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Choline, folic acid, and Vitamin D are essential for fetal brain development that may be the first steps in the pathogenesis of the psychotic spectrum. Micronutrient deficiencies have been associated with changes in fetal brain development, manifest as early problems in childhood behavior, and cognition, and later as increased incidence of psychotic and autism spectrum disorders. Micronutrient supplements may not only prevent deficiency, but they may also positively affect brain development in the context of other maternal risk factors, including maternal infection, stress, inflammation, and substance abuse. Many genes associated with later psychotic illness are highly expressed in the fetal brain, where they are responsible for various neurodevelopmental mechanisms. Interaction of micronutrient vitamins with these genetically programmed mechanisms to prevent pathological brain development associated with later psychosis is under active investigation. In addition to their effects on brain development, micronutrient vitamins have effects on other aspects of gestation and fetal development, including the prevention of premature delivery and other developmental abnormalities. Supplemental micronutrient vitamins should be part of good prenatal care, as has already happened for folic acid and Vitamin D and is now advocated by the American Medical Association for choline. The benefits of these micronutrient supplements include protection of brain development and the possibility of decreased risk for future psychotic disorders in those children who are either genetically or environmentally vulnerable. The purpose of this review is to present the current evidence supporting the safety and effectiveness of micronutrients in gestation and to suggest areas for future research.

Summary Background & aims Maternal gestational infection is a well-characterized risk factor for offsprings’ development of mental disorders including schizophrenia, autism, and attention deficit disorder. The inflammatory response elicited by the infection is partly directed against the placenta and fetus and is the putative pathogenic mechanism for fetal brain developmental abnormalities. Fetal brain abnormalities are generally irreversible after birth and increase risk for later mental disorders. Maternal immune activation in animals models this pathophysiology. SARS-CoV-2 produces maternal inflammatory responses during pregnancy similar to previously studied common respiratory viruses. Method Choline, folic acid, Vitamin D, and n-3 polyunsaturated fatty acids are among the nutrients that have been studied as possible mitigating factors for effects of maternal infection and inflammation on fetal development. Clinical and animal studies relevant to their use in pregnant women who have been infected are reviewed. Results Higher maternal choline levels have positive effects on the development of brain function for infants of mothers who experienced viral infections in early pregnancy. No other nutrient has been studied in the context of viral inflammation. Vitamin D reduces pro-inflammatory cytokines in some, but not all, studies. Active folic acid metabolites decrease anti-inflammatory cytokines. N-3 polyunsaturated fatty acids have no effect. Conclusions Vitamin D and folic acid are already supplemented in food additives and in prenatal vitamins. Despite recommendations by several public health agencies and medical societies, choline intake is often inadequate in early gestation when the brain is forming. A public health initiative for choline supplements during the pandemic could be helpful for women planning or already pregnant who also become exposed or infected with SARS-CoV-2.

Background Prenatal depression has lasting effects on development in offspring, including later mental illness risk. Maternal responses to depression include inflammation and hypothalamic-pituitary-adrenal axis stimulation. Effects on development of cerebral inhibitory neurocircuits may differ for female and male fetuses. Methods Mothers (N = 181) were assessed periodically, beginning at 16 weeks’ gestation, using the Center for Epidemiologic Studies–Depression Scale. Maternal prenatal C-reactive protein and hair cortisol and cortisone levels were determined. Cortisone was determined in neonatal hair. Development of cerebral inhibitory neurocircuits was assessed in 162 1-month-old newborns by inhibition of P50 electrophysiological responses to repeated sounds. Results Maternal depression was associated with decreased newborn P50 inhibition in both sexes. Maternal C-reactive protein levels were significantly associated with depression only in pregnancies with male fetuses and with decreased newborn P50 inhibition only in male newborns. Maternal cortisol levels were significantly associated with depression only in pregnancies with female fetuses and with decreased newborn P50 inhibition only in female newborns. In pregnancies with male fetuses compared with pregnancies with female fetuses, cortisol was more robustly metabolized to cortisone, which does not activate cortisol receptors. Conclusions This study finds sex-specific associations of C-reactive protein and cortisol levels with prenatal depression in women and with decreased development of newborn P50 inhibition. Sex-based differences in maternal response to depression with inflammation or cortisol and their developmental effects may reflect evolutionary influences to promote survival in adversity. Decreased newborn P50 inhibition is associated with later childhood behavioral problems, and decreased P50 inhibition is a pathophysiological feature of several mental illnesses.

