Cerebellum volume in high-risk offspring from multiplex alcohol dependence families: association with allelic variation in GABRA2 and BDNF.

Offspring from families with multiple cases of alcohol dependence have a greater likelihood of developing alcohol dependence (AD) and related substance use disorders. Greater susceptibility for developing these disorders may be related to structural differences in brain circuits that influence the salience of rewards or modify the efficiency of information processing and AD susceptibility. We examined the cerebellum of 71 adolescent/young adult high-risk (HR) offspring from families with multiple cases of alcohol dependence (multiplex families), and 60 low-risk (LR) controls with no family history of alcohol or drug dependence who were matched for age, gender, socioeconomic status and IQ, with attention given to possible effects of personal use of substances and maternal use during pregnancy. Magnetic resonance images were acquired on a General Electric 1.5-Tesla scanner and manually traced (BRAINS2) blind to clinical information. GABRA2 and BDNF variation were tested for their association with cerebellar volumes. High-risk offspring from multiplex AD families showed greater total volume of the cerebellum and total gray matter (GM), in comparison with LR controls. An interaction between allelic variation in GABRA2 and BDNF genes was associated with GM volumes, suggesting that inherited variation in these genes may promote early developmental differences in neuronal proliferation of the cerebellum.

Psychopathology in offspring from families of alcohol dependent female probands: a prospective study.

BACKGROUND: Despite the importance of understanding the long-term outcome for children of alcohol dependent (AD) women, the available literature is largely based on offspring of AD fathers and few have utilized prospective designs that include child, adolescent and young adult assessments. Multiplex AD families in which multiple cases of AD are present provide an ideal setting for understanding developmental variants of the adult phenotype. METHOD: Offspring from multiplex AD families identified through the mother or control families were evaluated multiple times during childhood and followed to young adulthood. Familial risk status and the presence of specific child/adolescent disorders were used as predictors of substance use disorder outcome by young adulthood. RESULTS: Offspring who were members of maternal multiplex families had elevated rates of child and young adulthood disorders. High risk offspring of alcohol dependent women were at increased risk for externalizing (Conduct Disorder and ADHD) and internalizing disorders (Major Depressive Disorder (MDD) and Anxiety Disorders). By young adulthood, offspring from these multiplex families had significantly greater odds of developing alcohol abuse or dependence (odds ratio [OR] = 3.63 [CI 1.36-9.64]) and drug abuse or dependence (OR = 4.23 [CI 1.73-10.32]). The prospective design of the study revealed that specific childhood disorders (Conduct Disorder, ADHD, MDD) increased the odds of subsequent development of substance use disorder (SUD). CONCLUSIONS: Multiplex familial risk for alcohol dependence is a significant predictor of substance use disorders by young adulthood. Familial risk and an earlier childhood disorder may set the stage for later development of SUD.

Longitudinal study of stressful life events and daily stressors among adolescents at high risk for psychotic disorders.

Psychosocial stress preceding the onset or recurrence of psychotic symptoms has been identified in patients with schizophrenia; yet there is limited understanding of the effects of stress in typically developing adolescents or those who show behavioral signs of risk for schizophrenia spectrum disorders. This study examined the developmental course of symptom progression as a function of stressful life events and daily hassles in adolescents with schizotypal personality disorder (SPD), other personality disorders, or no Axis II disorder. In this prospective longitudinal study, life events and daily stressors were assessed in adolescents aged 12 to 18 years. Results revealed that adolescents with SPD and other personality disorders reported significantly greater total, independent, and undesirable life events than individuals with no Axis II disorders. Youth with SPD report daily hassles to cause more distress compared to peers. Correlational analyses and hierarchal linear regression was used to evaluate the relationship of life events and daily stressors with psychiatric symptoms measured concurrently and 1 year later. Across diagnostic groups, the incidence of independent and undesirable life events were associated with current prodromal symptoms, while the frequency of daily stressors predicted a significant increment in positive, but not negative, prodromal symptoms over time. Therefore, adolescents who report greater daily stressors exhibit an increase in prodromal symptoms over a 1 year period. Psychosocial stress has been implicated in the etiology of schizophrenia, and these findings suggest the importance of life events and daily hassles as potential risk factors in the onset of psychotic symptoms during adolescence.

Temperament at 5 years of age predicts amygdala and orbitofrontal volume in the right hemisphere in adolescence.

