Isabelle M. Rosso

Amygdala and hippocampus volumes in pediatric major depression

BACKGROUND The purpose of this study was to measure amygdala and hippocampus volumes in pediatric major depressive disorder (MDD) and to address the question of neuroanatomical continuity with adult-onset depression. METHODS We studied 20 children and adolescents with MDD (17 female subjects) and 24 healthy comparison subjects (16 female subjects) using 1.5 Tesla magnetic resonance imaging. Group differences in left and right amygdala and hippocampus volumes were examined using repeated measures analyses of covariance, adjusting for age, gender, and whole brain volume. RESULTS Depressed children had significant reductions of left and right amygdala volumes compared with healthy subjects. Hippocampus volumes did not differ between the groups. No significant correlations were found between amygdala volumes and depressive symptom severity, age at onset, or illness duration. CONCLUSIONS Smaller amygdalas are present early in the course of pediatric depression and may predispose to the development of this disorder or perhaps more generally of childhood mood disorders. Future research should examine the longitudinal course and functional correlates of amygdala volume abnormalities in childhood-onset depression, including their possible moderation by gender.

Reduced amygdala volumes in first-episode bipolar disorder and correlation with cerebral white matter.

BACKGROUND Previous magnetic resonance imaging (MRI) findings on amygdala volume abnormalities in bipolar disorder have been inconsistent, which may partly reflect clinical heterogeneity. It is unclear whether amygdala abnormalities are present early in the course of illness and/or are the consequence of disease progression. METHODS Twenty patients with first-episode bipolar disorder and 23 matched healthy comparison subjects were included. Magnetic resonance images were used to measure amygdala volumes, as well as whole brain measures of gray and white matter volume. RESULTS First-episode bipolar patients had significant reductions in amygdala volume relative to healthy subjects in an analysis of covariance that accounted for the effects of age, sex, and whole brain volume. First-episode patients also showed a trend reduction in cerebral white matter volume, and there was a significant correlation between cerebral white matter volume and total amygdala volume in patients but not control subjects. CONCLUSIONS These findings indicate that amygdala volume deficits are present early in the course of bipolar disorder and may occur within a neuroanatomical context of reduced cerebral white matter. Additional research should examine whether the nature of regional white matter deficits, particularly in frontal-temporal tracts, may help parse the pathophysiology of amygdala volume abnormalities in bipolar disorder.

A prospective cohort study of neurodevelopmental processes in the genesis and epigenesis of schizophrenia.

A number of lines of evidence converge in implicating neurodevelopmental processes in the etiology and epigenesis of schizophrenia. In this study we used a prospective, longitudinal design to examine whether adverse obstetric experiences predict schizophrenia and whether there is a deviant functional-developmental trajectory during the first 7 years of life among individuals who manifest schizophrenia as adults. The 9,236 members of the Philadelphia cohort of the National Collaborative Perinatal Project were screened for mental health service utilization in adulthood, and chart reviews were performed to establish diagnoses according to DSM-IV criteria. The risk for schizophrenia increased linearly with the number of hypoxia-associated obstetric complications but was unrelated to maternal infection during pregnancy or fetal growth retardation. Preschizophrenic cases (and their unaffected siblings who were also cohort members) manifested cognitive impairment, abnormal involuntary movements and coordination deficits, and poor social adjustment during childhood. There was no evidence of intraindividual decline in any domain, but preschizophrenic cases did show deviance on an increasing number of functional indicators with age. Together, these findings suggest that both genetic and obstetric factors participate in creating a neural diathesis to schizophrenia, the phenotypic expressions of which are age dependent, probably reflecting the maturational status of a number of interconnected brain systems.

Cognitive and Emotional Components of Frontal Lobe Functioning in Childhood and Adolescence

Abstract: Frontal lobe functions include a range of cognitive, emotional, and social abilities that enable goal‐directed behavior. Although a number of studies have plotted the development of frontal lobe functions in childhood, few have extended into the adolescent years. There is also little information on which cognitive and emotional components of frontal functioning may be correlated. The aims of this study were to identify and compare age effects on different components of frontal functioning in childhood and adolescence and to examine whether abstract reasoning skills were associated with levels of emotional intelligence and social sensitivity. Twenty children (ages 9‐18) were recruited from the local community for a study of normal adolescent brain development. All subjects were free of psychiatric or developmental disorders, as determined by a structured interview. Subjects completed a comprehensive neuropsychological test battery, as well as self‐report measures of social sensitivity (anxiety) and emotional intelligence. Significant age effects were found for measures of abstract reasoning, response inhibition, and attentional set shifting. Levels of social anxiety increased moderately with age, although not significantly at this sample size. Abstract reasoning skills correlated positively with levels of social anxiety but not emotional intelligence. The pattern of results suggests differential developmental trajectories across various cognitive and emotional domains of frontal lobe functioning in childhood and adolescence. Increased abstract reasoning ability may be associated with increased vulnerability to social anxiety during this period.