Children with hearing loss (HL) remain at risk for poorer language abilities than normal hearing (NH) children despite targeted interventions; reasons for these differences remain unclear. In NH children, recent research suggests that speech discrimination is related to language outcomes, yet we know little about it in children with HL under the age of two years. We utilized a vowel contrast, /a-i/, and a consonant-vowel contrast, /ba-da/, to examine speech discrimination in 47 NH infants and 40 infants with HL. At Mean age = 3 months, EEG recorded from 11 scalp electrodes was used to compute the time-frequency mismatched response (TF-MMR(SE)) to the contrasts; at Mean age = 9 months, behavioral discrimination was assessed using a head turn task. A machine learning (ML) classifier was used to predict behavioral discrimination when given an arbitrary TF-MMR(SE) as input, achieving accuracies of 73% for exact classification and 92% for classification within a distance of one class. Linear fits revealed a robust relationship regardless of hearing status or speech contrast. TF-MMR(SE) responses in the delta (1–3.5 Hz), theta (3.5–8 Hz), and alpha (8–12 Hz) bands explained the most variance in behavioral task performance. Our findings demonstrate the feasibility of using TF-MMR(SE) to predict later behavioral speech discrimination.

Black Americans have increased risk for schizophrenia and other mental illnesses with prenatal origins. Prenatal choline promotes infant brain development and behavioral outcomes, but choline has not been specifically assessed in Black Americans. Pregnant women (N = 183, N = 25 Black Americans) enrolled in a study of prenatal stressors and interactions with prenatal choline. Black American women had lower 16-week gestation plasma choline than Whites. Lower choline was not related to obesity, income, or metabolic genotypes. Pregnant women in rural Uganda have higher choline levels than Black American women. Black Americans’ lower choline was associated with higher hair cortisol, indicative of higher stress. Lower maternal choline was associated with offsprings’ lower gestational age at birth and with decreased auditory P50 inhibition, a marker of inhibitory neuron development. Behavioral development was assessed on the Infant Behavior Questionnaire-R-SF (IBQ-R) at 3 months. Lower Black American maternal gestational choline was associated with lower infant IBQ-R Orienting/Regulation, indicating decreased attention and relation to caregivers. Additional evidence for developmental effects of choline in Black Americans comes from a randomized clinical trial of gestational phosphatidylcholine supplementation versus placebo that included 15 Black Americans. Phosphatidylcholine increased gestational age at birth and newborn P50 inhibition and decreased Social Withdrawn and Attention problems at 40 months of age in Black Americans’ offspring compared to placebo. Inhibitory and behavioral deficits associated with lower prenatal choline in offspring of Black American women indicate potential developmental predispositions to later mental illnesses that might be ameliorated by prenatal choline or phosphatidylcholine supplementation.

BackgroundMaternal inflammation in early pregnancy has been identified epidemiologically as a prenatal pathogenic factor for the offspring's later mental illness. Early newborn manifestations of the effects of maternal inflammation on human fetal brain development are largely unknown.MethodsMaternal infection, depression, obesity, and other factors associated with inflammation were assessed at 16 weeks gestation, along with maternal C-reactive protein (CRP), cytokines, and serum choline. Cerebral inhibition was assessed by inhibitory P50 sensory gating at 1 month of age, and infant behavior was assessed by maternal ratings at 3 months of age.ResultsMaternal CRP diminished the development of cerebral inhibition in newborn males but paradoxically increased inhibition in females. Similar sex-dependent effects were seen in mothers' assessment of their infant's self-regulatory behaviors at 3 months of age. Higher maternal choline levels partly mitigated the effect of CRP in male offspring.ConclusionsThe male fetal-placental unit appears to be more sensitive to maternal inflammation than females. Effects are particularly marked on cerebral inhibition. Deficits in cerebral inhibition 1 month after birth, similar to those observed in several mental illnesses, including schizophrenia, indicate fetal developmental pathways that may lead to later mental illness. Deficits in early infant behavior follow. Early intervention before birth, including prenatal vitamins, folate, and choline supplements, may help prevent fetal development of pathophysiological deficits that can have life-long consequences for mental health.

Objective Maternal depression during gestation is an adverse factor in fetal brain development that manifests in later childhood behavioral problems. Fetal heart rate variability (FHRV) mediated by parasympathetic input is a marker of gestational nervous system development. Biological mediators of adverse effects of maternal depression may involve the mother's corticosteroids; however, links between depression, corticosteroids, and early nervous system development remain inconclusive. Methods Heart rate was recorded in 23 fetuses by transabdominal Doppler at 28-33 weeks gestation. The SD of interbeat intervals over 20 min assessed FHRV. Maternal depression ratings and hair concentrations of cortisol and cortisone were assayed. An auditory sensory gating paradigm assessed newborn development of cerebral inhibition. Parents rated their infant's temperament characteristics on the Infant Behavior Questionnaire-Revised Short Form (IBQ-R). Results Maternal depression was associated with lower FHRV, especially for male fetuses, β = -0.633, P = 0.045. Maternal depression was associated with lower cortisol to total corticosteroids ratios, β = -0.519, P = 0.033. Lower cortisol ratios were associated with decreased FHRV, β = 0.485, P = 0.019. Decreased FHRV was associated with increased newborn sensory gating deficits, β = -0.992, P = 0.035, indicating poorer development of cerebral inhibition. Higher FHRV was related to increased infant IBQ-R self-regulatory behaviors, r = 0.454, P = 0.029. Conclusion Maternal depression is associated via corticosteroids with decreased development of nervous system control of fetal heart rate. Decreased FHRV indicates developmental alterations in gestation that correlate with altered brain function and subsequent regulatory challenges in early infancy.

