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.

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.

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.

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.

Brain T2 relaxation times correlate with regional cerebral blood volume.

We previously reported cerebellar and putaminal transverse relaxation time (T2) differences in children with ADHD and in adults with childhood trauma. As brain T2 can be altered by deoxyhemoglobin concentration ([dHb]) and because [dHb] is proportional to regional cerebral blood volume (rCBV), at steady state we attributed those differences to rCBV changes. Studies in other species have established a correlation between T2 and rCBV; however this has yet to be demonstrated in human brain. Echo planar imaging (EPI) T2 relaxometry and dynamic susceptibility-contrast (DSC) MRI were used to measure T2 and rCBV in 11 healthy adults. Significant T2-rCBV correlations were observed in both cerebellar vermis and putamen (r = 0.759,p = 0.007;r = 0.782,p = 0.004, respectively). These correlations predict 9 +/- 3% and 10 +/- 3% rCBV changes, respectively, for each 1-msec change in T2. Consequently, brain T2 measurements may be useful for estimating steady-state rCBV.

Dopamine receptor pruning during the peripubertal period is not attenuated by NMDA receptor antagonism in rat.

D(1) and D(2) receptors are overproduced and pruned in the mammalian striatum during the periadolescent period. The mechanism that underlies this process in striatum is unknown. However, previous research has shown that the activity-dependent pruning of dendrites and synapses in somatosensory cortex and the visual fields is mediated by glutamatergic actions via N-methyl-D- aspartate (NMDA) receptor and is prevented by pretreatment with the NMDA antagonist MK-801. In order to test the hypothesis that the pruning of dopamine D(1) and D(2) receptors that occurs in the striatum after puberty (which occurs at approximately 40 days of age; P40), male and female rats were treated with saline vehicle or MK-801 (0.3 mg/kg) for 20 or 40 days and sacrificed immediately after the 20 day treatment (P60), 40 day treatment (P80), or 40 day treatment with 40 day recovery (P120). Analyses of the data reveal that none of these three treatment regimens altered striatal D(1) or D(2) receptor density in males or females relative to vehicle controls. At P60, MK-801 treatment failed to alter either D(1) (F1,16=0.06, P>0.5) or D(2) receptors (F1,16=0.39, P>0.5) for either sex. Similarly, MK-801 treatment did not affect D(1) or D(2) receptors at P80 (P>0.3) or at P120 (P>0.7). These data suggest that the normal 40% reduction in striatal dopamine receptor density that occurs between puberty and adulthood is not dependent on post-pubertal glutamatergic transmission through NMDA receptors.

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.

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.

Core body temperature and sleep of older female insomniacs before and after passive body heating.

The purpose of this study was to investigate the relationship between core body temperature and sleep in older female insomniacs and changes in that relationship as a result of passive body heating (PBH). An increase in body temperature early in the evening by way of PBH in older female insomniacs increased SWS in the early part of the sleep period and improved sleep continuity. Fourteen older female insomniacs (60-73 years old) participated in at least two consecutive nights of PBH involving hot (40-40.5 degrees C) baths 1.5-2 hours before bedtime. Hot baths resulted in a significant delay in the phase of the core body temperature rhythm compared to baseline nights. This delay in temperature phase paralleled the improvements in sleep quality.

Degree of neuronal activation following FG-7142 changes across regions during development.

We report that FG-7142 (20 mg/kg) differentially increased c-fos in the prefrontal cortex, nucleus accumbens, and striatum of rats 10, 18, 45, and 100 days of age. FG-7142 selectively activated the cortex in adults (70.7+/-3.0%), but the pattern was stronger in nucleus accumbens (83.4+/-9.8%) in younger subjects. These results are consistent with the delayed maturation of the cortex, and show that stress produces more diffuse effects early in life.

Electroencephalogram, bilateral ear temperature, and affect changes induced by lateral visual field stimulation.

Fifteen subjects evaluated while wearing, in random order, four pairs of glasses, two limiting vision to either the left or right lateral visual field (LVF) and two monocular glasses (MGs) limiting vision to either eye, manifested significant differences in laterality indices in the predicted direction for the theta electroencephalogram (EEG) (P < .003) and ear canal temperature (P < .02) between the LVF glasses, but not the MGs. There was a significant correlation between lateral shifts in the theta EEG and ear canal temperature (r2 = .47, F(1,10) = 8.72, P < .015). The LVF glasses induced an absolute difference in anxiety greater (P < .05) than that induced by the MGs. LVF glasses appear to induce a shift in affect and hemispheric dominance.

Serotonin laterality in amygdala predicts performance in the elevated plus maze in rats.