It was of interest to determine if hemispheric differences in orbitofrontal cortex (OFC) volume would be related to behavioral inhibition observed in a peer-play setting. Magnetic resonance imaging (MRI) was carried out in 23 individuals (19 males and 4 females) at an average age of 14.87+/-1.14 years who were either at high or low risk for alcohol dependence. All subjects had previously been evaluated in a preschool peer play paradigm (5.03+/-0.78 years) assessing behavioral inhibition. Region of interest measures were traced for the OFC and the amygdala, and confirmed with voxel based morphometry. Behavioral inhibition, a behavioral tendency that often occurs in a novel setting in reaction to strangers, includes the following: greater time spent next to the mother, greater time staring at another child, and longer latency to begin play with another child. A significant relationship was seen between greater right OFC volume and indicators of behavioral inhibition including greater time spent proximal to their mother and greater time staring at the other child. Also, larger amygdala volume was associated with more time spent proximal to the mother. Behavioral control, including both over- and under-control, is likely to be subserved by neural circuitry associated with emotion regulation including the right OFC and the amygdala.

Neural circuitry associated with risk for alcohol use disorders.

The core features of risk for alcohol use disorders (AUD), including behavioral disinhibition, affective dysregulation, and executive dysfunction, map onto distinct neural circuits that have been found to be abnormal in the offspring of alcohol dependent individuals. Components of the cerebellothalamocortical system and the extended limbic network may provide the underpinnings for the behavioral and emotional dysfunction observed in individuals at heightened risk for AUD. In addition, abnormalities in these structures appear to be altered in individuals with the predisposition for other psychiatric conditions that may share a similar genetic diathesis. This review proposes several neurobehavioral mechanisms of genetic vulnerability that may account for phenotypic characteristics in individuals at risk for AUD.

Stress and the hypothalamic pituitary adrenal axis in the developmental course of schizophrenia.

Diathesis-stress models of schizophrenia and other psychotic disorders have dominated theorizing about etiology for over three decades. More recently, with advances in our understanding of the biological processes mediating the effects of stress, these models have incorporated mechanisms to account for the adverse impact of stress on brain function. This review examines recent scientific findings on the role of the hypothalamic-pituitary-adrenal (HPA) axis, one of the primary neural systems triggered by stress exposure, in the expression of vulnerability for schizophrenia. The results indicate that psychotic disorders are associated with elevated baseline and challenge-induced HPA activity, that antipsychotic medications reduce HPA activation, and that agents that augment stress hormone (cortisol) release exacerbate psychotic symptoms. The cumulative findings are discussed in light of a neural diathesis-stress model that postulates that cortisol has the potential to increase activity of dopamine pathways that have been implicated in schizophrenia and other psychotic disorders.

Schizophrenia.

Theoretical conceptualizations of schizophrenia have undergone significant change in the past century. Through the application of behavioral science methodology, psychologists have played a major role in the pivotal scientific advances that have led us to contemporary models. The field has moved from simplistic conceptualizations of mind-brain distinctions to models that encompass complex gene-environment interactions and neural pathways that mediate the relation between psychosocial events and brain dysfunction.

The relation of cortisol levels with hippocampus volumes under baseline and challenge conditions.

Several studies using animal models have revealed an inverse relation between gluco-corticoid levels and hippocampus volumes. This inverse relation has been interpreted as reflecting the role of the hippocampus in modulating glucocorticoid secretion, as well as the effect of glucocorticoids on the hippocampus. The objective of this study was to examine the relation between hippocampus volumes and baseline and post-challenge salivary cortisol levels in healthy young adults. A double-blind, placebo controlled design was used in which 14 males between 18 and 30 years of age received either 100 mg hydrocortisone or placebo on separate occasions approximately 1 week apart. Baseline and post-challenge cortisol levels were assessed prior to and after magnetic resonance imaging. Volumetric analyses of the hippocampus revealed no differences between the hydrocortisone and placebo conditions; however, post-challenge cortisol levels were inversely associated with total and right hippocampus volumes. Cortisol levels were not associated with the volume of the hippocampus in the placebo condition (i.e. under baseline conditions). The present findings are consistent with other evidence that the hippocampus, as reflected in volume, partially determines the efficacy of negative feedback in modulating cortisol levels.

Elevated social Internet use and schizotypal personality disorder in adolescents.