Maternal gestational inflammation from infection, obesity, depression, and adverse childhood experiences negatively affects offspring cognitive development. Choline is a key nutrient in fetal brain development. We investigated whether higher maternal plasma choline concentrations have a positive association with offspring cognition, specifically processing speed, in the presence of inflammation. Forty-eight children were evaluated at 4 years of age. Processing Speed Composite Score on the Wechsler Preschool & Primary Scales of Intelligence was the principal outcome. Maternal C-reactive protein (CRP), a marker of inflammation, and choline plasma concentration had been measured at 16 weeks’ gestation. Choline concentrations >7.07μM were compared to lower levels. Mothers with lower choline levels reported more depression and stress. Head circumference was larger for neonates of mothers with higher choline levels. In analyses with maternal CRP, higher maternal choline was associated with higher offspring Processing Speed Composite Scores for both sexes. For males, higher maternal choline competed with the negative association of maternal CRP on Processing Speed. Higher Processing Speed was related to the child’s behavioral ratings, with fewer Withdrawn Problems on the Child Behavior Checklist 11/2-5 years at 4 years and higher Infant Behavior Questionnaire Orienting/Regulation at 3 months of age, consistent with persistent developmental effects. Higher processing speed and decreased problems in social withdrawal are positively associated with prenatal maternal choline. Both lower processing speed and social withdrawal problems are precursors to later mental difficulties. Choline supplementation in pregnancy may mitigate effects of maternal inflammation that contribute to problems in offspring’s’ cognition and behavior.

BackgroundPrenatal choline is a key nutrient, like folic acid and vitamin D, for fetal brain development and subsequent mental function. We sought to determine whether effects of higher maternal plasma choline concentrations on childhood attention and social problems, found in an initial clinical trial of choline supplementation, are observed in a second cohort.MethodsOf 183 mothers enrolled from an urban safety net hospital clinic, 162 complied with gestational assessments and brought their newborns for study at 1 month of age; 83 continued assessments through 4 years of age. Effects of maternal 16 weeks of gestation plasma choline concentrations ⩾7.07 μM, 1 s.d. below the mean level obtained with supplementation in the previous trial, were compared to lower levels. The Attention Problems and Withdrawn Syndrome scales on Child Behavior Checklist 1½–5 were the principal outcomes.ResultsHigher maternal plasma choline was associated with lower mean Attention Problems percentiles in children, and for male children, with lower Withdrawn percentiles. Higher plasma choline concentrations also reduced Attention Problems percentiles for children of mothers who used cannabis during gestation as well as children of mothers who had gestational infection.ConclusionsPrenatal choline's positive associations with early childhood behaviors are found in a second, more diverse cohort. Increases in attention problems and social withdrawal in early childhood are associated with later mental illnesses including attention deficit disorder and schizophrenia. Choline concentrations in the pregnant women in this study replicate other research findings suggesting that most pregnant women do not have adequate choline in their diets.

Prenatal COVID-19 infection is anticipated by the U.S. Centers for Disease Control to affect fetal development similarly to other common respiratory coronaviruses through effects of the maternal inflammatory response on the fetus and placenta. Plasma choline levels were measured at 16 weeks gestation in 43 mothers who had contracted common respiratory viruses during the first 6–16 weeks of pregnancy and 53 mothers who had not. When their infants reached 3 months of age, mothers completed the Infant Behavior Questionnaire-Revised (IBQ-R), which assesses their infants’ level of activity (Surgency), their fearfulness and sadness (Negativity), and their ability to maintain attention and bond to their parents and caretakers (Regulation). Infants of mothers who had contracted a moderately severe respiratory virus infection and had higher gestational choline serum levels (≥7.5 mM consistent with U.S. Food and Drug Administration dietary recommendations) had significantly increased development of their ability to maintain attention and to bond with their parents (Regulation), compared to infants whose mothers had contracted an infection but had lower choline levels (, Highlights • Maternal COVID-19 may affect fetal development and later childhood behavior. • Higher prenatal choline levels mitigate the fetal impact of virus infection. • Choline levels sufficient to protect the fetus often require dietary supplements.