Peril and Pleasure: An RDoC-inspired examination of threat responses and reward processing in anxiety and depression

As a step toward addressing limitations in the current psychiatric diagnostic system, the National Institute of Mental Health recently developed the Research Domain Criteria (RDoC) to stimulate integrative research—spanning self‐report, behavior, neural circuitry, and molecular/genetic mechanisms—on core psychological processes implicated in mental illness. Here, we use the RDoC conceptualization to review research on threat responses, reward processing, and their interaction. The first section of the manuscript highlights the pivotal role of exaggerated threat responses—mediated by circuits connecting the frontal cortex, amygdala, and midbrain—in anxiety, and reviews data indicating that genotypic variation in the serotonin system is associated with hyperactivity in this circuitry, which elevates the risk for anxiety and mood disorders. In the second section, we describe mounting evidence linking anhedonic behavior to deficits in psychological functions that rely heavily on dopamine signaling, especially cost/benefit decision making and reward learning. The third section covers recent studies that document negative effects of acute threats and chronic stress on reward responses in humans. The mechanisms underlying such effects are unclear, but the fourth section reviews new optogenetic data in rodents indicating that GABAergic inhibition of midbrain dopamine neurons, driven by activation of the habenula, may play a fundamental role in stress‐induced anhedonia. In addition to its basic scientific value, a better understanding of interactions between the neural systems that mediate threat and reward responses may offer relief from the burdensome condition of anxious depression.

Frontal lobe γ-aminobutyric acid levels during adolescence: associations with impulsivity and response inhibition.

BACKGROUND The brain undergoes major remodeling during adolescence, resulting in improved cognitive control and decision-making and reduced impulsivity, components of behavior mediated in part by the maturing frontal lobe. γ-Aminobutyric acid (GABA), the main inhibitory neurotransmitter system, also matures during adolescence, with frontal lobe GABA receptors reaching adult levels late in adolescence. Thus, the objective of this study was to characterize in vivo developmental differences in brain GABA levels. METHODS Proton magnetic resonance spectroscopy was used at 4 T to acquire metabolite data from the anterior cingulate cortex (ACC) and the parieto-occipital cortex (POC) in adolescents (n=30) and emerging adults (n = 20). RESULTS ACC GABA/creatine (Cr) levels were significantly lower in adolescents relative to emerging adults, whereas no age differences were observed in the POC. Lower ACC GABA/Cr levels were significantly associated with greater impulsivity and worse response inhibition, with relationships being most pronounced for ACC GABA/Cr and No-Go response inhibition in adolescent males. CONCLUSIONS These data provide the first human developmental in vivo evidence confirming frontal lobe GABA maturation, which was linked to impulsiveness and cognitive control. These findings suggest that reduced GABA may be an important neurobiological mechanism in the immature adolescent brain, contributing to the reduced yet rapidly developing ability to inhibit risky behaviors and to make suboptimal decisions, which could compromise adolescent health and safety.

Paternal age as a risk factor for schizophrenia: How important is it?

Advanced paternal age has been widely cited as a risk factor for schizophrenia among offspring and even claimed to account for one-quarter of all cases. We carried out a new study on 25,025 offspring from the Collaborative Perinatal Project (CPP), including 168 diagnosed with psychosis and 88 with narrowly defined schizophrenia. We also conducted a meta-analysis of this and nine other studies for which comparable age-cohort data were available. The mean paternal age for the CPP cases was slightly, but not significantly, higher than the matched controls (p=0.28). Meta-analyses including these new results were conducted to determine the relative risk associated with alternative definitions of advanced paternal age (35, 45 or 55 years and older). These yielded pooled odds ratios and 95% confidence intervals of 1.28 (1.10, 1.48), 1.38 (0.95, 2.01) and 2.22 (1.46, 3.37), respectively. Thus, increased paternal age appears to be a risk factor for schizophrenia primarily among offspring of fathers ages 55 and over. In these 10 studies, such fathers accounted for only 0.6% of all births. Compared with other known risk factors for schizophrenia, advanced paternal age appears to be intermediate in magnitude. Advanced paternal age is also known to be a risk factor for some chromosomal and neoplastic diseases in the offspring where the cause is thought to be chromosomal aberrations and mutations of the aging germline. Similar mechanisms may account for the relationship between advanced paternal age and schizophrenia risk.

