Very little is known about cortical development in the first years of life, a time of rapid cognitive development and risk for neurodevelopmental disorders. We studied regional cortical and subcortical gray matter volume growth in a group of 72 children who underwent magnetic resonance scanning after birth and at ages 1 and 2 years using a novel longitudinal registration/parcellation approach. Overall, cortical gray matter volumes increased substantially (106%) in the first year of life and less so in the second year (18%). We found marked regional differences in developmental rates, with primary motor and sensory cortices growing slower in the first year of life with association cortices growing more rapidly. In the second year of life, primary sensory regions continued to grow more slowly, while frontal and parietal regions developed relatively more quickly. The hippocampus grew less than other subcortical structures such as the amygdala and thalamus in the first year of life. It is likely that these patterns of regional gray matter growth reflect maturation and development of underlying function, as they are consistent with cognitive and functional development in the first years of life.
amygdala; cerebral cortex; hippocampus; lateral ventricle; magnetic resonace imaging
The true benefit of pharmacological intervention to improve cognition in schizophrenia may not be evident without regular cognitive enrichment. Clinical trials assessing the neurocognitive effects of new medications may require engagement in cognitive remediation exercises to stimulate the benefit potential. However, the feasibility of large-scale multi-site studies using cognitive remediation at clinical trials sites has not been established.
Patients with DSM-IV schizophrenia from nine sites were randomized to a cognitive remediation condition that included the Posit Science Brain Fitness auditory training program with weekly NEAR ‘bridging groups,’ or a control condition of computer games and weekly healthy lifestyles groups. Patients were expected to complete 3–5 one-hour sessions weekly for 40 sessions or 12 weeks, whichever came first.
The primary outcomes were feasibility results as measured by rate of enrollment, retention, and completion rate of primary outcome measures. Within the 3-month enrollment period, 53 of a projected 54 patients were enrolled and 47 completed the study. Thirty-one patients completed all 40 sessions and all patients completed all primary outcome measures. Preliminary efficacy results indicated that after 20 sessions, patients in the cognitive remediation condition demonstrated mean MCCB composite score improvements that were 3.7 (95% CI: 7.34, 0.05) T-score points greater than in patients in the computer games control group (F=4.16, df=1,46, p=0.047). At the end of treatment, a trend favoring cognitive remediation was not statistically significant (F=2.26, df=1,47, p=0.14).
Multi-site clinical trials of cognitive remediation using the Posit Science auditory training program with the NEAR method of weekly bridging groups in traditional clinical sites appear feasible.
Youth with serious mental illness may experience improved psychiatric stability with second generation antipsychotic (SGA) medication treatment, but unfortunately may also experience unhealthy weight gain adverse events. Research on weight loss strategies for youth who require ongoing antipsychotic treatment is quite limited. The purpose of this paper is to present the design, methods, and rationale of the Improving Metabolic Parameters in Antipsychotic Child Treatment (IMPACT) study, a federally funded, randomized trial comparing two pharmacologic strategies against a control condition to manage SGA-related weight gain.
The design and methodology considerations of the IMPACT trial are described and embedded in a description of health risks associated with antipsychotic-related weight gain and the limitations of currently available research.
The IMPACT study is a 4-site, six month, randomized, open-label, clinical trial of overweight/obese youth ages 8–19 years with pediatric schizophrenia-spectrum and bipolar-spectrum disorders, psychotic or non-psychotic major depressive disorder, or irritability associated with autistic disorder. Youth who have experienced clinically significant weight gain during antipsychotic treatment in the past 3 years are randomized to either (1) switch antipsychotic plus healthy lifestyle education (HLE); (2) add metformin plus HLE; or (3) HLE with no medication change. The primary aim is to compare weight change (body mass index z-scores) for each pharmacologic intervention with the control condition. Key secondary assessments include percentage body fat, insulin resistance, lipid profile, psychiatric symptom stability (monitored independently by the pharmacotherapist and a blinded evaluator), and all-cause and specific cause discontinuation. This study is ongoing, and the targeted sample size is 132 youth.
