David J. Crowley

Prenatal stress and risk for autism.

This paper reviews several converging lines of research that suggest that prenatal exposure to environmental stress may increase risk for Autistic Disorder (AD). We first discuss studies finding that prenatal exposure to stressful life events is associated with significantly increased risk of AD, as well as other disorders, such as schizophrenia and depression. We then review evidence from animal and human studies that prenatal stress can produce both (a) abnormal postnatal behaviors that resemble the defining symptoms of AD, and (b) other abnormalities that have elevated rates in AD, such as learning deficits, seizure disorders, perinatal complications, immunologic and neuroinflammatory anomalies, and low postnatal tolerance for stress. We explain why an etiologic role for prenatal stress is compatible with genetic factors in AD, and describe how stress can disrupt fetal brain development. Finally, we discuss implications for understanding underlying processes in AD, including potential gene-environment interactions, and developing new therapies and early prevention programs.

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.

Altered anterior cingulate neurochemistry in emerging adult binge drinkers with a history of alcohol-induced blackouts

BACKGROUND Binge alcohol consumption is associated with multiple neurobiological consequences, including altered neurophysiology, brain structure, and functional activation. Magnetic resonance spectroscopy (MRS) studies have demonstrated neurochemical alterations in the frontal lobe of alcohol users, although most studies focused on older, alcohol-dependent subjects. METHODS In this study, neurochemical data were acquired using MRS at 4.0 Tesla from emerging adults (18 to 24 years old) who were binge alcohol drinkers (BD, n = 23) or light drinkers (LD, n = 31). Since binge drinking is also associated with increased prevalence of experiencing an alcohol-induced blackout, BD were stratified into alcohol-induced blackout (BDBO) and non-blackout (BDN) groups. RESULTS Overall, BD had significantly lower gamma amino-butyric acid (GABA) and N-acetyl-aspartate (NAA) in the anterior cingulate cortex (ACC) than LD. When stratified by blackout history, BDBO also had lower ACC glutamate (Glu) than LD. No group differences in MRS metabolites were observed in the parietal-occipital cortex. Lower ACC GABA and Glu remained significant after accounting for lower gray matter content in BD, however, NAA differences were no longer evident. In addition, low ACC GABA levels were associated with greater alcohol use consequences, and worse response inhibition and attention/mental flexibility in BD. CONCLUSIONS These data indicate that binge drinking affects frontal lobe neurochemistry, more so in those who had experienced an alcohol-induced blackout. Characterization of the neurochemical profiles associated with binge alcohol consumption and blackout history may help identify unique risk factors for the later manifestation of alcohol abuse and dependence, in young individuals who are heavy, frequent drinkers, but who do not meet the criteria for alcohol abuse disorders.

Differential Effects of Binge Drinking on Learning and Memory in Emerging Adults

Alterations in memory function due to alcohol exposure have been observed in both animal models and human populations. The human literature on neurocognitive consequences of binge alcohol use in emerging adults has not systematically investigated its potential negative impacts on visuospatial memory. For instance, these impacts have not yet been assessed using a human analogue of the Morris Water Maze Task (WMT), a key memory measure in the animal literature. Accordingly, this study compared performance between emerging adult binge drinkers (BD, n=22) and age- and sex-matched light drinkers (LD, n=29) using the Morris WMT, as well as verbal memory using the California Verbal Learning Test (CVLT). Emerging adult BD demonstrated worse performance on verbal learning and memory relative to LD. However, no significant group differences were observed on spatial learning and memory. Furthermore, no sex differences or interactions with drinking status were observed on either memory domain. These data suggest that in emerging adults who are at a heightened risk for alcohol abuse disorders, but who do not yet meet diagnostic criteria, verbal learning is uniquely impacted by the neurotoxic effects of binge drinking, whereas spatial learning is relatively spared between bouts of intoxication.

Sex differences in spatial navigation and perception in human adolescents and emerging adults

Males typically outperform females on spatial tasks, beginning early in life and continuing into adulthood. This study aimed to characterize age and sex differences in human spatial ability using a virtual Water Maze Task (vWMT), which is based on the classic Morris water maze spatial navigation task used in rodents. Performance on the vWMT and on a task assessing visuospatial perception, Mental Rotations Test (MRT), was examined in 33 adolescents and 39 emerging adults. For the vWMT, significant effects of age and sex were observed for path length in the target region (narrower spatial sampling), and heading error, with emerging adults performing better than adolescents, and an overall male advantage. For the MRT, males scored higher than females, but only in emerging adulthood. Overall, sex differences in visuospatial perception (MRT) emerge differently from those observed on a classic navigation task, with age and sex-specific superior vWMT performance likely related to the use of more efficient strategies. Importantly, these results extend the developmental timeline of spatial ability characterization to include adolescent males and females performing a virtual version of the classic vWMT.

