A.E. Bennett Research Award. Developmental traumatology. Part II: Brain development.

BACKGROUND: Previous investigations suggest that maltreated children with a diagnosis of posttraumatic stress disorder (PTSD) evidence alterations of biological stress systems. Increased levels of catecholaminergic neurotransmitters and steroid hormones during traumatic experiences in childhood could conceivably adversely affect brain development. METHODS: In this study, 44 maltreated children and adolescents with PTSD and 61 matched controls underwent comprehensive psychiatric and neuropsychological assessments and an anatomical magnetic resonance imaging (MRI) brain scan. RESULTS: PTSD subjects had smaller intracranial and cerebral volumes than matched controls. The total midsagittal area of corpus callosum and middle and posterior regions remained smaller; while right, left, and total lateral ventricles were proportionally larger than controls, after adjustment for intracranial volume. Brain volume robustly and positively correlated with age of onset of PTSD trauma and negatively correlated with duration of abuse. Symptoms of intrusive thoughts, avoidance, hyperarousal or dissociation correlated positively with ventricular volume, and negatively with brain volume and total corpus callosum and regional measures. Significant gender by diagnosis effect revealed greater corpus callosum area reduction in maltreated males with PTSD and a trend for greater cerebral volume reduction than maltreated females with PTSD. The predicted decrease in hippocampal volume seen in adult PTSD was not seen in these subjects. CONCLUSIONS: These data suggest that the overwhelming stress of maltreatment experiences in childhood is associated with adverse brain development.     

A.E. Bennett Research Award. Developmental traumatology. Part I: Biological stress systems.

BACKGROUND: This investigation examined the relationship between trauma, psychiatric symptoms and urinary free cortisol (UFC) and catecholamine (epinephrine [EPI], norepinephrine [NE], dopamine [DA]) excretion in prepubertal children with posttraumatic stress disorder (PTSD) secondary to past child maltreatment experiences (n = 18), compared to non-traumatized children with overanxious disorder (OAD) (n = 10) and healthy controls (n = 24). METHODS: Subjects underwent comprehensive psychiatric and clinical assessments and 24 hour urine collection for measurements of UFC and urinary catecholamine excretion. Biological and clinical measures were compared using analyses of variance. RESULTS: Maltreated subjects with PTSD excreted significantly greater concentrations of urinary DA and NE over 24 hours than OAD and control subjects and greater concentrations of 24 hour UFC than control subjects. Post hoc analysis revealed that maltreated subjects with PTSD excreted significantly greater concentrations of urinary EPI than OAD subjects. Childhood PTSD was associated with greater co-morbid psychopathology including depressive and dissociative symptoms, lower global assessment of functioning, and increased incidents of lifetime suicidal ideation and attempts. Urinary catecholamine and UFC concentrations showed positive correlations with duration of the PTSD trauma and severity of PTSD symptoms. CONCLUSIONS: These data suggest that maltreatment experiences are associated with alterations of biological stress systems in maltreated children with PTSD. An improved psychobiological understanding of trauma in childhood may eventually lead to better treatments of childhood PTSD.     

A.E. Bennett Research Award. Reversal of phencyclidine-induced effects by glycine and glycine transport inhibitors.

BACKGROUND: Phencycline (PCP, "angel dust") and other noncompetitive antagonists of N-methyl-D-aspartate (NMDA)-type glutamatergic neurotransmission induce psychotic effects in humans that closely resemble positive, negative, and cognitive symptoms of schizophrenia. Behavioral effects of PCP in rodents are reversed by glycine (GLY) and other NMDA augmenting agents. In rodents, behavioral effects of PCP are mediated, in part, by secondary dysregulation of subcortical dopaminergic neurotransmission. This study evaluates effects of GLY and GLY transport antagonists on behavioral and neurochemical consequences of PCP administration in rodents. METHODS: Two separate experiments were performed. In the first, effects of GLY on PCP-induced stimulation of dopaminergic neurotransmission in nucleus accumbens were evaluated using in vivo microdialysis in awake animals. In the second, effects of a series of GLY transport antagonists were evaluated for potency in inhibiting PCP-induced hyperactivity. RESULTS: In microdialysis studies, GLY significantly inhibited PCP-induced stimulation of subcortical DA release in a dose-dependent fashion. In behavioral studies, the potency of a series of GLY transport antagonists for inhibiting PCP-induced hyperactivity in vivo correlated significantly with their potency in antagonizing GLY transport in vitro. CONCLUSIONS: These findings suggest, first, that GLY reverses not only the behavioral, but also the neurochemical, effects of PCP in rodents. Second, the findings suggest that GLY transport antagonists may induce similar effects to GLY, and may therefore represent an appropriate site for targeted drug development.     