Antipsychotic-related weight gain is an important public health issue for youth requiring ongoing antipsychotic treatment to maintain psychiatric stability. The IMPACT study provides a model for pediatric research on adverse event management using state-of-the art methods. The results of this study will provide needed data on risks and benefits of two pharmacologic interventions that are already being used in pediatric clinical settings but that have not yet been compared directly in randomized trials.
Clinical Trials.gov NCT00806234
While oxytocin (OT) has the potential to be an informative biomarker of social functioning in patients with eating disorders, the burden of invasive blood draws or lumbar punctures limits OT study. Salivary and urinary OT measurements may be advantageous, as they require less invasive sampling techniques which could be conducted in a wider variety of settings. Yet, the degree to which the concentration of OT in these fluids is correlated with blood levels is uncertain, as is the impact of vomiting on salivary secretion of OT. Therefore, we compared contemporaneously sampled OT concentration in blood, saliva, and urine from twenty women acutely ill with anorexia nervosa. Salivary OT was positively correlated with plasma OT in patients with no history of self-induced vomiting(r=0.89), but correlation was lower in those with recent history of self-induced vomiting(r=0.42). Urinary and plasma OT were not well-correlated(r=0.13), suggesting preliminarily that collection of plasma OT remains the method of choice. Self-induced vomiting in eating disorders may limit the applicability of salivary sampling for OT.
oxytocin; plasma; saliva; urine; eating disorder; self-induced vomiting
Enlargement of the lateral ventricles is thought to originate from abnormal prenatal brain development and is associated with neurodevelopmental disorders. Fetal isolated mild ventriculomegaly (MVM) is associated with enlargement of lateral ventricle volumes in the neonatal period and developmental delays in early childhood. However, little is known about postnatal brain development in these children.
Twenty-eight children with fetal isolated MVM and 56 matched controls were followed at ages 1 and 2 years with structural imaging on a 3T Siemens scanner and assessment of cognitive development with the Mullen Scales of Early Learning. Lateral ventricle, total gray and white matter volumes, and Mullen cognitive composite scores and subscale scores were compared between groups.
Compared to controls, children with prenatal isolated MVM had significantly larger lateral ventricle volumes at ages 1 and 2 years. Lateral ventricle volume at 1 and 2 years of age was significantly correlated with prenatal ventricle size. Enlargement of the lateral ventricles was associated with increased intracranial volumes and increased gray and white matter volumes. Children with MVM had Mullen composite scores similar to controls, although there was evidence of delay in fine motor and expressive language skills.
Children with prenatal MVM have persistent enlargement of the lateral ventricles through the age of 2 years; this enlargement is associated with increased gray and white matter volumes and some evidence of delay in fine motor and expressive language development. Further study is needed to determine if enlarged lateral ventricles are associated with increased risk for neurodevelopmental disorders.
magnetic resonance imaging; ultrasound; gray matter; white matter; cognitive development
Statistical shape analysis has emerged as an insightful method for evaluating brain structures in neuroimaging studies, however most shape frameworks are surface based and thus directly depend on the quality of surface alignment. In contrast, medial descriptions employ thickness information as alignment-independent shape metric. We propose a joint framework that computes local medial thickness information via a mean latitude axis from the well-known spherical harmonic (SPHARM-PDM) shape framework. In this work, we applied SPHARM derived medial representations to the morphological analysis of lateral ventricles in neonates. Mild ventriculomegaly (MVM) subjects are compared to healthy controls to highlight the potential of the methodology. Lateral ventricles were obtained from MRI scans of neonates (9–144 days of age) from 30 MVM subjects as well as age- and sex-matched normal controls (60 total). SPHARM-PDM shape analysis was extended to compute a mean latitude axis directly from the spherical parameterization. Local thickness and area was straightforwardly determined. MVM and healthy controls were compared using local MANOVA and compared with the traditional SPHARM-PDM analysis. Both surface and mean latitude axis findings differentiate successfully MVM and healthy lateral ventricle morphology. Lateral ventricles in MVM neonates show enlarged shapes in tail and head. Mean latitude axis is able to find significant differences all along the lateral ventricle shape, demonstrating that local thickness analysis provides significant insight over traditional SPHARM-PDM. This study is the first to precisely quantify 3D lateral ventricle morphology in MVM neonates using shape analysis.