Cognitive Inflexibility and Frontal-Cortical Activation in Pediatric Obsessive-Compulsive Disorder

OBJECTIVE Deficits in cognitive flexibility and response inhibition have been linked to perturbations in cortico-striatal-thalamic circuitry in adult obsessive-compulsive disorder (OCD). Although similar cognitive deficits have been identified in pediatric OCD, few neuroimaging studies have been conducted to examine its neural correlates in the developing brain. In this study, we tested hypotheses regarding group differences in the behavioral and neural correlates of cognitive flexibility in a pediatric OCD and a healthy comparison (HC) sample. METHOD In this functional magnetic resonance imaging (fMRI) study, a pediatric sample of 10- to 17-year-old subjects, 15 with OCD and 20 HC, completed a set-shifting task. The task, requiring an extradimensional shift to identify a target, examines cognitive flexibility. Within each block, the dimension (color or shape) that identified the target either alternated (i.e., mixed) or remained unchanged (i.e., repeated). RESULTS Compared with the HC group, the OCD group tended to be slower to respond to trials within mixed blocks. Compared with the HC group, the OCD group exhibited less left inferior frontal gyrus/BA47 activation in the set-shifting contrast (i.e., HC > OCD, mixed versus repeated); only the HC group exhibited significant activation in this region. The correlation between set shifting-induced right caudate activation and shift cost (i.e., reaction time differential in response to mixed versus repeated trials) was significantly different between HC and OCD groups, in that we found a positive correlation in HC and a negative correlation in OCD. CONCLUSIONS In pediatric OCD, less fronto-striatal activation may explain previously identified deficits in shifting cognitive sets.

INSULA AND ANTERIOR CINGULATE GABA LEVELS IN POSTTRAUMATIC STRESS DISORDER: PRELIMINARY FINDINGS USING MAGNETIC RESONANCE SPECTROSCOPY

Increased reactivity of the insular cortex and decreased activity of the dorsal anterior cingulate cortex (ACC) are seen in functional imaging studies of posttraumatic stress disorder (PTSD), and may partly explain the persistent fear and anxiety proneness that characterize the disorder. A possible neurochemical correlate is altered function of the inhibitory neurotransmitter gamma‐aminobutyric acid (GABA). We report results from what we believe is the first study applying proton magnetic resonance spectroscopy (1H‐MRS) to measure brain GABA in PTSD.

Regional Prefrontal Cortex Gray Matter Volumes in Youth at Familial Risk for Schizophrenia from the Harvard Adolescent High Risk Study

BACKGROUND Regional prefrontal cortex gray matter reductions have been identified in schizophrenia, likely reflecting a combination of genetic vulnerability and disease effects. Few morphometric studies to date have examined regional prefrontal abnormalities in non-psychotic biological relatives who have not passed through the age range of peak risk for onset of psychosis. We conducted a region-of-interest morphometric study of prefrontal subregions in adolescent and young adult relatives of schizophrenia patients. METHODS Twenty-seven familial high-risk (FHR) first-degree relatives of schizophrenia patients and forty-eight control subjects without a family history of psychosis (ages 13-28) underwent high-resolution magnetic resonance imaging at 1.5Tesla. The prefrontal cortex was parcellated into polar, dorsolateral, ventrolateral, ventromedial and orbital subregions. The Chapman scales measured subpsychotic symptoms. General linear models examined associations of prefrontal subregion volumes with familial risk and subpsychotic symptoms. RESULTS FHR subjects had significantly reduced bilateral ventromedial prefrontal and frontal pole gray matter volumes compared with controls. Ventromedial volume was significantly negatively correlated with magical ideation and anhedonia scores in FHR subjects. CONCLUSIONS Selective, regional prefrontal gray matter reductions may differentially mark genetic vulnerability and early symptom processes among non-psychotic young adults at familial risk for schizophrenia.