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PubMed2006

Analysis of coding-polymorphisms in NOTCH-related genes reveals NUMBL poly-glutamine repeat to be associated with schizophrenia in Brazilian and Danish subjects.

Abnormality in neurodevelopment is one of the most robust hypotheses on the etiology of schizophrenia and has found substantial support from brain imaging and genetic studies. Neurodevelopmental processes involve several signaling pathways, including the Notch, but little is known at present regarding their possible involvement in schizophrenia. In the present study we investigated the link of non-synonymous variants of five genes of the Notch pathway (NOTCH2, NOTCH3, JAGGED2, ASCL1 and NUMBL) to schizophrenia in a group of 200 Brazilian patients and 200-paired controls. Also, we replicated the association of the NUMBL variant, our most promising finding, in an unrelated set of 684 Danish patients and controls. When the Brazilian and Danish cohorts were merged, a total of 1084 subjects, we found the allele 18 CAG of NUMBL (p=0.003, x2=8.88, OR=1.30, 95% CI 1.09-1.56) as well as the 18/18 CAG genotype (p=0.002, x2=9.46, OR=1.46, 95% CI 1.15-1.87) to be associated with schizophrenia. The consistency of this finding in two independent and unrelated populations reinforces the veracity of this association.

Adult↗

PubMed2026

Generation of a hiPSC from a patient with an ITSN1-associated neurodevelopmental disorder spectrum carrying biallelic c.2893_2894insA (p.Tyr965Ter) genetic variant.

De novo truncating variants in ITSN1 are implicated in neurodevelopment disorders spectrum, however, biallelic variants in ITSN1 have not been previously identified. Here we present a hiPSC line generated from a patient dermal fibroblast carrying biallelic variant, c.2893_2894insA (p.Tyr965Ter). The hiPSC line expresses core stemness markers, mycoplasma free with normal karyotype and demonstrate trilineage differentiation capacity. The hiPSC line provides a valuable in-vitro model system to investigate its role in early brain development and neurodevelopmental disorders.

Humans↗

PubMed2005

Young adult outcomes of very-low-birth-weight children.

Information on the young adult outcomes of the initial survivors of neonatal intensive care has been reported from the United States, Canada, Australia, Great Britain and other European countries. The studies have varied with regard to whether they were regional or hospital-based, their birth-weight group and gestational age, rates of survival, socio-demographic background, and measures of assessment and types of outcome studied. Despite these differences the overall results reveal that neurodevelopment and growth sequelae persist to young adulthood. Very-low-birth-weight young adults have, with few exceptions, poorer educational achievement than normal-birth-weight controls, and fewer continue with post-high-school study. Rates of employment are, however, similar. There are no major differences in general health status, but the young adults demonstrate poorer physical abilities, higher mean blood pressure and poorer respiratory function. There is no evidence of major psychiatric disorder, although anxiety and depression are reported more often. The young adults report less risk-taking than control populations. They report fairly normal social lives and quality of life. When differences are noted they are usually due to neurosensory disabilities. Longer-term studies are needed to evaluate ultimate educational and occupational achievement. It will also be important to assess the effects of preterm birth, early growth failure and catch-up growth on later metabolic and cardiovascular health.

Adolescent↗

PubMed2006

Long-term consequences of pain in human neonates.

The low tactile threshold in preterm infants when they are in the neonatal intensive care unit (NICU), while their physiological systems are unstable and immature, potentially renders them more vulnerable to the effects of repeated invasive procedures. There is a small but growing literature on pain and tactile responsivity following procedural pain in the NICU, or early surgery. Long-term effects of repeated pain in the neonatal period on neurodevelopment await further research. However, there are multiple sources of stress in the NICU, which contribute to inducing high overall 'allostatic load', therefore determining specific effects of neonatal pain in human infants is challenging.

Analgesia↗

PubMed2004

Mercury exposure in children: a review.