Statistical shape analysis; pediatric imaging; magnetic resonance image biomarkers; mild ventriculomegaly; lateral ventricles
The current study describes detailed eating behaviors, dieting behaviors, and attitudes about shape and weight in 4,023 women ages 25 to 45.
The survey was delivered on-line and participants were identified using a national quota-sampling procedure.
Disordered eating behaviors, extreme weight loss measures, and negative cognitions about shape and weight were widely endorsed by women in this age group and were not limited to White participants. Thirty-one percent of women without a history of anorexia or binge eating reported having purged to control weight, and 74.5% of women reported that their concerns about shape and weight interfered with their happiness.
Unhealthy approaches to weight control and negative attitudes about shape and weight are pervasive even among women without eating disorders. The development of effective approaches to address the impact of these unhealthy behaviors and attitudes on the general well-being and functioning of women is required.
Eating Disorders; Race; Ethnicity; Dieting
We explored the impact of eating disorders on birth outcomes in the Norwegian Mother and Child Cohort Study (MoBa).
35,929 pregnant women in the MoBa included women with broadly defined anorexia nervosa (AN; n=35), bulimia nervosa (BN; n=304), binge eating disorder (BED; n=1,812), and EDNOS-purging type (EDNOS-P; n=36) in the six months prior to or during pregnancy and the referent group--women who reported no eating disorders (no-ED; n=33,742).
Pre-pregnancy BMI was significantly lower in mothers with AN and higher in mothers with BED than the referent. Mothers with AN, BN, and BED reported greater weight gain during pregnancy and more mothers with eating disorders reported smoking during pregnancy than the referent. Women with BED had higher birth weight babies, lower risk of small for gestational age babies, and higher risk for large for gestational age babies and cesarean section than the referent.
BED influences birth outcomes. The absence of differences in birth outcomes in women with AN and EDNOS-P may reflect small sample size and differential severity of illness in population versus clinical samples. The detection of eating disorders in pregnancy could help identify modifiable factors (e.g., binge eating, smoking) that could influence birth outcomes.
The neurosteroid pregnenolone and its sulfated derivative enhance learning and memory in rodents. Pregnenolone sulfate also positively modulates NMDA receptors and could thus ameliorate hypothesized NMDA receptor hypofunction in schizophrenia. Furthermore, clozapine increases pregnenolone in rodent hippocampus, possibly contributing to its superior efficacy. We therefore investigated adjunctive pregnenolone for cognitive and negative symptoms in patients with schizophrenia or schizoaffective disorder receiving stable doses of second-generation antipsychotics in a pilot randomized, placebo-controlled, double-blind trial. Following a 2-week single-blind placebo lead-in, patients were randomized to pregnenolone (fixed escalating doses to 500 mg/day) or placebo, for 8 weeks. Primary end points were changes in BACS and MCCB composite and total SANS scores. Of 21 patients randomized, 18 completed at least 4 weeks of treatment (n = 9/group). Pregnenolone was well tolerated. Patients receiving pregnenolone demonstrated significantly greater improvements in SANS scores (mean change = 10.38) compared with patients receiving placebo (mean change = 2.33), p = 0.048. Mean composite changes in BACS and MCCB scores were not significantly different in patients randomized to pregnenolone compared with placebo. However, serum pregnenolone increases predicted BACS composite scores at 8 weeks in the pregnenolone group (rs = 0.81, p = 0.022). Increases in allopregnanolone, a GABAergic pregnenolone metabolite, also predicted BACS composite scores (rs = 0.74, p = 0.046). In addition, baseline pregnenolone (rs = −0.76, p = 0.037), pregnenolone sulfate (rs = − 0.83, p = 0.015), and allopregnanolone levels (rs = −0.83, p = 0.015) were inversely correlated with improvements in MCCB composite scores, further supporting a possible role for neurosteroids in cognition. Mean BACS and MCCB composite scores were correlated (rs = 0.74, p <0.0001). Pregnenolone may be a promising therapeutic agent for negative symptoms and merits further investigation for cognitive symptoms in schizophrenia.