INTRODUCTION: In the past decade, the use of the Internet as a forum for communication has exponentially increased, and research indicates that excessive use is associated with psychiatric symptoms. The present study examined the rate of Internet use in adolescents with personality disorders, with a focus on schizotypal personality disorder (SPD), which is characterized by marked interpersonal deficits. Because the Internet provides an easily accessible forum for anonymous social interaction and constitutes an environment where communication is less likely to be hampered by interpersonal deficits, it was hypothesized that SPD youth will spend significantly more time engaging in social activities on the Internet than controls. METHODS: Self-reports of daily Internet use in adolescents with SPD (n=19), a control group with other personality disorders (n=22) and a non-psychiatric control group (n=28) were collected. RESULTS: Analyses revealed that the SPD participants reported significantly less social interaction with 'real-life' friends, but used the Internet for social interaction significantly more frequently than controls. Chat room participation, cooperative Internet gaming, and to a lesser degree, e-mail use, were positively correlated with ratings of SPD symptom severity and Beck Depression Inventory scores. DISCUSSION: Findings are discussed in light of the potential benefits and risks associated with Internet use by socially isolated SPD youth.

Movement abnormalities and the progression of prodromal symptomatology in adolescents at risk for psychotic disorders.

The link between movement abnormalities and psychotic disorders is presumed to reflect common neural mechanisms that influence both motor functions and vulnerability to psychosis. The prodromal period leading to psychotic disorders represents both a viable point for intervention and a developmental period that, if studied, could shed light on etiology; however, no published studies have examined the temporal progression of this link. A group with high levels of prodromal symptomatology (i.e., adolescents with schizotypal personality disorder [SPD]; n = 42) and both psychiatric controls (with other personality disorders or conduct disorder [OD]; n = 30) and nonpsychiatric controls ([NC]; n = 49) were recruited. Videotapes of structured psychiatric interviews were coded for movement abnormalities by raters blind to participants' diagnostic status, and follow-up assessments were conducted 1 year later. Controlling for psychotropic medications, the authors found that adolescents with SPD exhibited significantly more motor abnormalities in the face and upper body than did OD and NC controls. At baseline, movement abnormalities were positively correlated with the severity of positive, negative, and total prodromal symptoms. Within the SPD group, baseline movement abnormalities predicted symptom severity 1 year later. Movement abnormalities represent an early risk indicator that may be predictive of later symptom severity and potentially of psychosis onset.

The relations among putative biorisk markers in schizotypal adolescents: minor physical anomalies, movement abnormalities, and salivary cortisol.

BACKGROUND: Evidence suggests that prenatal insult may play a role in the etiology of psychotic disorders. Minor physical anomalies (MPA) are an indicator of abnormal fetal development and are elevated in individuals at genetic and behavioral risk for psychosis. Yet, there has been little empirical research on the relationships between MPAs and other neurobiological risk indicators. We hypothesized that the frequency of MPAs (an external marker of prenatal central nervous system [CNS] disruption) would be associated with two other biomarkers suggestive of disruptions in fetal neurodevelopment: movement abnormalities (an indicator of striatal abnormalities) and heightened cortisol secretion (an indicator of hypothalamic-pituitary-adrenal [HPA]/hippocampal function). METHODS: Participants with schizotypal personality disorder (SPD; n = 39) and both normal (n = 47) and other personality disorders (n = 28) control subjects were administered structured diagnostic interviews and assessed for MPAs, movement abnormalities, and salivary cortisol. RESULTS: Schizotypal personality disorder participants showed significantly greater MPAs and movement abnormalities and higher cortisol than both the normal and other personality disorders groups. Hierarchical linear regression analyses revealed that higher rates of MPAs were linked with greater movement abnormalities and salivary cortisol. CONCLUSIONS: The findings suggest that MPAs serve as a marker of neurodevelopmental abnormalities that affect striatal and hippocampal regions.

Gesture behavior in unmedicated schizotypal adolescents.

Schizotypal personality disorder is characterized by interpersonal and verbal communication deficits. Despite the important role of gesture in social communication, no published reports examine the use of gesture by individuals with SPD. In this study, raters code gesture from videotaped interviews of unmedicated adolescents with SPD, other personality disorders, or no Axis II disorder. Results indicate that SPD adolescents show significantly fewer gestures but do not differ from the other groups in overall rate of movement. The findings are discussed in light of brain regions involved in dysfunction, parallels to schizophrenia, and treatment implications.

Cortisol responses of healthy volunteers undergoing magnetic resonance imaging.