A.E. Bennett Research Award. Anatomic basis for differential regulation of the rostrolateral peri-locus coeruleus region by limbic afferents.

BACKGROUND: Neurochemical and electrophysiological studies indicate that the locus coeruleus (LC)-norepinephrine system is activated by physiological and external stressors. This activation is mediated in part by corticotropin-releasing factor (CRF), the hypothalamic neurohormone that initiates the endocrine response to stress. We have previously shown that the central nucleus of the amygdala (CNA) provides CRF afferents to noradrenergic processes in the peri-LC area that may serve to integrate emotional and cognitive responses to stress. The bed nucleus of the stria terminalis (BNST) shares many anatomical and neurochemical characteristics with the CNA, including a high density of CRF-immunoreactive cells and fibers; however, recent studies have suggested that the CNA and the BNST may differentially regulate responses to conditioned and unconditioned fear, respectively, suggesting divergent neuroanatomical circuits underlying these processes. METHODS: In the present study, neuroanatomical substrates subserving regulation of the LC by the BNST were examined. Anterograde tract-tracing was combined with immunoelectron microscopy to test the hypotheses that BNST efferents target noradrenergic neurons of the LC and that these efferents exhibit immunolabeling for CRF. RESULTS: Ultrastructural analysis of sections that were dually labeled for the anterograde tracer biotinylated dextran amine (BDA) injected into the BNST and tyrosine hydroxylase (TH)-immunoreactivity demonstrated that BDA-labeled axon terminals formed synaptic specializations (primarily inhibitory) with TH-labeled dendrites and dendrites that lacked TH immunoreactivity. In contrast to CNA efferents that exhibited substantial immunolabeling for CRF, far fewer BDA-labeled terminals from the BNST in the rostrolateral peri-LC contained CRF. CONCLUSIONS: The present results indicate that the BNST may provide distinct neurochemical regulation of the peri-LC as compared to other limbic afferents such as the CNA. These data are interesting in light of behavioral studies showing that the CNA and BNST may be differentially involved in fear versus anxiety, respectively.     

A. E. Bennett Award paper. Expression of the dopamine D2 receptor gene in brain.

The cloning of the dopamine (DA) D2 receptor now permits the characterization and regulation of D2 messenger RNA (mRNA) in the brain. In this article, the authors describe their studies delineating the distribution of D2 receptor mRNA in the rodent and primate brain, and compare the distribution of message to D2 receptor binding sites. The effects of chronic DA agonist and antagonist treatment on D2 receptor mRNA are also presented, and provide insights into receptor regulation. Finally, the autoreceptor role of D2 receptors located in the midbrain is examined with a combination of 6-hydroxydopamine lesions and anatomic colocalization studies with tyrosine hydroxylase. These preclinical results provide a framework for subsequent investigation into the nature of D2 receptor gene expression in postmortem brains from patients with disorders putatively associated with dopaminergic dysfunction, especially schizophrenia. They also lay the groundwork for a more profound understanding of DA neurocircuitry by combining molecular biological and traditional anatomical techniques.     