schizophrenia; negative symptoms; cognitive symptoms; neurosteroid; pregnenolone; allopregnanolone
The relative lengths of the 2nd and 4th digits (2D:4D) may provide an easily measurable and stable anthropometric index of prenatal androgen exposure, but no study has examined the development of 2D:4D in infancy and the potential impact of neonatal testosterone levels. We collected 2D:4D ratios from 364 children between 0 and 2 years of age. Saliva samples were collected from 236 of these children 3 months after birth and analyzed for testosterone. In addition, 259 children provided DNA samples which were genotyped for the CAG repeat polymorphism in the androgen receptor. There was substantial variability across age in 2D:4D. Sex differences were small compared to adults and did not consistently reach statistical significance. This suggests that 2D:4D may not function well as a proxy measure of prenatal testosterone exposure in infancy. In addition, the interaction of salivary T and CAG repeats predicted right hand digit ratio at 12 months and left hand digit ratio at 12 months and 24 months in males. The interaction of salivary testosterone and CAG repeat length also predicted change in left hand 2D:4D from 2 weeks to 12 months in males. This suggests that 2D:4D in adults may reflect, in part, neonatal testosterone exposure. No significant relationships were observed within females. No significant relationships were observed when salivary testosterone and CAG repeats were examined independent of each other. Results have important implications for the design and interpretation of studies which use 2D:4D as a proxy measure of prenatal testosterone exposure.
testosterone; androgen; 2D:4D; digit ratio
After recovery, women with anorexia nervosa (AN) tend to maintain lower body mass indices (BMI) than women in the general population. Reasons for this are unknown as little is known about diet, food choices, physical activity levels (PAL), and reasons for exercise in women recovered from AN.
Diet, reasons for food choice, PAL, and reasons for exercise were measured in an exploratory study of 15 women recovered from AN and 22 women with no eating disorder history.
In these hypotheses generating analyses, mean BMI in recovered women was numerically lower than control women [21.4kg/m2 (2.0) and 23.6 kg/m2 (4.4); respectively (p<0.06)]. Recovered women were more likely to base food choice on health benefits (p <0.04) compared with control women.
Pathological behaviors that are pathognomonic of AN may resolve into healthy food and activity choices that help maintain BMIs lower in the healthy range in recovered individuals.
Anorexia nervosa; Recovery; Body mass index; Diet; Physical activity; Reasons for food choice
To identify factors associated with incidence and course of broadly defined binge eating disorder (BED) in pregnancy.
As a part of the Norwegian mother and child cohort study (MoBa), 45,644 women completed a questionnaire at approximately 18 weeks of gestation.
Incidence of BED was significantly associated with lifetime sexual abuse, lifetime physical abuse, lifetime major depression, symptoms of anxiety and depression, low life satisfaction, low self-esteem, low partner relationship satisfaction, smoking, alcohol use, lack of social support, and several weight-related factors. Continuation was negatively associated with thoughts of being overweight before pregnancy. Remission was positively associated with thoughts of being overweight before pregnancy and negatively associated with overvaluation of weight.
Onset of BED in pregnancy was associated with psychological, social and weight-related factors, as well as health behaviors and adverse life events. In women with pre-pregnancy BED, thoughts of being overweight before pregnancy and overvaluation of weight were associated with course of BED during pregnancy.