Self-reported anxiety is associated with various medical procedures, including structural and functional magnetic resonance imaging (MRI). The present study tested the hypothesis that MRI scanning would be associated with elevated cortisol levels in participants with no prior scanning experience. Baseline and post-scan cortisol levels, as well as measures of state and trait anxiety, were obtained from scanner-naive (n = 6) and scanner-experienced (n = 8) research participants. The anxiety scores and cortisol responses of the scanner-naive and scanner-experienced participants were compared. Subjects novel to MRI were no more anxious before the scan than were subjects familiar with the MRI examination, but the scanner-naive subjects manifested heightened post-scan cortisol secretion when compared to their pre-scan level and when compared to the scanner-experienced participants. The results are consistent with the hypothesis that the scanning environment can induce cortisol elevations and are congruent with the well-established effects of acute stressors on activity of the hypothalamic-pituitary-adrenal (HPA) axis. The implications for neuroimaging studies are discussed.

The stress cascade and schizophrenia: etiology and onset.

Psychosocial stress is included in most etiologic models of schizophrenia, frequently as a precipitating factor for psychosis in vulnerable individuals. Nonetheless, the stress-diathesis model has not been tested prospectively in prodromal patients as a predictor of psychosis. The biological effects of stress are mediated by the hypothalamic-pituitary-adrenal (HPA) axis, which governs the release of steroids, including cortisol. The past few decades have witnessed an increased understanding of the neural effects of stress and cortisol, including both normal and abnormal diatheses. As few biological markers have been evaluated as risk factors for psychosis in prodromal patients, the HPA axis and its interaction with intervening life events are apt candidates for study. In this article, we review the HPA axis and its neural effects, present a model for how stress might precipitate psychosis in vulnerable individuals, review the empirical evidence of a link between stress and schizophrenia symptoms, and propose a research design and appropriate statistical models to test the stress-diathesis model for psychosis onset in prodromal patients.

Regional brain shape abnormalities persist into adolescence after heavy prenatal alcohol exposure.

We assessed regional brain shape abnormalities and spatial relationships between brain shape and abnormalities observed in the underlying tissue in children and adolescents prenatally exposed to large quantities of alcohol. We used high resolution, 3-D, structural magnetic resonance imaging data and novel, whole-brain, surface-based image analysis procedures to study 21 subjects with heavy prenatal alcohol exposure (8-22 years, mean age 12.6 years) and 21 normally developing control subjects (8-25 years, mean age 13.5 years). Significant brain size and shape abnormalities were observed in the alcohol-exposed subjects in inferior parietal/ perisylvian regions bilaterally, where their brains appeared to be narrower than those of the controls in the same general location where they also had increased gray matter density. Highly significant decreased brain surface extent or reduced brain growth was also observed in the ventral aspects of the frontal lobes most prominent in the left hemisphere. For the first time in this report we have mapped brain morphologic abnormalities to the cortical surface in subjects with prenatal alcohol exposure and have shown that the size and shape of the brain is altered in these individuals. The results imply that brain growth continues to be adversely affected long after the prenatal insult of alcohol exposure to the developing brain and the brain regions most implicated, frontal and inferior parietal/ perisylvian, may be consistent with behavioral deficits characteristic of individuals prenatally exposed to alcohol.

Mapping sulcal pattern asymmetry and local cortical surface gray matter distribution in vivo: maturation in perisylvian cortices.

Previous in vivo morphometric studies of human brain maturation between childhood and young adulthood have revealed a spatial and temporal pattern of progressive brain changes that is consistent with the post mortem cytoarchitectonic and cognitive developmental literatures. In this study, we mapped age differences in structural asymmetries at the cortical surface in groups of normally developing children (7-11 years), adolescents (12-16 years) and young adults (23-30 years) using novel surface-based mesh modeling image analytic methods. We also assessed relationships between cortical surface sulcal asymmetry and the local density of the underlying cortical gray matter. Results from this study reveal that perisylvian sulcal asymmetries are much more prominent in the adults than in the children studied. The superior posterior extent of the Sylvian fissure in the right hemisphere is approximately 7 mm more superior in the average adult than in the average child studied, whereas little difference is observed during this age range in the location of this anatomical structure in the left hemisphere. Age-related differences in Sylvian fissure asymmetry were significant (P = 0.0129, permutation test), showing increased asymmetry with increasing age. We also show age-related increases in local gray matter proportion bilaterally in the temporo-parietal cortices that are anatomically and temporally related to the sulcal asymmetries. Results from this cross-sectional study imply that asymmetries in the Sylvian fissure are dynamically changing into young adulthood and show that variability in brain tissue density is related to asymmetry in this region. These morphological differences may be related to changing cognitive abilities and are relevant in interpreting results from studies of abnormal brain development where perisylvian brain regions are implicated.