Genes, infection, malnutrition, and other factors affecting fetal brain development are a major component of risk for a child's emotional development and later mental illnesses, including schizophrenia, bipolar disorder, and autism. Prenatal interventions to ameliorate that risk have yet to be established for clinical use. A systematic review of prenatal nutrients and childhood emotional development and later mental illness was performed. Randomized trials of folic acid, phosphatidylcholine, and omega-3 fatty acid supplements assess effects of doses beyond those adequate to remedy deficiencies to promote normal fetal development despite genetic and environmental risks. Folic acid to prevent neural tube defects is an example. Vitamins A and D are currently recommended at maximum levels, but women's incomplete compliance permits observational studies of their effects. Folic acid and phosphatidylcholine supplements have shown evidence for improving childhood emotional development associated with later mental illnesses. Vitamins A and D decreased the risk for schizophrenia and autism in retrospective observations. Omega-3 fatty acid supplementation during early pregnancy increased the risk for schizophrenia and increased symptoms of attention deficit hyperactivity disorder, but in later pregnancy it decreased childhood wheezing and premature birth. Studies are complicated by the length of time between birth and the emergence of mental illnesses like schizophrenia, compared with anomalies like facial clefts identified at birth. As part of comprehensive maternal and fetal care, prenatal nutrient interventions should be further considered as uniquely effective first steps in decreasing risk for future psychiatric and other illnesses in newborn children. [AJP at 175: Remembering Our Past As We Envision Our Future July 1959: Longitudinal Observations of Biological Deviations in a Schizophrenic Infant Barbara Fish described the course of an infant born with fluctuating motor problems who developed schizophrenia. (Am J Psychiatry 1959; 116:25-31 )].

OBJECTIVE: To examine the utility of the mismatch response (MMR) and acoustic change complex (ACC) for assessing speech discrimination in infants. METHODS: Continuous EEG was recorded during sleep from 48 (24 male, 20 female) normally hearing infants aged 1.77 to 4.57 months in response to two auditory discrimination tasks. ACC was recorded in response to a three-vowel sequence (/i/-/a/-/i/). MMR was recorded in response to a standard vowel, /a/, (probability 85%), and to a deviant vowel, /i/, (probability of 15%). A priori comparisons included: age, sex, and sleep state. These were conducted separately for each of the three bandpass filter settings were compared (1-18, 1-30, and 1-40 Hz). RESULTS: A priori tests revealed no differences in MMR or ACC for age, sex, or sleep state for any of the three filter settings. ACC and MMR responses were prominently observed in all 44 sleeping infants (data from four infants were excluded). Significant differences observed for ACC were to the onset and offset of stimuli. However, neither group nor individual differences were observed to changes in speech stimuli in the ACC. MMR revealed two prominent peaks occurring at the stimulus onset and at the stimulus offset. Permutation t-tests revealed significant differences between the standard and deviant stimuli for both the onset and offset MMR peaks (p

These initial data suggest that with prenatal vitamins and choline supplements, we might decrease one risk factor associated with poorer health outcomes disproportionally affecting Black families, ie, preterm birth. Dissemination of this research fulfills the principle of Justice in the Belmont Report, to ensure that participants from different racial, ethnic and socioeconomic groups receive benefits from research directed to their specific problems.

OBJECTIVE: To assess whether choline decreases effects of maternal infections on fetal brain circuit development and on expression of infant behavior at 3 months of age. STUDY DESIGN: A case-control study was conducted in a public hospital obstetrics and midwifery service, with prenatal assessments of maternal infection, C-Reactive Protein (CRP), and choline levels and postnatal assessments of cerebral neuronal inhibition in 162 newborns. At 3 months, 136 parents completed reports of their child’s behavior. RESULTS: Maternal infection at 16 weeks gestation, experienced by 41% of mothers, raised mean maternal CRP (d’ = 0.47, P = 0.002) and decreased the development of cerebral inhibition of auditory response at 1 month of age (d’ = 0.39, P

Objective:α7-Nicotinic receptors are involved in the final maturation of GABA inhibitory synapses before birth. Choline at levels found in the amniotic fluid is an agonist at α7-nicotinic receptors. The authors conducted a double-blind placebo-controlled trial to assess whether high-dose oral phosphatidylcholine supplementation during pregnancy to increase maternal amniotic fluid choline levels would enhance fetal development of cerebral inhibition and, as a result, decrease childhood behavior problems associated with later mental illness.Method:The authors previously reported that newborns in the phosphatidylcholine treatment group have increased suppression of the cerebral evoked response to repeated auditory stimuli. In this follow-up, they report parental assessments of the children’s behavior at 40 months of age, using the Child Behavior Checklist.Results:At 40 months, parent ratings of children in the phosphatidylcholine group (N=23) indicated fewer attention problems and less social withdrawal comp...

