Childhood stress, grown-up brain networks: corticolimbic correlates of threat-related early life stress and adult stress response.

BACKGROUND: Exposure to threat-related early life stress (ELS) has been related to vulnerability for stress-related disorders in adulthood, putatively via disrupted corticolimbic circuits involved in stress response and regulation. However, previous research on ELS has not examined both the intrinsic strength and flexibility of corticolimbic circuits, which may be particularly important for adaptive stress responding, or associations between these dimensions of corticolimbic dysfunction and acute stress response in adulthood. METHODS: Seventy unmedicated women varying in history of threat-related ELS completed a functional magnetic resonance imaging scan to evaluate voxelwise static (overall) and dynamic (variability over a series of sliding windows) resting-state functional connectivity (RSFC) of bilateral amygdala. In a separate session and subset of participants (n = 42), measures of salivary cortisol and affect were collected during a social-evaluative stress challenge. RESULTS: Higher severity of threat-related ELS was related to more strongly negative static RSFC between amygdala and left dorsolateral prefrontal cortex (DLPFC), and elevated dynamic RSFC between amygdala and rostral anterior cingulate cortex (rACC). Static amygdala-DLPFC antagonism mediated the relationship between higher severity of threat-related ELS and blunted cortisol response to stress, but increased dynamic amygdala-rACC connectivity weakened this mediated effect and was related to more positive post-stress mood. CONCLUSIONS: Threat-related ELS was associated with RSFC within lateral corticolimbic circuits, which in turn was related to blunted physiological response to acute stress. Notably, increased flexibility between the amygdala and rACC compensated for this static disruption, suggesting that more dynamic medial corticolimbic circuits might be key to restoring healthy stress response.

Functional deficits in basal ganglia of children with attention-deficit/hyperactivity disorder shown with functional magnetic resonance imaging relaxometry.

Attention-deficit/hyperactivity disorder is a highly heritable and prevalent neuropsychiatric disorder estimated to affect 6% of school-age children. Its clinical hallmarks are inattention, hyperactivity and impulsivity, which often respond substantially to treatment with methylphenidate or dextroamphetamine. Etiological theories suggest a deficit in corticostriatal circuits, particularly those components modulated by dopamine. We developed a new functional magnetic resonance imaging procedure (T2 relaxometry) to indirectly assess blood volume in the striatum (caudate and putamen) of boys 6-12 years of age in steady-state conditions. Boys with attention-deficit/hyperactivity disorder had higher T2 relaxation time measures in the putamen bilaterally than healthy control subjects. Relaxation times strongly correlated with the child's capacity to sit still and his accuracy in accomplishing a computerized attention task. Daily treatment with methylphenidate significantly changed the T2 relaxation times in the putamen of children with attention-deficit/hyperactivity disorder, although the magnitude and direction of the effect was strongly dependent on the child's unmedicated activity state. There was a similar but nonsignificant trend in the right caudate. T2 relaxation time measures in thalamus did not differ significantly between groups, and were not affected by methylphenidate. Attention-deficit/hyperactivity disorder symptoms may be closely tied to functional abnormalities in the putamen, which is mainly involved in the regulation of motor behavior.

Suckling.

Suckling is the only behavior that is common among mammals. In newborn albino rats it is originally elicited by amniotic fluid deposited by the mother during parturition. Subsequent suckling is stimulated by saliva deposited on the nipples by the infant rats. Internal controls over the volume of milk suckled do not appear until infant rats are about 2 weeks of age at which time gastric distension, milk, systemic dehydration, and intestinal hormone cholecystokinin suppress milk intake derived through suckling. The development of controls over suckling appetite appears to parallel that of consummatory control. Until about 2 weeks of age infant rats choose to suckle a nonlactating nipple with the same frequency as a lactating nipple. Thereafter, the lactating nipple is unanimously chosen. These studies suggest differences and commonalities in the suckling behavior of laboratory rats and other mammals.

Suckling in newborn rats: eliminated by nipple lavage, reinstated by pup saliva.

