODS: Plasma ACTH levels were measured after restraint stress in 19 male monkeys pretreated with saline or hydrocortisone. Monkeys were then randomized to an undisturbed control condition or intermittent social separations followed by new pair formations. After 17 months of exposure to the intermittent social manipulations, restraint stress tests were repeated to determine test/retest correlations. RESULTS: Individual differences in postrestraint stress ACTH levels over the 17-month test/retest interval were remarkably consistent for the saline (r(s) = .82, p = .0004) and hydrocortisone (r(s) = .78, p = .001) pretreatments. Social manipulations did not affect postrestraint stress ACTH levels, but monkeys with smaller hippocampal volumes responded to restraint after saline pretreatment with greater increases in ACTH levels with total brain volume variation controlled as a statistical covariate (beta = -.58, p = .031). Monkeys with smaller hippocampal volumes also responded with diminished sensitivity to glucocorticoid feedback determined by greater postrestraint ACTH levels after pretreatment with hydrocortisone (beta = -.68, p = .010). CONCLUSIONS: These findings support clinical reports that small hippocampi may be a risk factor for impaired regulation of the hypothalamic-pituitary-adrenal axis in humans with stress-related psychiatric disorders.     

Early life stress and novelty seeking behavior in adolescent monkeys

Recent evidence suggests that early exposure to mild stress promotes the development of novelty seeking behavior. Here we test this hypothesis in squirrel monkeys and investigate whether novelty seeking behavior is associated with differences in cerebrospinal fluid (CSF) levels of the serotonin metabolite 5-hydroxyindoleacetic acid (5HIAA), the dopamine metabolite homovanillic acid (HVA), the norepinephrine metabolite 3-methoxy-4-hydroxyphenylethylene glycol (MHPG), and the neuropeptide corticotrophin-releasing factor (CRF). Monkeys were randomized early in life to either mild intermittent stress (IS) or no stress (NS) conditions, and subsequently presented with opportunities to interact with a familiar or novel object in a test box that was connected to each monkey's home cage. To further minimize the potentially stressful nature of the test situation, monkeys were acclimated to the test procedures prior to study initiation. Post-test plasma levels of cortisol in IS and NS monkeys did not differ significantly from baseline levels measured in undisturbed conditions. During testing, more IS than NS monkeys voluntarily left the home cage, and IS monkeys spent more time in the test box compared to NS monkeys. More IS than NS monkeys engaged in object exploration in the test box, and IS monkeys preferred to interact with the novel vs. familiar object. Novelty seeking was not associated with differences in 5HIAA, HVA, MHPG, or CRF, but correlated with differences in object exploration observed in a different test situation at an earlier age. These trait-like differences in novelty seeking appear to reflect mild early stress-induced adaptations that enhance curiosity and resilience.     

Abnormal prefrontal cortex function during response inhibition in Turner syndrome: functional magnetic resonance imaging evidence.

BACKGROUND: Turner syndrome (TuS) arises from the partial or complete absence of one X chromosome. Although neuropsychological studies report impaired attentional function and response inhibition in TuS, the neural correlates of these cognitive problems are unknown. METHODS: Eleven female subjects with TuS and 11 individually matched normal control subjects were imaged using functional magnetic resonance imaging while performing a Go/NoGo task. RESULTS: Groups did not differ on accuracy or reaction time; however, the TuS group activated more in the bilateral superior and middle frontal gyri than control subjects. Control subjects did not activate more than the TuS group in any region. CONCLUSION: These findings suggest that female subjects with TuS compensate for executive dysfunction via recruitment of additional prefrontal cortex regions involved in inhibition, attention, and working memory, functions necessary for successful performance of Go/NoGo tasks. Elucidating brain function in TuS will advance our understanding of the influence of X-chromosome genes on neurodevelopment and brain function and contribute to planning future intervention strategies.     

GABAA receptor-acting neurosteroids: A role in the development and regulation of the stress response

Regulation of hypothalamic–pituitary–adrenocortical (HPA) axis activity by stress is a fundamental survival mechanism and HPA-dysfunction is implicated in psychiatric disorders. Adverse early life experiences, e.g. poor maternal care, negatively influence brain development and programs an abnormal stress response by encoding long-lasting molecular changes, which may extend to the next generation. How HPA-dysfunction leads to the development of affective disorders is complex, but may involve GABA_A receptors (GABA_ARs), as they curtail stress-induced HPA axis activation. Of particular interest are endogenous neurosteroids that potently modulate the function of GABA_ARs and exhibit stress-protective properties. Importantly, neurosteroid levels rise rapidly during acute stress, are perturbed in chronic stress and are implicated in the behavioural changes associated with early-life adversity. We will appraise how GABA_AR-active neurosteroids may impact on HPA axis development and the orchestration of the stress-evoked response. The significance of these actions will be discussed in the context of stress-associated mood disorders.     