BACKGROUND: Complex diseases, including mental illnesses, are the result of interactions between genetic and environmental factors. Maternal illness, smoking, nutritional deficits, psychosocial stress, and psychiatric symptoms during pregnancy are examples of environmental factors associated with increased risk for later mental illness, including schizophrenia, in offspring; pathophysiology in cholinergic mechanisms involved in inhibitory neurocircuit functioning is a demonstrated heritable defect in adults with schizophrenia and their families. Cholinergic mechanisms also have an important role in early brain development. CHRNA7 and its receptor product, the a7-nicotinic acetylcholine receptor, are expressed at significantly higher levels in fetuses compared to adults or children, and a7-nicotinic receptors are more widely dispersed in fetal brain. Since cholinergic innervation does not reach the cerebrum until near birth, a7-nicotinic receptors are activated by choline present in the amniotic fluid during fetal development. There is additional high fetal demand for choline for the membrane phospholipids required for fetal growth. Together these demands can overwhelm the mother’s ability to supply fetal needs through synthesis and dietary intake, particularly in the presence of other environmental challenges. We propose that schizophrenia-associated inhibitory neurocircuit dysfunction occurs as a result of an interaction between α7 nicotinic receptor density and choline availability during fetal brain development and provides a target intervention/prevention strategy. METHODS: Inhibitory neurocircuit dysfunction is related to auditory cerebral inhibition deficits assessed using a paired-click paradigm. Each click elicits a preattentive event-related brain response (P50) that occurs approximately 50 msec (~ 75 msec in infants) after presentation. Reductions in amplitudes of the response to the second click by at least 50% compared to the response to the first click indicates intact cerebral inhibition. Our previous studies have shown that cerebral inhibition is developed at birth, stable over first 4 years of life, and diminished in infants of mothers who smoked during pregnancy and in infants of parents with major mental illness. RESULTS: In a double-blind placebo control trial of 100 pregnant mothers, participants either received 6300 mg of phosphatidylcholine (900 mg choline) or corn oil. Until approximately 3 months of age, infants received 600 mg of phosphatidylcholine (100 mg choline) or placebo once daily in an oral suspension. At 4 weeks of age, infants of mothers in the supplemented group had better cerebral inhibition than those in the placebo group. Supplementation also improved cerebral inhibition in infants with an increased genetic risk associated with reduced receptor density. Cerebral inhibition at 4 weeks also predicted 40-month attention and withdrawal ratings on the Child Behavior Checklist 1 ½-5. In an observational study of 162 pregnant women, free serum choline levels at 16 weeks gestation were associated with improved cerebral inhibition in infants at 4 weeks and appeared to protect neurocircuit development in infants of mothers who 1) developed infection during pregnancy, 2) had elevated depression ratings during pregnancy, or 3) used marijuana during pregnancy. Behaviorally, higher maternal serum choline levels were associated with higher Orientation/Regulation scores on the Infant Behavior Questionnaire-R at 12 months of age. CONCLUSIONS: In human pregnancy, perinatal choline supplementation enhances the development of cerebral inhibition, rescues genetically vulnerable individuals, and improves behavioral outcomes.

Background: Maternal phosphatidylcholine supplements have shown benefit in the development of the human fetal brain, as assessed both by newborn physiological measurements and by a related decrease in later childhood behavioral abnormalities. However, the relatively low choline component of phosphatidylcholine mandates high doses that are difficult for pregnant women to consume. Objective: Betaine can substitute for some choline effects. The hypothesis was that betaine supplementation would significantly increase women's serum choline. Design: A three-arm crossover clinical trial was used to assess serum concentrations of choline after betaine supplements at two doses, in comparison with phosphatidylcholine supplementation. The effects of both a single dose and of one-week twice-daily doses were assessed in normal non-pregnant women. Results: Betaine supplements at two doses failed to increase serum choline concentrations after single administration or one-week twice-daily dosing. Phosphatidylcholine supplements raised choline concentrations after both single doses (mean change from baseline 8.34 ± 7.29 ng/ml, paired t = 3.24, df 7, p = 0.014, range 1–21 ng/ml, d’ = 1.15) and one-week twice-daily doses (mean change from baseline 4.58 ± 3.68 ng/ml standard deviation; paired t = 3.51, df 7, p

AIMS There are an increasing number of reports suggesting an association between maternal anxiety experienced during pregnancy and adverse outcomes of the offspring. However, exploration of the biological changes in the brain that mediate that relationship has been hampered by the lack of appropriate biomarkers. This report represents an initial step exploring whether a potential infant biomarker, smooth pursuit eye movements, may be associated with prenatal exposure to maternal anxiety. STUDY DESIGN Blinded cross-sectional study. PLACE AND DURATION OF STUDY Department of Psychiatry, University of Colorado School of Medicine. Data collected from July 2011 to May 2012. METHODOLOGY Forty-three infants including 34 whose prenatal maternal anxiety status was identified (12 with a known maternal prenatal anxiety diagnosis and 22 without) had eye movements recorded during a smooth pursuit eye movement task at four and/or six months of age. RESULTS At 6 months of age, infants with prenatal exposure to maternal anxiety, compared to infants without such exposure, spent a higher percentage of time utilizing smooth pursuit (t=2.7, df=24, P=.013), had longer duration of smooth pursuit uninterrupted by saccades (t=2.5, df=24, P=.019), and had decreased frequency of forward saccades (t=3.8, df=24, P=.001). No differences between groups were identified at 4 months of age. CONCLUSION Smooth pursuit abnormalities may, at six months of age, be a potential biomarker for prenatal maternal anxiety exposure.