Prenatal nutritional deficiency and risk of adult schizophrenia

Converging evidence suggests that a neurodevelopmental disruption plays a role in the vulnerability to schizophrenia. The authors review evidence supporting in utero exposure to nutritional deficiency as a determinant of schizophrenia. We first describe studies demonstrating that early gestational exposure to the Dutch Hunger Winter of 1944--1945 and to a severe famine in China are each associated with an increased risk of schizophrenia in offspring. The plausibility of several candidate micronutrients as potential risk factors for schizophrenia and the biological mechanisms that may underlie these associations are then reviewed. These nutrients include folate, essential fatty acids, retinoids, vitamin D, and iron. Following this discussion, we describe the methodology and results of an epidemiologic study based on a large birth cohort that has tested the association between prenatal homocysteine, an indicator of serum folate, and schizophrenia risk. The study capitalized on the use of archived prenatal serum specimens that make it possible to obtain direct, prospective biomarkers of prenatal insults, including levels of various nutrients during pregnancy. Finally, we discuss several strategies for subjecting the prenatal nutritional hypothesis of schizophrenia to further testing. These approaches include direct assessment of additional prenatal nutritional biomarkers in relation to schizophrenia in large birth cohorts, studies of epigenetic effects of prenatal starvation, association studies of genes relevant to folate and other micronutrient deficiencies, and animal models. Given the relatively high prevalence of nutritional deficiencies during pregnancy, this work has the potential to offer substantial benefits for the prevention of schizophrenia in the population.     

Gender,premorbid characteristics and negative symptoms in schizophrenia

The interrelationships among gender, premorbid functioning, and negative symptoms were examined in a first-admission inpatient sample with DSM-III-R schizophrenia. Fifty-two subjects were assessed with the Schedule for the Assessment of Negative Symptoms (SANS) at baseline and 6-month follow-up. Three indicators of premorbid functioning were examined: the Premorbid Adjustment Scale, the Quick Test, and the GAF for the best month in the year prior to the baseline interview. Men and women had relatively similar ratings on each of the 5 SANS global subscales at both times; they were also relatively similar on most of the indicators of premorbid functioning. The men and women were categorized into low vs moderate-high negative symptom groups at baseline, and no differences in premorbid functioning were detected. When the sample was classified into those with and without consistent negative symptoms at baseline and 6-month follow-up, the enduring negative men and women had significantly poorer premorbid functioning in several areas than the consistently non-negative patients. Our findings support the importance of assessing negative symptoms longitudinally and suggest that gender is not strongly associated with negative symptoms and premorbid functioning in patients ascertained at early stages of schizophrenia.     

Prenatal infectious and nutritional factors and risk of adult schizophrenia

Schizophrenia is a severely disabling psychiatric disorder. Despite a considerable amount of research on the underpinnings of the disorder, its etiology and pathogenesis remain unknown. In utero exposures, including infection and nutritional deficiencies, are emerging important risk factors for schizophrenia, in which neurodevelopmental influences probably play an important role. Our group and others have embarked on investigations aimed at identifying these risk factors and examining the mechanisms by which they increase vulnerability to this disorder. This work has the potential to lead to strategies aimed at preventing this disorder and to reveal new molecular targets for pharmacotherapeutic intervention.     

Prenatal exposure to maternal genital and reproductive infections and adult schizophrenia

OBJECTIVE: In this birth cohort study, the authors examined the relation between prenatal exposure to maternal genital/reproductive (G/R) infections and schizophrenia in offspring. METHOD: The birth cohort consisted of 7,794 offspring of pregnancies with prospectively acquired data on maternal G/R infections from obstetric records. The authors diagnosed 71 cases of schizophrenia and other schizophrenia spectrum disorders in this cohort. The relationship between maternal G/R infections and schizophrenia risk was modeled. RESULTS: Exposure to G/R infections during the periconceptional period was associated with a significantly increased risk of schizophrenia and other schizophrenia spectrum disorders, with adjustment for maternal race, education, age, and mental illness. CONCLUSIONS: Maternal G/R infection during periconception appears to increase the risk of schizophrenia in offspring.     