Exposure to toxic mercury (Hg) is a growing health hazard throughout the world today. Recent studies show that mercury exposure may occur in the environment, and increasingly in occupational and domestic settings. Children are particularly vulnerable to Hg intoxication, which may lead to impairment of the developing central nervous system, as well as pulmonary and nephrotic damage. Several sources of toxic Hg exposure in children have been reported in biomedical literature: (1) methylmercury, the most widespread source of Hg exposure, is most commonly the result of consumption of contaminated foods, primarily fish; (2) ethylmercury, which has been the subject of recent scientific inquiry in relation to the controversial pediatric vaccine preservative thimerosal; (3) elemental Hg vapor exposure through accidents and occupational and ritualistic practices; (4) inorganic Hg through the use of topical Hg-based skin creams and in infant teething powders; (5) metallic Hg in dental amalgams, which release Hg vapors, and Hg2+ in tissues. This review examines recent epidemiological studies of methylmercury exposure in children. Reports of elemental Hg vapor exposure in children through accidents and occupational practices, and the more recent observations of the increasing use of elemental Hg for magico-religious purposes in urban communities are also discussed. Studies of inorganic Hg exposure from the widespread use of topical beauty creams and teething powders, and fetal/neonatal Hg exposure from maternal dental amalgam fillings are reviewed. Considerable attention was given in this review to pediatric methylmercury exposure and neurodevelopment because it is the most thoroughly investigated Hg species. Each source of Hg exposure is reviewed in relation to specific pediatric health effects, particularly subtle neurodevelopmental disorders.

Child↗

PubMed2004

Environmental contaminant-mixture effects on CNS development, plasticity, and behavior.

Environmental contaminants within the polycyclic aromatic hydrocarbon (PAH) and halogenated aromatic hydrocarbon class have been shown to cross the placenta exposing the fetus to the contaminant body burden of the mother. Consequently, a gestational exposure to environmental contaminants may result in increased adverse health outcomes, possibly affecting cognitive performance. Benzo(a)pyrene [B(a)P] and 2,3,7,8, tetrachlorodibenzo-p-dioxin (TCDD) are two prototypical environmental contaminants. A systematic review of the literature suggests that there may be a relationship between vulnerability in susceptible populations and health disparities. The purpose of this mini-review is to provide a point of reference for neurotoxicological studies of environmental contaminant mixture effects on indices of development in general, and on neurodevelopment in particular. Environmental contaminant-mixture-induced decrements in (1) birth index, (2) N-methyl-D-aspartate receptor (NMDA) mRNA expression, (3) long-term potentiation (LTP), (4) fixed-ratio performance learning behavior, and (5) experience-dependent activity related cytoskeletal-associated protein (Arc) mRNA and protein expression collectively support associations between neurobehavioral deficits and gestational exposure to environmental levels of these contaminants. Collectively, data are presented in this mini-review evaluating the effect of gestational exposure to environmental contaminant-mixtures on specific indices of learning and memory, including hippocampal-based synaptic plasticity mechanisms. These indices serve as templates for learning and memory, and as such, from a vulnerability perspective, may serve as targets for dysregulation during development in susceptible populations that have been disproportionately exposed to these contaminants. Included in this review is also a discussion of the relevance of developing biomarkers for use within the framework of cumulative risk-assessment.

Animals↗

PubMed2004

Monkey homologues of language areas: computing the ambiguities.

The 'language-readiness' of human brains most probably resulted from modification of structures present in non-human primate brains, but identifying such homologues and the nature of their modifications has been highly problematic. In a recent article, Arbiband Bota suggest that these problems can be overcome using a neuroinformatics approach. But its assumptions ignore many non-local, activity-dependent, regressive, and allometric effects of neurodevelopment that violate assumptions of classic homology. What if these effects are what matter most?

Animals↗

PubMed2006

Effects of perinatal exposure to low doses of cadmium or methylmercury on thyroid hormone metabolism in metallothionein-deficient mouse neonates.

Perinatal exposure to cadmium (Cd) or methylmercury (MeHg) results in impaired neurodevelopment. Thyroid hormone is essential for normal brain development. However, the issue whether Cd or MeHg, especially at low doses, interrupts thyroid hormone action remains to be investigated. In the present study, effects of perinatal exposure to low levels of Cd or MeHg on thyroid hormone metabolism were examined using metallothionein I and II (MT-I/II) null or wild-type neonatal mice. Dams were exposed to 10 mg/L water of Cd or 5 mg/kg chow of MeHg from gestational day 0 to post-natal day 10 (PND 10). Sera, livers and brains were collected from neonates on PND 10. Iodothyronine deiodinase activities and serum thyroxine (T4) concentrations were measured. MeHg exposure failed to induce changes in serum T4 levels and liver type 1 deiodinase (D1) and brain type 2 deiodinase (D2) activities regardless of the MT genotype. However, exposure to MeHg resulted in a decrease in brain type 3 deiodinase (D3) activity in MT-I/II null and wild-type neonates. In contrast, exposure to Cd resulted in a decrease in serum T4 levels in MT-I/II null neonates. Consistently, brain D2 activity was increased in Cd-exposed MT-I/II null neonates. No significant changes in liver D1 and brain D3 activities were induced by Cd administration. Our study demonstrates that perinatal exposure to low doses of Cd or MeHg can induce changes in brain deiodinase activities in the neonates, suggesting that thyroid hormone metabolism in fetuses and neonates might be a potential target of Cd and MeHg.