AIMS Theory of Mind (ToM) is an important component of social cognition. Deficits in ToM are found in various neurodevelopmental disorders and social and environmental factors have been found to influence ToM development. Little previous research has focused on effects of exposure to toxins; this report examines the impact of tobacco. PLACE OF STUDY Department of Psychiatry, University of Colorado School of Medicine, between April 2006 - August 2012. METHODOLOGY 101 children, 18 with prenatal exposure to tobacco, underwent ToM testing at 40 (n=89) and 48 (n=77) months of age. Test questions received dichotomous pass/fail scores and percentage of correct responses was utilized as the primary dependent variable. RESULTS At 40 months of age children were rarely able to correctly answer false belief questions and there were no significant differences according to prenatal tobacco exposure. At 48 months of age, there was a significant effect of prenatal tobacco exposure with non-exposed 48-month-olds correctly answering 45±40.6% of content false belief questions correctly, compared to 13.9±25.3% for 48-month-olds with prenatal tobacco exposure (F=4.79, df= 1,73, p=.032). CONCLUSION ToM abilities are rapidly developing between 40 and 48 months of age. Prenatal exposure to tobacco is associated with impairment at 48 but not 40 months of age. This finding supports consideration of nicotinic mechanisms as contributors to early development of social cognition.

Aims: To determine whether maternal affective and anxiety disorders are associated with cognitive inhibitory deficits in four-year-old children utilizing a chimeric animal stroop task, a childhood adaptation of the traditional stroop task. Study Design: Blinded Cross-Sectional Study. Place and Duration of Study: Department of Psychiatry, University of Colorado School of Medicine, data collected from June 2009 to October 2010. Methodology: Four-year-olds of mothers with (n=29) and without (n=31) a history of affective or anxiety disorders completed a chimeric animal version of the stroop task. Incongruent, neutral, and congruent stimuli were presented over three trial blocks. Mean reaction time and response accuracy were the primary dependent measures. Results: The increase in the number of incorrect responses to incongruent versus congruent or neutral stimuli was larger for offspring of a mother with a history of an affective or anxiety disorder than without (t=2.4, P=.02); there was no significant main effect of maternal psychiatric illness (F(1, 58)=0.9, P=.34) or a stimulus type by maternal illness (F(1 , 58)=1.1, P=.30) interaction on reaction time. Conclusion: The association between maternal affective and anxiety disorders and cognitive inhibitory deficit is already identifiable by four years of age.

It is unclear whether information obtained from a one parent can be used to infer the other parent's history of psychopathology. Two hundred and one parental dyads were asked to complete psychiatric interviews. Based on maternal report, non-participating husbands/ fathers had higher rates than participating fathers of psychiatric illness. For fathers who did participate, maternal report did not match direct interview of paternal psychopathology with sensitivities less than 0.40 and positive predictive values of 0.33 to 0.74. Psychopa -thology may be over-represented among fathers who do not participate in research. Mother report of paternal symptoms is not an effective proxy. Alternative methods need to be developed to: i) improve father participation or ii) identify psychiatric status in fathers who do not participate in research projects.

Prenatal maternal anxiety has detrimental effects on the offspring's neurocognitive development, including impaired attentional function. Antidepressants are commonly used during pregnancy, yet their impact on offspring attention and their interaction with maternal anxiety has not been assessed. The authors used P50 auditory sensory gating, a putative marker of early attentional processes measurable in young infants, to assess the impact of maternal anxiety and antidepressant use.A total of 242 mother-infant dyads were classified relative to maternal history of anxiety and maternal prenatal antidepressant use. Infant P50 auditory sensory gating was recorded during active sleep at a mean age of 76 days (SD=38).In the absence of prenatal antidepressant exposure, infants whose mothers had a history of anxiety diagnoses had diminished P50 sensory gating. Prenatal antidepressant exposure mitigated the effect of anxiety. The effect of maternal anxiety was limited to amplitude of response to the second stimulus, while antidepressant exposure had an impact on the amplitude of response to both the first and second stimulus.Maternal anxiety disorders are associated with less inhibition during infant sensory gating, a performance deficit mitigated by prenatal antidepressant exposure. This effect may be important in considering the risks and benefits of antidepressant use during pregnancy. Cholinergic mechanisms are hypothesized for both anxiety and antidepressant effects, although the cholinergic receptors involved are likely different for anxiety and antidepressant effects.