Gender, premorbid social functioning, and long-term outcome in DSM-III schizophrenia

The present study examined the relationships among premorbid social functioning, gender, and long-term outcome in a group of 82 subjects (41 men and 41 women) who were retrospectively rediagnosed to meet the criteria for DSM-III schizophrenia. The Premorbid Adjustment Scale was used to assess premorbid social functioning along a developmental continuum. The Community Adjustment Scale provided outcome data related to the subjects' degree of productivity, ability to maintain close relationships, and presence/absence of symptomatology an average of 32 years after initial admission. The results indicated that females tended to exhibit better premorbid functioning than males. Although the outcome data did not reveal a statistically significant relationship between gender and long-term functioning, the results were in the predicted direction, with females again demonstrating more favorable outcome than males. Despite the absence of a statistically significant gender effect, a relationship did appear to exist between premorbid functioning and very long-term outcome, with premorbid asocial functioning predicting poor outcome.     

Premorbid abnormalities in mania,schizomania, acute schizophrenia and chronic schizophrenia

The aim of this study was to examine the hypothesis that differences in outcome among affective and non-affective psychoses are associated with differences in the degree of developmental deviance. We conducted a retrospective survey of first contact cases treated over a 20-year period in a psychiatric hospital serving a catchment area in South London. All patients with non-depressive functional psychoses residing in the catchment area who received their first psychiatric treatment between 1965 and 1984 were included in the study. Cases were classified according to the relative chronicity of their illness into four non-overlapping groups: mania, schizomania, acute schizophrenia and chronic schizophrenia. There was a linear trend in the association between illness chronicity and proxy measures of developmental deviance, such as premorbid unemployment, single status and poor academic achievement. Compared to individuals with mania, schizophrenic patients had a 3–6 times increased risk of premorbid abnormality. For patients with schizomania and acute schizophrenia, the risk was 1.5–3 times greater than for manic subjects. We conclude that the prevalence of premorbid abnormalities is highest among chronic schizophrenia, but similar disturbances also occur, to a lesser degree, in less disabling affective and non-affective psychotic disorders.MRC Social Psychiatry Unit, Institute of Psychiatry     

A prospective cohort study of childhood behavioral deviance and language abnormalities as predictors of adult schizophrenia

Language and behavioral deviance in early childhood in preschizophrenia individuals suggests that the pathologic processes predisposing to schizophrenia are present from early in life. However, the etiologic antecedents of such impairments, and the degree to which they predict adult schizophrenia, have not been conclusively demonstrated. To address this, we examined language and behavioral predictors of adult psychiatric outcome in a population cohort (72 individuals with schizophrenia or schizoaffective disorder, 63 of their unaffected siblings, and 7,941 with no diagnosis) evaluated prospectively with behavioral examinations and a speech and language evaluation at 8 months, 4 years, and 7 years of age. Psychiatric outcome was ascertained via adult treatment contacts, and diagnoses were made by chart review according to DSM-IV criteria. Social maladjustment at age 7 was found to predict adult schizophrenia, and focal deviant behaviors (e.g., echolalia, meaningless laughter) at ages 4 and 7 were significantly associated with both schizophrenia and sibling status. Unintelligible speech at age 7 was a highly significant predictor of adult schizophrenia (odds ratio = 12.7), and poor expressive language ability predicted both schizophrenia and unaffected sibling outcome. Early behavioral and language dysfunction did not differentially characterize preschizophrenia subjects with a history of fetal hypoxia or an early age of first treatment contact. Given that unaffected siblings show similar signs of deviance, such problems may indicate genotypic susceptibility to the disorder, or shared environmental influences, or both.     