Administration, Oral↗

PubMed2005

Nutrition for preterm infants after hospital discharge.

Preterm infants accrue significant nutrient deficits during hospitalization, and at the time of discharge most VLBW preterm infants have moderate to severe growth failure. Infants with significant morbidities and infants with ELBW have more severe growth failure since they regain birth weight at a later age, and they gain weight more slowly. Catch-up growth accelerates after hospital discharge. The rates of catch-up growth vary according to many factors including birth weight, gestational age, parental size, adequacy of intrauterine growth, neurologic impairment, clinical course, and nutrition. Most catch-up growth occurs within the first 2 to 3 years of life; however, compensatory catch-up growth may continue into adolescence and adulthood. Despite evidence of ongoing catch-up growth, the mean growth measurements of children and adults who were born preterm and with VLBW are lower than their term-born peers. Accelerated rates of catch-up growth are associated with better neurodevelopmental outcomes. Inadequate head circumference growth, in particular, may have long-term prognostic significance for later neurodevelopment in preterm infants. Nutrient-enriched formulas that provide 22 kcal/oz are often prescribed for VLBW preterm infants after hospital discharge. Several studies have reported that preterm infants fed the enriched versus standard term infant formulas have greater rates of catch-up growth during the first year of life, including greater increases in head circumference. The nutrient-enriched formulas appear to be of particular benefit for male infants. There is less information regarding the nutrient needs of breast-fed infants after hospital discharge. However, several studies have demonstrated that preterm infants fed unfortified human milk after discharge have growth rates and bone mass that are lower than formula-fed infants during infancy. The use of fortified human milk, or alternate feedings with a nutrient-enriched formula may be useful for breast-fed infants who have delays in catch-up growth. Additional studies are needed to determine whether enriched feedings might be of particular benefit for preterm infants who are at greater risk for postnatal growth failure, including infants born SGA, or with extremely low birth weights, intrauterine growth restriction, or chronic conditions such as bronchopulmonary dysplasia. The potential effect of nutritional programming on long-term outcomes of preterm infants also requires further investigation.

Humans↗

PubMed2006

Defects in eye development in transgenic mice overexpressing the heparan sulfate proteoglycan agrin.

The importance of heparan sulfate proteoglycans (HSPGs) in neurodevelopment is becoming increasingly clear. However, studies on HSPGs are hampered by pleiotropic effects when synthesis or modification of heparan sulfate itself is targeted, and by redundancy when the core proteins are altered. Gain-of-function experiments can sometimes circumvent these issues. Here we establish that transgenic mice overexpressing the HSPG agrin have severe ocular dysgenesis. The defects occur through a gain-of-function mechanism and penetrance is dependent on agrin dosage. The agrin-induced developmental defects are highly variable, and include anophthalmia, persistence of vitreous vessels, and fusion of anterior chamber structures. A frequently observed defect is an optic stalk coloboma leading to the misdifferentiation of the optic stalk as retina, which becomes continuous with the forebrain. The defects in optic-stalk differentiation correlate with reduced sonic hedgehog immunoreactivity and overexpansion of the PAX6 domain from the retina into the optic stalk. The ocular phenotypes associated with agrin overexpression are dependent on genetic background, occurring with high penetrance in inbred C57BL/6J mice. Distinct loci sensitizing C57BL/6J mice to agrin-induced dysgenesis were identified. These results indicate that agrin overexpression will provide a tool to explore the molecular interactions of the extracellular matrix and cell surface in eye development, and provide a means for identifying modifier loci that sensitize mice to developmental eye defects.