The onset of diagnostic symptomology for neuropsychiatric diseases is often the end result of a decades-long process of aberrant brain development. Identification of novel treatment strategies aimed at normalizing early brain development and preventing mental illness should be a major therapeutic goal. However, there are few models for how this goal might be achieved. This review uses the development of a psychophysiological correlate of attentional deficits in schizophrenia to propose a developmental model with translational primary prevention implications. Review of genetic and neurobiological studies suggests that an early interaction between alpha7 nicotinic receptor density and choline availability may contribute to the development of schizophrenia-associated attentional deficits. Therapeutic implications, including perinatal dietary choline supplementation, are discussed.

Attentional deficits are common in a variety of neuropsychiatric disorders including attention deficit-hyperactivity disorder, autism, bipolar mood disorder, and schizophrenia. There has been increasing interest in the neurodevelopmental components of these attentional deficits; neurodevelopmental meaning that while the deficits become clinically prominent in childhood or adulthood, the deficits are the results of problems in brain development that begin in infancy or even prenatally. Despite this interest, there are few methods for assessing attention very early in infancy. This report focuses on one method, infant auditory P50 sensory gating. Attention has several components. One of the earliest components of attention, termed sensory gating, allows the brain to tune out repetitive, noninformative sensory information. Auditory P50 sensory gating refers to one task designed to measure sensory gating using changes in EEG. When identical auditory stimuli are presented 500 ms apart, the evoked response (change in the EEG associated with the processing of the click) to the second stimulus is generally reduced relative to the response to the first stimulus (i.e. the response is "gated"). When response to the second stimulus is not reduced, this is considered a poor sensory gating, is reflective of impaired cerebral inhibition, and is correlated with attentional deficits. Because the auditory P50 sensory gating task is passive, it is of potential utility in the study of young infants and may provide a window into the developmental time course of attentional deficits in a variety of neuropsychiatric disorders. The goal of this presentation is to describe the methodology for assessing infant auditory P50 sensory gating, a methodology adapted from those used in studies of adult populations.

This is an exciting and highly important paper describing a novel perinatal treatment of a risk factor for schizophrenia. Deficient cerebral inhibition is a brain deficit related to poor sensory gating and attention in schizophrenia and other disorders. This inhibition develops perinatally, influenced by genetic and in utero factors. Amniotic choline activates fetal α7-nicotinic acetylcholine receptors and facilitates development of cerebral inhibition. Increasing this activation may protect infants from future illness by promoting normal brain development. That supplementation of the diet with choline improves P50 inhibition in infants represents a paradigm shifting approach to the prevention of psychiatric illness. It was a finding like this that led to the now routine regimen for pregnant women to take folic acid supplements.

Understanding parental psychopathology interaction is important in preventing negative family outcomes. This study investigated the effect of paternal psychiatric history on maternal depressive symptom trajectory from birth to 12 months postpartum. Maternal Edinburgh Postpartum Depression screens were collected at 1, 6 and 12 months and fathers’ psychiatric diagnoses were assessed with the Structured Clinical Interview for DSM-IV from 64 families. There was not a significant difference in the trajectory of maternal depressive symptoms between mothers with partners with history of or a current psychiatric condition or those without a condition. However, mothers with partners with substance abuse history had higher levels of depressive symptoms relative to those affected by mood/anxiety disorders or those without a disorder. Our results call for a closer look at paternal history of substance abuse when treating postpartum maternal depression.

Mastery motivation is a psychological force that stimulates an individual to attempt to master a task that is challenging to him or her. This prospective longitudinal study examined the relationship between maternal stress, using the Parenting Stress Index-Short Form, and infant mastery motivation, using the Dimensions of Mastery Questionnaire, for 150 mother-infant pairs assessed at both 6- and 18-months of age. Infants of mothers with elevated stress levels at 6 months tended to show lower mastery motivation at 18 months (standardized beta = −.46, p=.001). Conversely, infants with lower general competence (standardized beta = −.24, p=.021) and lower persistence during social interactions with other children (standardized beta = −.18, p=.037) at 6 months of age had mothers with elevated total stress at 18 months of age. Implications for programs which simultaneously intervene with child and mother are discussed.