Cognitive-behavioral therapy (CBT) is currently the “gold standard” for treatment of bulimia nervosa (BN), and is effective for approximately 40–60% of individuals receiving treatment; however, the majority of individuals in need of care do not have access to CBT. New strategies for service delivery of CBT and for maximizing maintenance of treatment benefits are critical for improving our ability to treat BN. This clinical trial is comparing an Internet-based version of CBT (CBT4BN) in which group intervention is conducted via therapeutic chat group with traditional group CBT (CBTF2F) for BN conducted via face-to-face therapy group. The purpose of the trial is to determine whether manualized CBT delivered via the Internet is not inferior to the gold standard of manualized group CBT. In this two-site randomized controlled trial, powered for non-inferiority analyses, 180 individuals with BN are being randomized to either CBT4BN or CBTF2F. We hypothesize that CBT4BN will not be inferior to CBTF2F and that participants will value the convenience of an online intervention. If not inferior, CBT4BN may be a cost-effective approach to service delivery for individuals requiring treatment for BN.
Nearly half of Operation Enduring Freedom / Operation Iraqi Freedom (OEF/OIF) veterans experience continued pain post-deployment. Several investigations report analgesic effects of allopregnanolone and other neurosteroids in animal models, but few data are currently available focusing on neurosteroids in clinical populations. Allopregnanolone positively modulates GABAA receptors and demonstrates pronounced analgesic and anxiolytic effects in rodents, yet studies examining the relationship between pain and allopregnanolone in humans are limited. We thus hypothesized that endogenous allopregnanolone and other neurosteroid levels may be negatively correlated with self-reported pain symptoms in humans.
We determined serum neurosteroid levels by gas chromatography / mass spectrometry (allopregnanolone, pregnenolone) or radioimmunoassay (dehydroepiandrosterone [DHEA], progesterone, DHEA sulfate [DHEAS]) in 90 male veterans who served in the U.S. military after September 11, 2001. Self-reported pain symptoms were assessed in four areas (low back pain, chest pain, muscle soreness, headache). Stepwise linear regression analyses were conducted to investigate the relationship between pain assessments and neurosteroids, with the inclusion of smoking, alcohol use, age, and history of traumatic brain injury as covariates.
Durham VA Medical Center.
Allopregnanolone levels were inversely associated with low back pain (p=0.044) and chest pain (p=0.013), and DHEA levels were inversely associated with muscle soreness (p=0.024). DHEAS levels were positively associated with chest pain (p=0.001). Additionally, there was a positive association between traumatic brain injury and muscle soreness (p=0.002).
Neurosteroids may be relevant to the pathophysiology of self-reported pain symptoms in this veteran cohort, and could represent future pharmacological targets for pain disorders.
neuroactive steroid; allopregnanolone; pregnenolone; DHEA; nociception; pain; neurosteroid
Schizophrenia is a neurodevelopmental disorder associated with abnormalities of brain structure and white matter, although little is known about when these abnormalities arise. This study was conducted to identify structural brain abnormalities in the prenatal and neonatal periods associated with genetic risk for schizophrenia.
Prenatal ultrasound scans and neonatal structural magnetic resonance imaging (MRI) and diffusion tensor imaging were prospectively obtained in the offspring of mothers with schizophrenia or schizoaffective disorder (N=26) and matched comparison mothers without psychiatric illness (N=26). Comparisons were made for prenatal lateral ventricle width and head circumference, for neonatal intracranial, CSF, gray matter, white matter, and lateral ventricle volumes, and for neonatal diffusion properties of the genu and splenium of the corpus callosum and corticospinal tracts.
Relative to the matched comparison subjects, the offspring of mothers with schizophrenia did not differ in prenatal lateral ventricle width or head circumference. Overall, the high-risk neonates had nonsignificantly larger intracranial, CSF, and lateral ventricle volumes. Subgroup analysis revealed that male high-risk infants had significantly larger intracranial, CSF, total gray matter, and lateral ventricle volumes; the female high-risk neonates were similar to the female comparison subjects. There were no group differences in white matter diffusion tensor properties.
Male neonates at genetic risk for schizophrenia had several larger than normal brain volumes, while females did not. To the authors' knowledge, this study provides the first evidence, in the context of its limitations, that early neonatal brain development may be abnormal in males at genetic risk for schizophrenia.