Chemical lavage of the nipples of anesthetized maternal rats virtually eliminated suckling by their 4- to 5-day-old pups. Normal suckling was immediately reinstated, however, by painting a vacuum distillate of the wash or of pup saliva onto the nipples. Thus, a substance necessary to direct and release suckling, possibly rat pup saliva, appears to coat the nipple surface.

Lateral preoptic lesions in rats separate urge to drink from amount of water drunk.

Rats with bilaterally symmetrical lesions in the laterla preoptic area do not drink after acute intracellular dehydration, but they drink normally after water deprivation. They, like normal rats, also drink more when cellular dehydration is superimposed upon water deprivation. Unlike normal rats, however, rats with lesions in the lateral preoptic area do not increase their rate of lever-pressing in response to the combined stimulus. Thus, the urge to drink can be separated from the amount of fluid drunk.

First suckling response of the newborn albino rat: the roles of olfaction and amniotic fluid.

Washing the nipples of anesthetized parturient rats virtually eliminated nipple attachment by their young. Normal attachment was induced only by painting the washed nipples with a distillate of the nipple wash, parturient-mother saliva, or her amniotic fluids. Reinstatement was not achieved by coating the washed nipples with the saliva of virgin females eating the same diet, the parturient mother's urine, isotonic saline, amyl acetate, or vanilla extract. These experiments also provide behavioral evidence for olfactory function in the newborn albino rat.

Environmental influences on body weight and behavior in developing rats after neonatal 6-hydroxydopamine.

There is less hyperactive motor activity and better avoidance performance in rat pups treated with 6-hydroxydopamine as neonates and reared with vehicle-treated littermates than in pups reared in litters composed solely of other 6-hydroxydopamine-treated animals. Thus, in this experimental model of hyperactivity, an environmental manipulation provides an alternative to pharmacologic agents in reducing activity and improving learning performance.

Early neglect is a key determinant of adult hair cortisol concentration and is associated with increased vulnerability to trauma in a transdiagnostic sample.

BACKGROUND: Childhood adversities and traumatic events have each been associated with hypothalamus-pituitary-adrenal (HPA) axis dysregulation and trauma-related symptoms in adulthood. Hair cortisol concentration (HCC) reflects cumulative cortisol levels over the course of months and is discussed as a potential marker between trauma-induced neuroendocrine dysfunction and trauma-related symptoms. The present study examines this hypothetical link by delineating the impact of exposure to categories of abuse and neglect during development and lifetime traumatic experiences on HCC and trauma-related symptoms. METHODS: The Maltreatment and Abuse Chronology Exposure (MACE) scale, Life Events Checklist, and predictive analytics were used to evaluate the importance of type and timing of maltreatment and trauma load on HCC in inpatients (n = 183) with different psychiatric diagnoses. Additionally, a comparison group of n = 75 controls were recruited from the community. The extent to which the relationship between trauma load and trauma-related symptoms was influenced by childhood adversities and HCC was determined by analysis of variance. RESULTS: Early neglect, in particular neglect at 3 years, emerged as the most important predictor of adult HCC. Post-hoc explanatory analysis showed that patients with high neglect at age 3 had lower HCC compared to patients with low neglect at age 3 and controls. Patients with high neglect at age 3 and low cortisol reported increased trauma-related symptoms upon trauma exposure. CONCLUSION: Results strengthen evidence that inadequate care and neglect during critical periods alter HPA axis biology towards enduring reduction in cortisol, the latter being associated with augmented trauma-related symptoms upon trauma exposure. If validated by longitudinal assessments these cross-sectional findings suggest biological mechanisms of childhood adversities into psychopathology in adulthood.

Relations among maternal withdrawal in infancy, borderline features, suicidality/self-injury, and adult hippocampal volume: A 30-year longitudinal study.