Diminished inhibitory gating of cerebral auditory evoked responses is transmitted in families with psychoses as an endophenotype related to the genetic risk for these illnesses. To assess whether the endophenotype is already expressed in infants of parents with psychotic illness and to assess effects of other known risk factors for schizophrenia, ie, maternal cigarette smoking and depression, inhibitory gating of cerebral auditory evoked responses was evaluated by comparing the P1 evoked responses to the first and second of paired auditory stimuli. Cerebral evoked responses were recorded during active sleep from 22 infants with a parent diagnosed with a psychotic illness and 129 infants with parents with no such history. Of these infants, 25 were prenatally exposed to nicotine (16 from the comparison group and 9 from the group with parental psychosis). Mothers of 35 infants had diagnoses of major depressive disorder. Parental psychosis (P = .032) and exposure to maternal smoking (P = .012) both resulted in diminished inhibitory gating in infant offspring. Compared to infants of mothers who did not smoke and who had neither parental psychosis nor maternal depression, diminished inhibitory gating was observed in infants with parental psychosis (P = .027) and in infants with maternal depression (P = .049). Diminished inhibitory gating of auditory evoked response in infants who have risk factors for schizophrenia mirrors reports of its familial transmission in adults. The results further indicate that the phenotypic expression of familial genetic and environmental risks for psychosis is already manifest very early in development.

This study assessed reliability of auditory sensory gating in young infants from 1^ 4 months of age using a paired-click paradigm in which auditory ‘clicks’ were presented at an interstimulus interval of 500 ms. Evoked potential component P1 was measured during periods of active sleep on two diierent occasions. Amplitudes, latencies, and ratio of the evoked potentials to each of the auditory clicks were compared. Signi¢cant reliability was found in the response ratio, response latency to the ¢rst stimulus, and response amplitude to the second stimulus, with a trend toward signi¢cance for response latency to the second stimulus and response amplitude to the ¢rst stimulus. The results suggest that auditory sensory gating can be reliably measured during active sleep in young infants and might be a useful tool in the study of neurodevelopmental disorders. NeuroReport 19:79^ 82 � c 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins.

This study examined the effect of attention in young infants on the saccadic localization of peripheral stimuli. Infants ranging in age from 5 to 14 weeks were tested using a peripheral stimulus detection paradigm. The presence of a central fixation stimulus decreased detection probability, particularly if attention was engaged with the central stimulus. Peripheral stimulus localization usually was accomplished with a single eye movement. When localization was accomplished by multiple eye movements, corrective saccades occurred most frequently and fixed-amplitude hypometric saccades occurred less frequently. A decrease in the slope of the linear component of the main sequence was found from 5 to 11 weeks of age, and this decrease was independent of attention.

Several models of the development of infant visual attention have used information about neural development. Most of these models have been based on nonhuman animal studies and have relied on indirect measures of neural development in human infants. This article discusses methods for studying a "neurodevelopmental" model of infant visual attention using indirect and direct measures of cortical activity. We concentrate on the effect of attention on eye movement control and show how animal-based models, indirect measurement in human infants, and direct measurement of brain activity inform this model.

Korey P Wylie,1,* Donald C Rojas,1,* Randal G Ross,1 Sharon K Hunter,1 Keeran Maharajh,1 Marc-Andre Cornier,2 Jason R Tregellas1,3 1Department of Psychiatry, 2Division of Endocrinology, Metabolism and Diabetes, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA; 3Denver Veterans Affairs Medical Center, Denver, CO, USA *These authors contributed equally to this work Purpose: Infant resting-state networks do not exhibit the same connectivity patterns as those of young children and adults. Current theories of brain development emphasize developmental progression in regional and network specialization. We compared infant and adult functional connectivity, predicting that infants would exhibit less regional specificity and greater internetwork communication compared with adults.Patients and methods: Functional magnetic resonance imaging at rest was acquired in12healthy, term infants and17adults. Resting-state networks were extracted, using independent components analysis, and the resulting components were then compared between the adult and infant groups.Results: Adults exhibited stronger connectivity in the posterior cingulate cortex node of the default mode network, but infants had higher connectivity in medial prefrontal cortex/anterior cingulate cortex than adults. Adult connectivity was typically higher than infant connectivity within structures previously associated with the various networks, whereas infant connectivity was frequently higher outside of these structures. Internetwork communication was significantly higher in infants than in adults.Conclusion: We interpret these findings as consistent with evidence suggesting that resting-state network development is associated with increasing spatial specificity, possibly reflecting the corresponding functional specialization of regions and their interconnections through experience. Keywords: functional connectivity magnetic resonance imaging, networks, development, infancy, resting-state, connectivity

Biological traits that are predictive of the later development of psychosis have not yet been identified. The complex, multidetermined nature of schizophrenia and other psychoses makes it unlikely that any single biomarker will be both sensitive and specific enough to unambiguously identify individuals who will later become psychotic. However, current genetic research has begun to identify genes associated with schizophrenia, some of which have phenotypes that appear early in life. While these phenotypes have low predictive power for identifying individuals who will become psychotic, they do serve as biomarkers for pathophysiological processes that can become the targets of prevention strategies. Examples are given from work on the role of the alpha(T)nicotinic receptor and its gene CHRNA7 on chromosome 15 in the neurobiology and genetic transmission of schizophrenia.