Twin studies suggest that global and regional brain volumes are highly heritable. However, estimates of heritability vary across development. Given that all twin studies are open to the potential criticism of non-generalizability due to differences in intrauterine environment between twins and singletons, these age effects may reflect the influence of perinatal environmental factors which are unique to twins and which may be especially evident early in life. To address this question, we compared brain volumes and the relationship of brain volumes to gestational age in 136 singletons (67 male, 69 female) and 154 twins (75 male, 79 female; 82 DZ, 72 MZ) who had received high resolution MRI scans of the brain in the first month of life. Intracranial volume, total white matter, and ventricle volumes did not differ between twins and singletons. However, cerebrospinal fluid and frontal white matter volume was greater in twins compared to singletons. While gray matter volumes at MRI did not differ between groups, the slope of the relationship between total and cortical gray matter and gestational age at the MRI scan was steeper in MZ twins compared to DZ twins. Post-hoc analyses suggested that gray matter development is delayed in MZ twins in utero and that they experience “catch-up” growth in the first month of life. These differences should be taken into account when interpreting and designing studies in the early postnatal period.
Efficient and reliable assessments of cognitive treatment effects are essential for the comparative evaluation of procognitive effects of pharmacologic therapies. Yet, no studies have addressed the sensitivity and efficiency with which neurocognitive batteries evaluate cognitive abilities before and after treatment. Participants were primarily first episode schizophrenia patients who completed baseline (n = 367) and 12-week (n = 219) assessments with the BACS (Brief Assessment of Cognition in Schizophrenia) and CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness) neuropsychological batteries in a clinical trial comparing olanzapine, quetiapine, and risperidone. Exploratory factor analysis revealed that performance on both batteries was characterized by a single factor of generalized cognitive deficit for both baseline performance and cognitive change after treatment. Both batteries estimated similar levels of change following treatment, although the BACS battery required half the administration time. Because a unitary factor characterized baseline cognitive abilities in early psychosis as well as cognitive change after treatment with atypical antipsychotic medications, short batteries such as the BACS may efficiently provide sufficient assessment of procognitive treatment effects with antipsychotic medications. Assessment of cognitive effects of adjunctive therapies targeting specific cognitive domains or impairments may require more extensive testing of the domains targeted to maximize sensitivity for detecting specific predicted cognitive outcomes.
Schizophrenia; Neuropsychology; Antipsychotics; Cognition; Clinical trials methodology; CATIE; BACS
To examine the long-term safety and efficacy of three antipsychotics in early-onset schizophrenia spectrum disorders (EOSS).
Patients (age 8–19 years) who had improved during an 8-week, randomized double-blind acute trial of olanzapine, risperidone, or molindone (plus benztropine) were eligible to continue on the same medication for up to 44 additional weeks under double-blind conditions. Adjunctive medications were allowed following defined algorithms. Standardized symptom, safety, and functional assessments were conducted every 4 weeks.
Of the 116 youth randomized in the acute trial, 54 entered maintenance treatment (molindone, N=20; olanzapine, N=13; risperidone, N=21). Fourteen (26%) completed 44 weeks of treatment. Adverse effects (N=15), inadequate efficacy (N=14), or study non-adherence (N=8) were the most common reasons for discontinuation. The three treatment arms did not significantly differ in symptom reduction or time to discontinuation. Akathisia was more common with molindone and elevated prolactin concentrations more common with risperidone. Although weight gain and metabolic adverse events had occurred more often with olanzapine and risperidone during the acute trial, no significant between-drug differences emerged in most of these parameters during maintenance treatment.