The hippocampus plays an important role in stress regulation and has been the focus of research regarding the effects of early life stress on brain development. Much of this research has focused on severe forms of early adversity, particularly maltreatment. However, a handful of studies are now examining the effects of more subtle variations in quality of early caregiving on hippocampal development. In addition, both early caregiving and hippocampal volumes have been linked to psychopathology, particularly borderline personality disorder (BPD) and its associated features, such as suicidality. In the context of a 30-year longitudinal study, we assessed associations between maternal withdrawal in infancy, hippocampal volume, and BPD features in adulthood. Hippocampal volume was assessed among 18 adults (29.33 ±â€¯0.49 years) assessed for caregiving quality at 18 months (M =18.55 months, SD = 1.21 months) and followed longitudinally to age 29. Left hippocampal volume in adulthood was associated with maternal withdrawal in infancy, but not by other components of disrupted parenting. Other risk factors, including maternal psychosocial risk and severity of maltreatment in childhood, were not significantly related to left hippocampal volume. Left hippocampal volume was further associated with increased BPD features and suicidality/self-injury. In addition, left hippocampal volume partially mediated the association between early maternal withdrawal and later suicidality/self-injury. Results point to the importance of quality of early care for hippocampal development and suggest that the first two years of life may be an early sensitive period during which intervention could have important consequences for long-term psychological functioning into adulthood.

Disorganized attachment in infancy predicts greater amygdala volume in adulthood.

Early life stress in rodents is associated with increased amygdala volume in adulthood. In humans, the amygdala develops rapidly during the first two years of life. Thus, disturbed care during this period may be particularly important to amygdala development. In the context of a 30-year longitudinal study of impoverished, highly stressed families, we assessed whether disorganization of the attachment relationship in infancy was related to amygdala volume in adulthood. Amygdala volumes were assessed among 18 low-income young adults (8M/10F, 29.33±0.49years) first observed in infancy (8.5±5.6months) and followed longitudinally to age 29. In infancy (18.58±1.02mos), both disorganized infant attachment behavior and disrupted maternal communication were assessed in the standard Strange Situation Procedure (SSP). Increased left amygdala volume in adulthood was associated with both maternal and infant components of disorganized attachment interactions at 18 months of age (overall r=0.679, p<0.004). Later stressors, including childhood maltreatment and attachment disturbance in adolescence, were not significantly related to left amygdala volume. Left amygdala volume was further associated with dissociation and limbic irritability in adulthood. Finally, left amygdala volume mediated the prediction from attachment disturbance in infancy to limbic irritability in adulthood. Results point to the likely importance of quality of early care for amygdala development in human children as well as in rodents. The long-term prediction found here suggests that the first two years of life may be an early sensitive period for amygdala development during which clinical intervention could have particularly important consequences for later child outcomes.

Significance of neuroleptic dose and plasma level in the pharmacological treatment of psychoses.

The clinical use of antipsychotic agents may be enhanced by considering their dose-effect characteristics. In particular, assessment of immediate and later follow-up treatment of psychotic patients (1) indicates that moderate doses are adequate for most patients, (2) fails to support the utility of unusually high doses, and (3) even suggests the existence of a biphasic relationship of antipsychotic efficacy to dose of neuroleptics and possibly to plasma concentrations of the drugs as well. Trends toward lesser overall clinical benefits of high doses may reflect untoward extrapyramidal or other central nervous system effects leading to behavioral and cognitive symptoms. Thus, moderate doses of neuroleptics appear, on average, to be about as effective as, and probably safer than, the larger doses that have been popular in the United States in recent years.

Seasonal mood disorders. Patterns of seasonal recurrence in mania and depression.

DSM-III-R criteria, applied retrospectively in a research-oriented psychiatric clinic, identified patients (N = 146) with a mood disorder and a seasonal pattern of recurrence (seasonal mood disorder). The seasonal mood disorder syndrome was not rare (10% of all mood disorders); diagnostic distribution was as follows: recurrent depression, 51%, and bipolar disorder, 49%, with 30% of the latter having mania (bipolar disorder type I) and 19% having hypomania (bipolar disorder type II). Most patients were women (71%); onset age averaged 29 years, with a mean of eight cycles in 12 years of illness; mean episode duration was 5.0 months. Mood disorder was found in a high proportion (68%) of the families. All but one patient followed one of two seasonal patterns in equal frequency: type A, fall-winter depression with or without spring-summer mania or hypomania; and type B, spring-summer depression with or without fall-winter mania or hypomania. Both types showed consistent times of onset and remission. These results emphasize that DSM-III-R seasonal mood disorder includes severe cases of recurrent depression and bipolar disorder and support a distinction between two seasonal subtypes.