Behavior in the elevated plus maze was correlated with hemispheric asymmetries in neurotransmitter content in limbic brain regions assayed with HPLC-EC in adult rats. A strong (r=0.86, p < 0.003) correlation exists between increased anxiety (more time spent in the closed arm) and the lateralization of serotonin in the amygdala. Greater serotonin in the right versus left amygdala relates to greater anxiety. In addition, increased dopamine in right prefrontal cortex is strongly correlated with anxiety (r=0.84, p < 0.01). No such correlations were observed for accumbens, hippocampus, or striatum. These data support the hypothesis that the right hemisphere is involved in emotional states: increased serotonin in the right amygdala is related to anxiety, while cortical dopamine may be associated with attention to the environment.

Preliminary evidence for aberrant cortical development in abused children: a quantitative EEG study.

The objectives of this study were to investigate cortical development and hemispheric asymmetry in abused children. Fifteen hospitalized children (mean age 10.7 +/- 2.5 years) with severe physical or sexual abuse and 15 normal children (10.1 +/- 3.1 years) were studied with quantitative EEG. Abused children had higher levels of left hemisphere coherence and a reversed asymmetry, with left hemisphere coherence significantly exceeding right hemisphere coherence. Left hemisphere coherence decreased more rapidly across electrode distance in normal subjects, suggesting that increased left coherence in abused patients stemmed from a deficit in left cortical differentiation. These findings support the hypothesis that early severe abuse may have a deleterious effect on brain development.

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.

Progressive accumbens degeneration after neonatal striatal 6-hydroxydopamine in rats.

Parkinson's disease is associated with progressive loss of nigrostriatal dopamine (DA). Models of the disorder, produced with neurotoxins (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine or 6-hydroxydopamine) that selectively lesion DA neurons, are characterized by acute removal and gradual recovery of DA. We report slowly progressive loss of DA in ipsilateral nucleus accumbens following profound (>90%) acute unilateral depletion of DA in the caudate-putamen of neonatal rats, from 50% at age 27 days to 94% by 100 days. Metabolic turnover of DA markedly increased in ipsilateral accumbens, and may yield tissue-damaging neurotoxic by-products. This paradigm may help in elucidating mechanisms responsible for gradual degeneration of DA neurons and for screening potential neuroprotective agents.

Increased nocturnal activity and impaired sleep maintenance in abused children.

OBJECTIVE: Previous studies have suggested that sleep disturbance may be the "hallmark of posttraumatic stress disorder," although several investigations have failed to find evidence for sleep disruption. The purpose of this study was to determine whether intense averse stimulation during early development, in the form of physical and/or sexual abuse, led to disruption of sleep and nocturnal activity. METHOD: Nineteen prepubertal children with documented abuse were compared with 15 nonabused normal controls and 10 depressed children. All subjects received a complete semistructured diagnostic interview. Ambulatory activity monitoring was used to evaluate sleep-related activity for three consecutive nights. Data were analyzed for nocturnal activity and algorithmic estimation of sleep initiation and continuity. RESULTS: Abused subjects were twice as active at night as normal and depressed children, and abused subjects emitted a greater percentage of their total daily activity during the night. Actigraph-derived sleep measures suggested that abused children had prolonged sleep latency and decreased sleep efficiency. Physically abused children had more impaired sleep efficiency than sexually abused children. CONCLUSION: Abused children have higher levels of nocturnal activity than normal controls or depressed children and appear to have more difficulty falling and staying asleep. Physical abuse appears to be the salient factor rather than posttraumatic stress disorder.

Developmental differences in dopamine synthesis inhibition by (+/-)-7-OH-DPAT.

Dopamine synthesis modulation by the D2-family agonist (+/-)-7-OH-DPAT was explored in striatum, accumbens, and prefrontal cortex of 10-40 day old rats using the gamma-butyrolactone (GBL) autoreceptor model. GBL produced an age-dependent increase in dopamine synthesis that was inhibited by (+/-) 7-OH-DPAT (0.1-13.5 mg/kg) at all ages and antagonized by eticlopride in the nucleus accumbens and striatum. The ID50 of (+/-) 7-OH-DPAT increased with age, suggesting decreased autoreceptor sensitivity with maturation. In prefrontal cortex, (+/-) 7-OH-DPAT inhibited synthesis between 10-30 days, with no evidence of autoreceptor function at 40 days. Dopamine synthesis was also inhibited with the D3/D2 agonist quinpirole at 15 days of age in vivo and yielded similar results to those obtained with (+/-) 7-OH-DPAT. Finally, under conditions that result in low D2 receptor affinity, D3 specificity was examined in vitro at 15 days with (+/-) 7-OH-DPAT, which produced comparable (yet more potent) effects to those observed in vivo. These findings illustrate D3 autoreceptor-like activity in ascending dopamine regions and provide further support for transient prefrontal cortex autoreceptor-like function that recedes by puberty.