Only 12 % of youth with EOSS continued on their originally randomized treatment at 52 weeks. No agent demonstrated superior efficacy, and all were associated with side effects, including weight gain. Improved treatments are needed for EOSS.
adolescent; schizophrenia; schizoaffective disorder; antipsychotic; treatment
The impact of eating disorders on maternal feeding practices and children's eating behaviors is not well understood. In the prospective Norwegian Mother and Child Cohort Study (MoBa),we compared self-reported feeding behavior in mothers with anorexia nervosa (AN), bulimia nervosa (BN), binge eating disorder (BED), and no eating disorders (No ED) as well as child eating behaviors and psychological symptoms. The sample was comprised of 13 006 women and their children from a prospective population-based study of 100,000 births throughout Norway. Eating disorder status was measured 6 months prior to pregnancy and during pregnancy. Maternal feeding, child eating, and psychological variables were reported by mothers when their child was 36 months old. Mothers with BN and BED were more likely to report restrictive feeding styles and infant eating problems than mothers without eating disorders. Regarding pressured feeding style, no significant differences emerged across groups. Differences in self-reported feeding styles and children’s eating behavior exist between mothers with and without eating disorders. Longitudinal follow-up will assist with determining the implications of feeding style on later growth trajectories and development.
Eating disorders; anorexia nervosa; bulimia; binge eating; mothers; child psychology
Extremely low body mass index (BMI) values are associated with increased risk for death and poor long-term prognosis in individuals with AN. The present study explores childhood personality characteristics that could be associated with the ability to attain an extremely low BMI.
Participants were 326 women from the Genetics of Anorexia Nervosa (GAN) Study who completed the Structured Interview for Anorexia Nervosa and Bulimic Syndromes and whose mother completed the Child Behavioral Check List and/or Revised Dimensions of Temperament Survey.
Children who were described as having greater fear or anxiety by their mothers attained lower BMIs during AN (p <0.02). Path analysis in the GAN and a validation sample, Price Foundation Anorexia Nervosa Trios Study, confirmed the relation between early childhood anxiety, caloric restriction, qualitative food item restriction, excessive exercise, and low BMI. Path analysis also confirmed a relation between childhood anxiety and caloric restriction, which mediated the relation between childhood anxiety and low BMI in the GAN sample only.
Fearful or anxious behavior as a child was associated with the attainment of low BMI in AN and childhood anxiety was associated with caloric restriction. Measures of anxiety and factors associated with anxiety-proneness in childhood may index children at risk for restrictive behaviors and extremely low BMIs in AN.
Anorexia Nervosa; Anxiety; Body Mass Index
Neural cell adhesion molecule (NCAM) is a membrane-bound cell recognition molecule that exerts important functions in normal neurodevelopment including cell migration, neurite outgrowth, axon fasciculation, and synaptic plasticity. Alternative splicing of NCAM mRNA generates three main protein isoforms: NCAM-180, -140, and -120. Ectodomain shedding of NCAM isoforms can produce an extracellular 105–115 kDa soluble NCAM fragment (NCAM-EC) and a smaller intracellular cytoplasmic fragment (NCAM-IC). NCAM also undergoes a unique post-translational modification in brain by the addition of polysialic acid (PSA)-NCAM. Interestingly, both PSA-NCAM and NCAM-EC have been implicated in the pathophysiology of schizophrenia. The developmental expression patterns of the main NCAM isoforms and PSA-NCAM have been described in rodent brain, but no studies have examined NCAM expression across human cortical development. Western blotting was used to quantify NCAM in human postmortem prefrontal cortex in 42 individuals ranging in age from mid-gestation to early adulthood. Each NCAM isoform (NCAM-180, -140, and -120), post-translational modification (PSA-NCAM) and cleavage fragment (NCAM-EC and NCAM-IC) demonstrated developmental regulation in frontal cortex. NCAM-180, -140, and -120, as well as PSA-NCAM, and NCAM-IC all showed strong developmental regulation during fetal and early postnatal ages, consistent with their identified roles in axon growth and plasticity. NCAM-EC demonstrated a more gradual increase from the early postnatal period to reach a plateau by early adolescence, potentially implicating involvement in later developmental processes. In summary, this study implicates the major NCAM isoforms, PSA- NCAM and proteolytically cleaved NCAM in pre- and postnatal development of the human prefrontal cortex. These data provide new insights on human cortical development and also provide a basis for how altered NCAM signaling during specific developmental intervals could affect synaptic connectivity and circuit formation, and thereby contribute to neurodevelopmental disorders.