Circadian rest-activity disturbances in seasonal affective disorder.

BACKGROUND: Previous studies hypothesized that seasonal affective disorder (SAD) was caused by a circadian rhythm abnormality. The purpose of this study was to ascertain whether rest-activity rhythms were phase delayed, diminished in amplitude, or more poorly entrained to the 24-hour day. METHOD: Twenty healthy adult controls and 25 outpatients meeting Rosenthal-National Institute of Mental Health criteria for SAD and DSM-III-R criteria for major or bipolar depression with seasonal pattern had their levels of activity recorded for 72 hours (weekdays) using wrist-worn actigraphs. RESULTS: Subjects with SAD had activity levels that were 11% lower than controls (P = .03), and their levels of activity were most attenuated during the first 2 hours after arising (P = .004). The relative amplitude of the circadian rhythm did not differ between groups. Patients with SAD were phase delayed by 50 minutes for the entire period (P = .02). Analysis of each individual day indicated that patients were delayed by up to 70 minutes (P = .007). Interdaily stability, an index of coupling between the rhythm and its zeitigeber was reduced in SAD (P = .01). Compared with controls, patients with SAD had best-fit circadian periods that were 92% more deviated from 24 hours (P = .007) and daily acrophase (time of the peak of the fit circadian rhythm) times that were 110% more variable between days (P < .001). CONCLUSIONS: Patients with SAD have circadian rest-activity rhythms that are significantly phase delayed and more poorly entrained to the 24-hour day.

Increased activity and phase delay in circadian motility rhythms in geriatric depression. Preliminary observations.

Locomotor activity levels and rhythms of eight hospitalized geriatric unipolar depressed patients (DSM-III criteria) were compared with those of eight healthy elderly controls in a similar environment. Activity was measured using a wrist-worn electronic activity monitor with solid-state memory. Depressed patients had a 29% higher mean total 24-hour activity level, with no change in circadian amplitude or frequency. Daily peak activity (acrophase) averaged 2.05 hours later in depressed patients, with no overlap between the groups. The degree of phase delay correlated significantly with the 4 PM postdexamethasone serum cortisol level. These tentative findings suggest that elderly unipolar depressed patients have prominent chronobiological disturbances in the modulation of activity levels and possibly other physiological processes. These differ strikingly from reported disturbances in younger or bipolar depressed patients.

Sex differences in dopamine receptors and their relevance to ADHD.

Gender differences in ADHD may be attributable to gender differences in dopamine receptor density. Striatal male D2 receptor density increases 144+/-26% between 25 and 40 days (the onset of puberty), while female D2 receptor density increases only 31+/-7%. Male receptor density is then sharply eliminated by 55% by adulthood. Periadolescent females show little overproduction and pruning of striatal D1 and D2 receptors, though adult density is similar to males. The rise of male, but not female, striatal dopamine receptors parallels the early developmental appearance of motor symptoms of ADHD and may explain why prevalence rates are 2-4 fold higher in men than women. Pruning of striatal dopamine receptors coincides with the estimated 50-70% remission rate by adulthood. Transient lateralized D2, dopamine receptors (left > right) in male striatum may increase vulnerability to ADHD. More persistent attentional problems may be associated with the overproduction and delayed pruning of dopamine receptors in prefrontal cortex. Differences in D1 receptor density in nucleus accumbens may have implications for increased substance abuse in males.

Cortisol regulation in posttraumatic stress disorder and major depression: a chronobiological analysis.

