Sharon K. Hunter

Research review: Cholinergic mechanisms, early brain development, and risk for schizophrenia.

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.

Antidepressants may mitigate the effects of prenatal maternal anxiety on infant auditory sensory gating.

OBJECTIVE Prenatal maternal anxiety has detrimental effects on the offsprings 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. METHOD 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). RESULTS 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. CONCLUSIONS 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.

Diminished Cerebral Inhibition in Neonates Associated With Risk Factors for Schizophrenia: Parental Psychosis, Maternal Depression, and Nicotine Use

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.

Perinatal Phosphatidylcholine Supplementation and Early Childhood Behavior Problems: Evidence for CHRNA7 Moderation

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 childrens 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 compared with the placebo group (N=26). The improvement is comparable in magnitude to similar deficits at this age associated with later schizophrenia. The childrens behavior is moderated by CHRNA7 variants associated with later mental illness and is related to their enhanced cerebral inhibition as newborns. CONCLUSIONS CHRNA7, the α7-nicotinic acetylcholine receptor gene, has been associated with schizophrenia, autism, and attention deficit hyperactivity disorder. Maternal phosphatidylcholine treatment may, by increasing activation of the α7-nicotinic acetylcholine receptor, alter the development of behavior problems in early childhood that can presage later mental illness.

Maternal parenting stress and mothers' reports of their infants' mastery motivation.

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.

Reduced brain resting-state network specificity in infants compared with adults.

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 in 12 healthy, term infants and 17 adults. 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.

Diminished Infant P50 Sensory Gating Predicts Increased 40-Month-Old Attention, Anxiety/Depression, and Externalizing Symptoms.

Objective: When behavioral problems resulting from attentional difficulties present, often in preschool, it is unknown whether these problems represent preexisting altered brain development or new brain changes. This study examines whether infant sensory gating of auditory evoked potentials predicts parent-reported behavior at 40 months. Method: P50 sensory gating, an auditory evoked potential measure reflective of inhibitory processes in the brain, was measured in 50 infants around 70 days old. Parents, using the Child Behavior Checklist, reported on the child’s behavior at 40 months. Results: Controlling for gender, infants with diminished sensory gating had more problems later with externalizing behavior (F = 4.17, ndf = 1, ddf = 46, p = .047), attentional problems (F = 5.23, ndf = 1, ddf = 46, p = .027), and anxious/depressed symptoms (F = 5.36, ndf = 1, ddf = 46, p = .025). Conclusion: Diminished infant P50 sensory gating predicts attention symptoms 3 years later. These results support the hypothesis that preschool attentional dysfunction may relate to altered brain development that is detectable years prior to symptom onset.

Cholinergic Mechanisms, Early Brain Development, and Risk for Schizophrenia

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.

Paternal psychopathology and maternal depressive symptom trajectory during the first year postpartum

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.

Prenatal Primary Prevention of Mental Illness by Micronutrient Supplements in Pregnancy

Genes, infection, malnutrition, and other factors affecting fetal brain development are a major component of risk for a childs 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 womens 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 )].