Maternal bonding behaviour in schizophrenia and schizoaffective disorder,considering premorbid personality traits

OBJECTIVE: Bonding between mother and child is described as a complex two-way process ensuring the needs of the child for nurture and protection. As such, it is dependent on the contribution of mother and child [1-3] whereby characteristics of personality of the child may have consequences on maternal bonding behaviour. In the current study the perception of maternal behaviour, premorbid personality traits and relationships between maternal behaviour and personality traits were investigated in schizophrenic and schizoaffective patients and their same-sex, healthy siblings. METHODS: We recruited 36 schizophrenic and schizoaffective patients and their same-sex healthy siblings. Information about maternal bonding behaviour was assessed by the Parental Bonding Instrument, information about premorbid personality traits was obtained from their mothers using the "Giessen-Test". RESULTS: Compared to their siblings, patients showed less social resonance, more permeability, less social competence and a more depressed and anxious mood. Furthermore, patients described their mothers to be less caring and to be more overprotective than their siblings described them. But there were strong associations between maternal bonding behaviour and premorbid personality traits. These findings were supported by missing significant differences in maternal care behaviour between patients and siblings when using premorbid characteristics as covariates. Significant high maternal overprotection perceived by patients with schizophrenia and schizoaffective disorders still remained after correcting for the influence of premorbid personality traits. CONCLUSION: The results suggest that premorbid personality traits should be considered not only in analyses of maternal care behaviour in schizophrenic and schizoaffective patients but also when studying other psychiatric patient groups.     

Social competence in schizophrenia: premorbid adjustment, social skill, and domains of functioning

The relations between premorbid adjustment, social skill, and domains of functioning (symptoms, social adjustment) were examined in a group of 107 schizophrenic, schizoaffective, and affective disorder patients. Premorbid sexual adjustment was moderately correlated with social skill in the schizophrenic and schizoaffective patients. Schizophrenic patients had the lowest premorbid adjustment and social skill, followed by schizoaffectives, and then affective patients. Within the schizophrenic group, social skill was significantly related to both current social adjustment and negative symptoms, but not positive symptoms. Similar but weaker effects were found for premorbid adjustment. The results suggest that deficits in social skill are correlated with poor premorbid and morbid social adjustment of schizophrenics.     

Gyrification abnormalities in childhood- and adolescent-onset schizophrenia.

BACKGROUND: Gyrification is an important index of brain development. We used magnetic resonance scanning technology to compare brain surface morphology and measures of gyrification in children and adolescents with a schizophrenia spectrum disorder and in age-equivalent healthy controls. METHODS: Magnetic resonance scans were obtained from 42 patients and 24 healthy controls, mean age 17.7 years for both groups. We employed novel quantitative measures of brain morphology, including cortical thickness and a variety of indices of sulcal and gyral curvature. We examined these measures in the whole brain and in the frontal, temporal, parietal, and occipital lobes. RESULTS: There were significant decreases in cortical thickness in the patients. This was most pronounced in the cortical tissue that underlies the sulci. The patient group had significantly more flattened curvature in the sulci and more steeped or peaked curvature in the gyri. CONCLUSIONS: This study quantitatively examines cortical thickness and surface morphology in children and adolescents with schizophrenia. Patients with schizophrenia demonstrated patterns of brain morphology that were distinctly different from healthy controls. In light of current theories of the formation of gyri and sulci, these changes may reflect aberrations in cerebral and subcortical connectivity.     

A retrospective study of premorbid ability and aging differences in cognitive clusters of schizophrenia

This retrospective, cross-sectional study evaluated whether age-related differences in patterns of cognitive deficit exist among four cognitively based schizophrenia subgroups. These subgroups had previously been identified through cluster analyses of a battery of abstraction and problem-solving tests in large samples. Evaluation of estimated premorbid intellectual ability and postmorbid cognitive functioning stratified by decade from the twenties through the fifties revealed different patterns across the schizophrenia subgroups and a clinical comparison sample. A near normal cognitive subgroup demonstrated relatively high premorbid intellectual ability and a pattern of age differences similar to the comparison sample, with the exception of deficits on the Wisconsin Card Sorting Test that were detectable in the twenties and remained stable thereafter. In contrast, a subgroup characterized by severe, pervasive cognitive deficit demonstrated low premorbid intellectual ability and extremely low test scores across the four decades studied. The remaining clusters were characterized by moderate cognitive impairment and showed age differences suggestive of a decline in cognitive function around the time of illness onset that remained stable. Results provide further support for the validity of these subgroups and encourage continued efforts to identify cognitively based candidate schizophrenia subtypes.