Agrin↗

PubMed2006

Febrile convulsions in developing rats induce a hyperanxious phenotype later in life.

Exposure of rodent pups to hyperthermia constitutes one of the best known models of febrile seizures. Studies designed to evaluate the behavioral impact of heat-induced convulsions (HCs) have focused mainly on hippocampus-dependent tasks and produced rather conflicting results. In this study, we assessed, in detail, developmental milestones, emotional behavior, and cognitive performance in animals submitted to HCs on Postnatal Day 10. There was no alteration in the acquisition of neurological reflexes, but there was an anticipation of eye opening in animals exposed to hyperthermia. As adults, the locomotor and exploratory behavior of these rats was unaffected. Interestingly, animals exposed to hyperthermia displayed signs of increased anxiety in the elevated-plus maze, although these signs were not associated with increased susceptibility to depression-like behavior. Additionally, we failed to observe impairments in spatial and working memory tasks. In conclusion, HCs at a particular period of neurodevelopment determine a hyperanxious phenotype later in life.

Animals↗

PubMed2006

Real-time PCR analysis of cytochrome P450 aromatase expression in zebrafish: gene specific tissue distribution, sex differences, developmental programming, and estrogen regulation.

In teleost fish, the predominant brain form of cytochrome P450 aromatase (P450aromB) is a neural marker of estrogen effect, and an entry point for studying the role of hormonal and environmental estrogens on neurodevelopment and neuroplasticity. As part of a project using zebrafish to investigate these issues, we developed and validated a rapid, sensitive, and reproducible real-time polymerase chain reaction (PCR) assay for quantifying and comparing P450aromB and P450aromA expression in unfertilized eggs, embryos/larvae, and dissected tissues of adult fish. Results confirm that P450aromB and -A predominate in brain and ovary, respectively, and further show that the degree of overlapping expression (ratio, B:A) is 100:1 in brain, 1:50 in ovary, 1:1 in eye, and 2:1 in testis. Sex differences were observed in eye only (female>male). When compared to whole ovaries, unfertilized eggs had similar levels of P450aromA but enrichment of P450aromB, which suggests preferential synthesis or accumulation in mature oocytes. Both of the maternally derived aromatase isoforms were rapidly degraded post-fertilization, but the onset of embryonic P450aromB expression (5 hpf) was much earlier than P450aromA (48 hpf), and reached higher maximum levels (e.g., 10-fold at 72 hpf). Consistent with earlier reports, P450aromB but not -A was estrogen-inducible, but the estrogen response system in embryos was far more robust than in adults (>100- vs. <4-fold maximal induction, respectively). Application of this real-time PCR assay to measurement of P450aromB and -A in zebrafish embryos has utility for routine screening of chemicals and environmental samples for estrogen-like bioactivity and neural effects.

Animals↗

PubMed1987

Preterm birth at 23 to 26 weeks' gestation: is active obstetric management justified?

To determine if active perinatal management was justified in preterm deliveries at less than or equal to 26 weeks' gestation, the outcome (survival and short- and long-term morbidity) of 43 infants (group I) born between 23 and 26 weeks' gestation was compared with that of 17 infants (group II) born at 27 weeks' gestation. Of the 12 surviving infants in group I (survival 28%), 11 were ventilated (median = 50 days), eight had moderate to severe bronchopulmonary dysplasia, and four had mild retrolental fibroplasia. At follow-up, two infants had physical disabilities with moderate to severe functional impairment, one had a minor disability, and nine had normal neurodevelopment. In contrast, of the 13 surviving infants in group II (survival 76%), nine were ventilated (median = 8 days), six had moderate to severe bronchopulmonary dysplasia, and six had mild RLF. At follow-up, one infant had a physical disability with moderate to severe functional impairment, four had minor disabilities, and eight had normal development. Perinatal factors that positively influenced survival in the two groups combined included active perinatal management, antenatal steroids, female sex, and absence of clinical chorioamnionitis and asphyxia. Although group I infants had a significantly higher mortality rate (p less than 0.05) and required a longer duration of ventilation (p less than 0.05), no differences in the incidence of postnatal complications or long-term morbidity at 2 to 4 years of age were evident between the two groups.

Child Development↗

PubMed1998

The one-year morphometric and neurodevelopmental outcome of the offspring of women who continued to exercise regularly throughout pregnancy.