Bilateral decrease in ventrolateral prefrontal cortex activation during motor response inhibition in mania

Mania has been frequently associated with impaired inhibitory control. The present study aimed to identify brain functional abnormalities specifically related to motor response inhibition in mania by using event-related fMRI in combination with a Go/NoGo task designed to control for extraneous cognitive processes involved in task performance. Sixteen manic patients and 16 healthy subjects, group-matched for age and sex, were imaged while performing a warned equiprobable Go/NoGo task during event-related fMRI. Between-group differences in brain activation associated with motor response inhibition were assessed using analyses of covariance. Although no significant between-group differences in task performance accuracy were observed, patients showed significantly longer response times on Go trials. After controlling for covariates, the only brain region that differentiated the two groups during motor response inhibition was the ventrolateral prefrontal cortex (VLPFC), where activation was significantly decreased in both the right and left hemispheres in manic patients. Our data suggest that response inhibition in mania is associated with a lack of engagement of the bilateral VLPFC, which is known to play a primary role in the suppression of irrelevant responses. This result might give clues to understanding the pathophysiology of dishinhibition and impulsivity that characterize mania.     

Diminished cortisol responses to psychosocial stress associated with lifetime adverse events a study among healthy young subjects

BACKGROUND: Animal and human studies have found that prior stressful events can result in an altered reactivity in the HPA axis. The aim of the present study was to investigate the role of adverse events in childhood on cortisol reactivity to psychosocial stress in young healthy subjects (n=80). METHODS: Salivary cortisol levels were measured before, during and after exposure to a psychosocial stress task in healthy men and women with high (n=33) and low (n=47) exposure to adverse childhood events. RESULTS: A significant blunted cortisol response was found in individuals with a history of adverse events compared to individuals with no adverse life events, with no differences in baseline cortisol levels. This finding appeared to be primarily driven by men. The groups did not differ on any other physiological or subjective stress measure, including heart rate, blood pressure, and subjective tension. CONCLUSIONS: These findings suggest that, at least in healthy young males, adverse childhood events are associated with changes in HPA-axis functioning. Longitudinal studies are needed to investigate whether the blunted cortisol response is a risk factor in the etiology of psychiatric disorders or rather reflects resiliency with regard to the development of psychopathology.     

Naturalistic stress and cortisol response to awakening: adaptation to seafaring

Study of the hypothalamic-pituitary adrenal (HPA) axis has been critical to advancing our understanding of human adaptation to stress. The cortisol response to awakening (CRA) is a potentially useful measure for understanding group and individual differences in HPA axis regulation. In this study, the CRA was examined in the context of a naturalistic stressor--a 6-week voyage of work and study aboard an oceangoing ship, including both experienced and novice sailors. Thirty-one subjects provided weekday and weekend baseline CRA data onshore prior to boarding, followed by three CRAs at sea and one shore leave CRA. Subjective measures of sleep, stress and control were also collected. Results suggest that novice sailors' cortisol response to awakening was elevated at sea relative to both a shoreside weekend and a shore leave during the voyage, but the most striking elevation was found during a workday onshore. Inexperienced students' profiles changed differently over the course of the voyage from those of professional crew. CRAs were not affected by sleep variables and were not predicted by subjective ratings. These data support the value of the cortisol response to awakening as a neuroendocrine marker of HPA regulatory responses to a naturalistic stressor, influenced by changes in work and living environment, and perhaps prior experience with the stressor.     

Blunted HPA axis response to stress influences susceptibility to posttraumatic stress response in rats.

BACKGROUND: Posttraumatic stress disorder (PTSD) is associated with low levels of circulating cortisol, and recent studies suggest that cortisol administration may reduce PTSD symptoms. This study investigated the role of cortisol in the manifestation of anxiety- and fear-like symptoms in an animal model of PTSD. METHOD: Magnitude of changes in prevalence of anxiety-like behaviors on the elevated plus-maze and nonhabituated exaggerated startle reaction were compared in three strains of rats exposed to predator stress, with and without prior corticosterone treatment. Extreme behavioral changes in both paradigms implied an extreme behavioral response (EBR), representing PTSD-like symptoms. RESULTS: Lewis rats exhibited greater baseline anxiety-like behaviors and greater stress-induced increases in anxiety-like behaviors than Fischer F344 or Sprague-Dawley rats, with only minor corticosterone increases following stress. Prevalence of EBR was 50% among Lewis rats compared with 10% of Fischer F344 and 25% of Sprague-Dawley rats. Administering corticosterone 1 hour before stress exposure reduced the prevalence of EBR from 50% to 8% in the Lewis rats. CONCLUSIONS: These results suggest that a blunted HPA response to stress may play a causal role in this model of PTSD and that this susceptibility may be prevented by administration of cortisol before stress exposure.     

Basal ganglia-thalamocortical circuitry disruptions in schizophrenia during delayed response tasks.