NCAM; adhesion molecules; synaptic plasticity; neurite outgrowth; adolescence; schizophrenia
Although there has been recent interest in the study of childhood and adolescent brain development, very little is known about normal brain development in the first few months of life. In older children, there are regional differences in cortical gray matter development, whereas cortical gray and white matter growth after birth has not been studied to a great extent. The adult human brain is also characterized by cerebral asymmetries and sexual dimorphisms, although very little is known about how these asymmetries and dimorphisms develop. We used magnetic resonance imaging and an automatic segmentation methodology to study brain structure in 74 neonates in the first few weeks after birth. We found robust cortical gray matter growth compared with white matter growth, with occipital regions growing much faster than prefrontal regions. Sexual dimorphism is present at birth, with males having larger total brain cortical gray and white matter volumes than females. In contrast to adults and older children, the left hemisphere is larger than the right hemisphere, and the normal pattern of fronto-occipital asymmetry described in older children and adults is not present. Regional differences in cortical gray matter growth are likely related to differential maturation of sensory and motor systems compared with prefrontal executive function after birth. These findings also indicate that whereas some adult patterns of sexual dimorphism and cerebral asymmetries are present at birth, others develop after birth.
human; magnetic resonance imaging; brain development; cortex; white matter; myelination
Brain development in the first 2 years after birth is extremely dynamic and likely plays an important role in neurodevelopmental disorders, including autism and schizophrenia. Knowledge regarding this period is currently quite limited. We studied structural brain development in healthy subjects from birth to 2. Ninety-eight children received structural MRI scans on a Siemens head-only 3T scanner with magnetization prepared rapid gradient echo T1-weighted, and turbo spin echo, dual-echo (proton density and T2 weighted) sequences: 84 children at 2–4 weeks, 35 at 1 year and 26 at 2 years of age. Tissue segmentation was accomplished using a novel automated approach. Lateral ventricle, caudate, and hippocampal volumes were also determined. Total brain volume increased 101% in the first year, with a 15% increase in the second. The majority of hemispheric growth was accounted for by gray matter, which increased 149% in the first year; hemispheric white matter volume increased by only 11%. Cerebellum volume increased 240% in the first year. Lateral ventricle volume increased 280% in the first year, with a small decrease in the second. The caudate increased 19% and the hippocampus 13% from age 1 to age 2. There was robust growth of the human brain in the first two years of life, driven mainly by gray matter growth. In contrast, white matter growth was much slower. Cerebellum volume also increased substantially in the first year of life. These results suggest the structural underpinnings of cognitive and motor development in early childhood, as well as the potential pathogenesis of neurodevelopmental disorders.
brain development; cortex; children; magnetic resonance imaging; hippocampus; caudate
Using time-lapse maps, we visualized the dynamics of schizophrenia progression, revealing spreading cortical changes that depend on the type of antipsychotic treatment. Dynamic, 4-dimensional models of disease progression were created from 4 repeated high-resolution brain magnetic resonance imaging scans of 36 first-episode schizophrenia patients (30 men/6 women; mean age: 24.2 ± 5.1 SD years) randomized to haloperidol (HAL) (n = 15) or olanzapine (OLZ) treatment (n = 21), imaged at baseline, 3, 6, and 12 months (144 scans). Based on surface-based cortical models and point-by-point measures of gray matter volume, we generated time-lapse maps for each treatment. Disease trajectories differed for atypical versus typical neuroleptic drugs. A rapidly advancing parietal-to-frontal deficit trajectory, in HAL-treated patients, mirrored normal cortical maturation but greatly intensified. The disease trajectory advanced even after symptom normalization, involving the frontal cortex within 12 months with typical drug treatment. Areas with fastest tissue loss shifted anteriorly in the first year of psychosis. This trajectory was not seen with OLZ. Whether this association reflects either reduced neurotoxicity or neuroprotection cannot be addressed with neuroimaging; changes may relate to glial rather than neural components. These maps revise current models of schizophrenia progression; due to power limitations, the findings require confirmation in a sample large enough to model group × time interactions.
cortex; development; imaging; neurotoxicity; schizophrenia