OBJECTIVE: Our purpose was to test the hypothesis that continuing regular exercise throughout pregnancy alters morphometric and neurodevelopmental outcome at 1 year. STUDY DESIGN: The offspring of 52 women who exercised were compared with those of 52 control subjects who were similar in terms of multiple prenatal and postnatal variables known to influence outcome. All women were enrolled before pregnancy and had clinically normal antenatal and postnatal courses. Neurodevelopment was assessed by blinded examiners at 1 year of age, and morphometrics were obtained at birth and at 1 year of age. RESULTS: At birth, the offspring of the exercising women weighed less (3.38 +/- 0.06 kg vs 3.58 +/- 0.07 kg) and had less body fat (9.5% +/- 0.8% vs 12.6% +/- 0.6%). However, at 1 year, all morphometric parameters were similar, and no clinically significant between-group differences were observed in performance on either the Bayley psychomotor (108 +/- 1 vs 101 +/- 2) or mental (120 +/- 1 vs 118 +/- 1) scales. CONCLUSIONS: These data indicate that the offspring of exercising mothers have normal growth and development during the first year of life.

Adult↗

PubMed1998

Clinical outcome of mild fetal ventriculomegaly.

OBJECTIVE: Our purpose was to evaluate the outcome of fetuses with mild cerebral ventriculomegaly. STUDY DESIGN: We prospectively collected all cases of mild cerebral ventriculomegaly (transverse diameter of the atrium of the cerebral lateral ventricles between 10 and 15 mm) diagnosed antenatally between January 1990 and December 1996. Associated ultrasonographic abnormalities including markers of aneuploidy, presence of chromosomal anomalies, structural malformations detected at birth, and neurologic outcome were recorded. Outcome information was available on all cases. In addition, published series of cases of fetal mild cerebral ventriculomegaly were reviewed to identify prognostic indicators. RESULTS: Eighty-two cases fulfilled the inclusion criteria: 48 were isolated and 34 were associated with other ultrasonographic markers or anomalies. Among the 45 surviving euploid isolated cases, neurologic follow-up was normal at a mean age of 28 months (range 3 to 72 months). Male fetuses and those with a transverse atrial size <12 mm had a good prognosis. Ventricular atria > or =12 mm were more often associated with other anomalies (56% vs 6%) and, when isolated, with abnormal postnatal neurodevelopment (23% vs 3%). Aneuploidy was present in two cases of isolated mild cerebral ventriculomegaly, both of which were associated with advanced maternal age, and in seven cases associated with other anomalies. CONCLUSIONS: Mild cerebral ventriculomegaly should prompt targeted ultrasonographic examination, inclusive of markers of aneuploidies, visualization of the corpus callosum, and echocardiogram as well as serologic evaluation for congenital infections. In isolated mild cerebral ventriculomegaly genetic counseling should take into account clinical, laboratory, and ultrasonographic findings. A review of the published series suggests that cognitive or motor delay is predominantly mild and that it occurs in about 9% of cases of isolated mild cerebral ventriculomegaly.

Adult↗

PubMed1999

Ultrasonographic differential diagnosis of fetal intracranial interhemispheric cysts.