BACKGROUND: Schizophrenia is characterized by executive functioning deficits, presumably mediated by prefrontal cortex dysfunction. For example, schizophrenia participants show performance deficits on ocular motor delayed response (ODR) tasks, which require both inhibition and spatial working memory for correct performance. METHODS: The present functional magnetic resonance imaging (fMRI) study compared neural activity of 14 schizophrenia and 14 normal participants while they performed ODR tasks. RESULTS: Schizophrenia participants generated: 1) more trials with anticipatory saccades (saccades made during the delay period), 2) memory saccades with longer latencies, and 3) memory saccades of decreased accuracy. Increased blood oxygenation level-dependent (BOLD) signal changes were observed in both groups in ocular motor circuitry (e.g., supplementary eye fields [SEF], lateral frontal eye fields [FEF], inferior parietal lobule [IPL], cuneus, and precuneus). The normal, but not the schizophrenia, group demonstrated BOLD signal changes in dorsolateral prefrontal regions (right Brodmann area [BA] 9 and bilateral BA 10), medial FEF, insula, thalamus, and basal ganglia. Correlations between percentage of anticipatory saccade trials and BOLD signal changes were more similar between groups for subcortical regions and less similar for cortical regions. CONCLUSIONS: These results suggest that executive functioning deficits in schizophrenia may be associated with dysfunction of the basal ganglia-thalamocortical circuitry, evidenced by decreased prefrontal cortex, basal ganglia, and thalamus activity in the schizophrenia group during ODR task performance.     

Effects of early life stress on adult male aggression and hypothalamic vasopressin and serotonin

Early life stress in humans enhances the risk for psychopathologies, including excessive aggression and violence. In rodents, maternal separation is a potent early life stressor inducing long-lasting changes in emotional and neuroendocrine responsiveness to stress, associated with depression- and anxiety-like symptoms. However, effects of maternal separation on adult male aggression and underlying neurobiological mechanisms remain unknown. Therefore, we investigated the effects of maternal separation on adult intermale aggression in Wistar rats and on hypothalamic arginine vasopressin (AVP) mRNA expression, and AVP and serotonin (5-HT) immunoreactivity, as both AVP and 5-HT have been implicated in stress-coping and aggression. We showed that maternal separation induced depression-like behaviour (increased immobility) and higher adrenocorticotropin hormone responses to an acute stressor (forced swimming). Intermale aggression (lateral threat, offensive upright and keep down) was significantly higher in maternally separated rats compared with control rats. AVP mRNA expression and AVP immunoreactivity were higher in the hypothalamic paraventricular and supraoptic nuclei upon resident-intruder test exposure, whereas 5-HT immunoreactivity was decreased in the anterior hypothalamus of maternally separated rats. Moreover, 5-HT immunoreactivity in the anterior hypothalamus and supraoptic nucleus correlated negatively with aggression. These findings show that exposure to early life stress increases adult male aggression in an animal model of maternal separation. Furthermore, the maternal separation-induced changes in hypothalamic AVP and 5-HT systems may underlie these behavioural alterations.     

Diurnal salivary cortisol in pediatric posttraumatic stress disorder.

BACKGROUND: The hypothalamic-pituitary-adrenal (HPA) axis has been implicated in the pathophysiology of posttraumatic stress disorder (PTSD). Additional information on basal cortisol levels in children exposed to trauma and experiencing PTSD symptoms may contribute to the understanding of the role of this axis in PTSD. METHODS: Fifty-one children (30 boys and 21 girls, mean age 10.7 years) with a history of exposure to trauma and PTSD symptoms were compared with 31 age- and gender-matched healthy control subjects. Salivary cortisol was obtained from participants during home measurements and was collected four times a day (prebreakfast, prelunch, predinner, and prebed) for up to 3 consecutive days. RESULTS: The clinical group demonstrated significantly elevated cortisol levels when compared with the control group. In addition, exploratory analyses revealed that girls with PTSD symptoms had significantly elevated cortisol levels when compared with boys with PTSD symptoms. CONCLUSIONS: The physiologic response of children with history of trauma and with PTSD symptoms may be characterized by heightened adrenal activity.     

Nutritional aspects modulating brain development and the responses to stress in early neonatal life

Nutrition is one of the critical factors insuring adequate growth and development in all species. In particular, brain development is sensitive to specific nutrient intake such as proteins and lipids, which are important for cell membrane formation and myelinization. Carbohydrate intake insures adequate short-term energy supply, but has important effects on the activity of the hypothalamic–pituitary–adrenal (HPA) axis to regulate stress responsiveness. This review focuses on the effects of carbohydrates and fat on the activity of the HPA axis as well as other brain-related functions such as pain modulation, neuropeptide and neurotransmitters release, and some aspects related to cognitive functions. The role of leptin, DHA and AA as mediators of the effects of fat on the brain is discussed.