The aim of the present study was to evaluate the pattern of basal cortisol release in PTSD and major depression using a chronobiological analysis. Plasma for cortisol determination was obtained from 15 combat veterans with PTSD, 14 subjects with major depression, and 15 normal men every 30 min during a 24-hour period of bed rest. Raw cortisol data were modeled using standard and multioscillator cosinor models to determine the best fitting functions for circadian, hemicircadian, and ultradian components of cortisol release. PTSD subjects had substantially lower cortisol levels, and displayed a pattern of cortisol release that was better modeled by circadian rhythm. PTSD subjects also showed a greater circadian signal-to-noise ratio than the other groups. In contrast, depressed patients displayed a less-rhythmic, more chaotic pattern of cortisol release. The pattern of cortisol secretion and regulation observed in the PTSD group under baseline conditions may reflect an exaggerated sensitization, whereas the chronobiological alterations in depression may reflect dysregulation, of the hypothalamic-pituitary-adrenal (HPA) axis.

Plasma norepinephrine and 3-methoxy-4-hydroxyphenylglycol concentrations and severity of depression in combat posttraumatic stress disorder and major depressive disorder.

BACKGROUND: Catecholamines are thought to play a significant role in the pathophysiology of posttraumatic stress disorder (PTSD), but findings in PTSD have been discrepant. METHODS: To obtain more information about catecholamine activity in PTSD, we sampled plasma norepinephrine (NE) and 3-methoxy-4-hydroxyphenylglycol (MHPG) concentrations over a 24-hour period in men with PTSD (n = 15) and major depressive disorder (MDD) (n = 12), and nonpsychiatric comparison subjects (n = 13), under unstimulated conditions. Chronobiological analyses were performed to determine possible changes in the circadian and ultradian release of these hormones. RESULTS: Significant group differences were present for mean plasma NE levels (p = .03), but not MHPG. NE levels were significantly associated with severity of depression in the PTSD group (p = .002). Therefore, PTSD subjects were further subdivided into those with and without a comorbid secondary depression. Increased NE levels were only present in PTSD subjects who did not have a secondary depression. This study also found no significant group differences on any of the chronobiological parameters. CONCLUSIONS: The results clarify that increased NE levels in PTSD may be confined to the subgroup of subjects who do not have comorbid depression, and as such, may help resolve some of the discrepancies in the literature regarding basal catecholamine activity.

Circadian rhythms of activity in healthy young and elderly humans.

Patterns of activity of healthy adult humans were monitored in a controlled environment for several days using a wrist-mounted ambulatory activity meter. Subjects were 15 young males, 14 young females, 17 elderly males and 23 elderly females. Substantial differences in the absolute levels and patterns of daily rest and activity across age groups were observed. The elderly subjects were somewhat more active than the young subjects overall, especially in the early morning. Consistent with their increased levels of daytime activity the elderly subjects reported less sleepiness, especially in the morning, than the young volunteers. The age groups also differed significantly on all circadian parameters. The mean acrophase (peak of a sinusoid fitted to the activity rhythms) of the elderly group occurred at 1326 hr, significantly earlier than in the young group (1513 hr). The amplitude and the mesor (mean level) of the rhythms were both greater in the elderly group. It is uncertain whether these differences reflect changes in behavior that occur as a consequence of the aging process, previously-established differences in the life styles of the different populations studied, or some other factor. These findings suggest that levels and rhythms of daily activity in healthy elderly people are often well preserved and may not deteriorate as readily as had been assumed.

Emergence of intense suicidal preoccupation during fluoxetine treatment.

Six depressed patients free of recent serious suicidal ideation developed intense, violent suicidal preoccupation after 2-7 weeks of fluoxetine treatment. This state persisted for as little as 3 days to as long as 3 months after discontinuation of fluoxetine. None of these patients had ever experienced a similar state during treatment with any other psychotropic drug.

Severe daytime somnolence in patients treated with an MAOI.

Eight patients with hypersomnolent, anergic major depression benefited markedly from treatment with relatively high doses of phenelzine or tranylcypromine but experienced intense afternoon somnolence and disrupted sleep. Reducing the dose of monoamine oxidase inhibitor (MAOI) or substituting isocarboxazid sometimes provided relief, but altering the schedule of drugs or meals did not. Bedtime sedation alleviated the disrupted sleep but had little effect on daytime somnolence. The mechanism underlying this side effect is unknown; sleep deprivation, narcolepsy, or hypotension does not account for it. Patients given an MAOI should be assessed for this disturbance and cautioned to avoid risk of injury when it occurs.