OBJECTIVE: Ultrasonographic differentiation between intracranial supratentorial interhemispheric pathologic cystlike lesions and those related to physiologic median structures is essential because the latter have no clinical relevance, whereas the former may carry a poor prognosis. We reviewed our experience with 19 consecutive cases of interhemispheric hypoechoic lesions without parenchymal involvement diagnosed between January 1990 and June 1997 to establish their clinical significance and provide prenatal ultrasonographic criteria to distinguish between pathologic cystlike lesions and those related to physiologic midline structures. STUDY DESIGN: All patients underwent targeted prenatal scans of intracranial anatomy to establish the relationship between the fluid collections and the surrounding parenchymal and ventricular structures. In addition, a detailed anatomic survey was performed to rule out associated malformations. Follow-up, including neurologic examination, imaging, autopsy evaluation, or a combination was performed in all cases. Statistical analysis used the Wilcoxon rank sum test, the Fisher exact test, and the chi2 test for trend. P <.05 was considered significant. RESULTS: Cystlike lesions related to physiologic median structures (n = 12) included enlargement of the cavum septi pellucidi (n = 3), enlargement of the cavum vergae (n = 2), and cysts of the velum interpositum (n = 7). These lesions were unilocular and had a median size of 10 mm (range 10-30 mm); they resolved in 5 cases and remained stable in the remainder. They were not associated with overt abnormalities, other than borderline ventriculomegaly in 2 cases. Pediatric follow-up (median 26 months, range 3-84 months) showed normal neurodevelopment in all cases. Pathologic cystlike lesions (n = 7) were significantly larger (median 40 mm, range 10-80 mm, P =.004) and had a significantly worsening trend, growing more at serial prenatal ultrasonographic examinations (P =.039) than fluid collections related to physiologic median structures. Moreover, prenatal ultrasonographic evidence of associated intracranial abnormalities, in the form of partial or total agenesis of the corpus callosum and overt hydrocephalus, was present in 5 of 7 cases of pathologic cystlike lesions and in none of the 12 related to physiologic structures (P =.002). Median gestational age at diagnosis was not different between those with cystlike lesions related to physiologic median structures and those with pathologic lesions (30 and 31 weeks, respectively). Among the latter group, 1 pregnancy was voluntarily terminated, 1 infant died at 4 months of age, 2 infants had neurodevelopmental delay, and 3 infants were neurologically healthy at a mean follow-up of 43 months. Cyst shunting was necessary in 5 of 6 cases. CONCLUSIONS: Interhemispheric cystlike lesions related to physiologic structures can be prenatally distinguished from pathologic fluid collections on the basis of location, cyst size, change in size with time, and absence of associated anomalies.

Brain Diseases↗

PubMed2000

A pilot study of amygdala volumes in pediatric generalized anxiety disorder.

BACKGROUND: The neurodevelopment of childhood anxiety disorders is not well understood. Basic research has implicated the amygdala and circuits related to these nuclei as being central to several aspects of fear and fear-related behaviors in animals. METHODS: Magnetic resonance imaging was used to measure amygdala volumes and comparison brain regions in 12 child and adolescent subjects with generalized anxiety disorder and 24 comparison subjects. Groups were matched on age, sex, height, and handedness and were also similar on measures of weight, socioeconomic status, and full scale IQ. RESULTS: Right and total amygdala volumes were significantly larger in generalized anxiety disorder subjects. Intracranial, cerebral, cerebral gray and white matter, temporal lobe, hippocampal, and basal ganglia volumes and measures of the midsagittal area of the corpus callosum did not differ between groups. CONCLUSIONS: Although these data are preliminary and from a small sample, the results are consistent with a line of thinking that alterations in the structure and function of the amygdala may be associated with pediatric generalized anxiety disorder.

Adolescent↗

PubMed2001

Brain structure, genetic liability, and psychotic symptoms in subjects at high risk of developing schizophrenia.

BACKGROUND: Structural magnetic resonance imaging (MRI) of the brain in patients with schizophrenia has consistently demonstrated several abnormalities. These are thought to be neurodevelopmental in origin, as they have also been described in first episode cases, although there may be a progressive component. It is not known at which point in development these abnormalities are evident, nor to what extent they are genetically or environmentally mediated. METHODS: One hundred forty-seven high-risk subjects (with at least two affected first or second degree relatives), 34 patients in their first episode, and 36 healthy control subjects received an MRI scan covering the whole brain. After inhomogeneity correction, regions of interest were traced by three group-blind raters with good inter-rater reliability. Regional brain volumes were related to measures of genetic liability to schizophrenia and to psychotic symptoms elicited at structured psychiatric interviews. RESULTS: High-risk subjects had statistically significantly reduced mean volumes of the left and right amygdalo-hippocampus and thalamus, as compared to healthy control subjects. They also had bilaterally larger amygdalo-hippocampi and bilaterally smaller lenticular nuclei than the schizophrenics. High-risk subjects with symptoms had smaller brains than those without. The volumes of the prefrontal lobes and the thalamus were the only consistent associates of genetic liability. CONCLUSIONS: Subjects at high risk of developing schizophrenia have abnormalities of brain structure similar to but not identical to those found in schizophrenia. Our results suggest that some structural abnormalities are genetic trait or vulnerability markers, others are environmentally mediated, and that the development of symptoms is associated with a third overlapping group of structural changes. Particular risk factors for schizophrenia may interact at discrete time points of neurodevelopment with different effects on specific brain regions and may represent relatively distinct disease processes.

Amygdala↗