Combined diffusion tensor imaging and transverse relaxometry in early-onset bipolar disorder.

OBJECTIVE Transverse relaxation time (T2) imaging provides the opportunity to examine membrane fluidity, which can affect a number of cellular functions. The objective of the present work was to examine T2 abnormalities in children with unmodified DSM-IV-TR bipolar disorder (BD) in bilateral cingulate-paracingulate (CPC) white matter. METHOD A total of 21 children and adolescents with BD and 16 healthy control subjects underwent magnetic resonance imaging at 1.5 Tesla and were compared using a region-of-interest analysis. A post hoc diffusion tensor imaging (DTI) analysis was also performed on selected subjects. RESULTS The T2 values were significantly decreased on the right-side of the subjects with BD compared with that of the control subjects. Hemispheric difference was also observed in the BD group, with decreased T2 on the right side compared with the left side. No significant difference was observed between left and right CPC T2 in control subjects. For participants who had both T2 and DTI measurements, significant DTI differences were observed: On the left side, fractional anisotropy was reduced and trace and radial diffusivity were increased, whereas on the right side, trace was increased and T2 was decreased in subjects with BD compared with control subjects. CONCLUSIONS Our findings suggest that the observed T2 difference is a reflection of cerebral blood flow rather than an alteration of the fluidity of cell membranes. It is possible that myelin damage occurs on the left side in early-onset BD, in addition to changes in the blood flow. Prospective studies with larger numbers of subjects are warranted to further explore the relevance of the presented results.

Dorsal Anterior Cingulate Thickness Is Related to Alexithymia in Childhood Trauma-Related PTSD

Alexithymia, or “no words for feelings”, is highly prevalent in samples with childhood maltreatment and posttraumatic stress disorder (PTSD). The dorsal anterior cingulate cortex (dACC) has been identified as a key region involved in alexithymia, early life trauma, and PTSD. Functional alterations in the dACC also have been associated with alexithymia in PTSD. This study examined whether dACC morphology is a neural correlate of alexithymia in child maltreatment-related PTSD. Sixteen adults with PTSD and a history of childhood sexual abuse, physical abuse, or exposure to domestic violence, and 24 healthy controls (HC) completed the Toronto Alexithymia Scale 20 (TAS–20) and underwent magnetic resonance imaging. Cortical thickness of the dACC was measured using FreeSurfer, and values were correlated with TAS–20 scores, controlling for sex and age, in both groups. Average TAS–20 score was significantly higher in the PTSD than the HC group. TAS–20 scores were significantly positively associated with dACC thickness only in the PTSD group. This association was strongest in the left hemisphere and for TAS–20 subscales that assess difficulty identifying and describing feelings. We found that increasing dACC gray matter thickness is a neural correlate of greater alexithymia in the context of PTSD with childhood maltreatment. While findings are correlational, they motivate further inquiry into the relationships between childhood adversity, emotional awareness and expression, and dACC morphologic development in trauma-related psychopathology.

Impact of family history of alcoholism on glutamine/glutamate ratio in anterior cingulate cortex in substance-naïve adolescents

Highlights • Family history of alcoholism was studied with MRS in adolescents and emerging adults.• Glutamine/glutamate ratio was measured at 4T to index glutamate neurotransmission.• Within FH−, emerging adults had significantly higher Gln/Glu ratios than adolescents.• Within FH+, no age-related differences were observed in Gln/Glu ratios.• Gln/Glu correlated with impulsivity in FH− adolescents and FH+ emerging adults.

Hippocampus Glutamate and N-Acetyl Aspartate Markers of Excitotoxic Neuronal Compromise in Posttraumatic Stress Disorder

Hippocampus atrophy is implicated in posttraumatic stress disorder (PTSD), and may partly reflect stress-induced glutamate excitotoxicity that culminates in neuron injury and manifests as re-experiencing symptoms and other memory abnormalities. This study used high-field proton magnetic resonance spectroscopy (MRS) to determine whether PTSD is associated with lower hippocampus levels of the neuron marker N-acetyl aspartate (NAA), along with higher levels of glutamate (Glu) and Glu/NAA. We also predicted that metabolite levels would correlate with re-experiencing symptoms and lifetime trauma load. Twenty-four adult PTSD patients and 23 trauma-exposed normal controls (TENC) underwent 4T MRS of the left and right hippocampus. Participants received psychiatric interviews, and completed the Traumatic Life Events Questionnaire to define lifetime trauma load. Relative to TENC participants, PTSD patients exhibited significantly lower NAA in right and left hippocampi, and significantly higher Glu and Glu/NAA in the right hippocampus. Re-experiencing symptoms were negatively correlated with left and right NAA, and positively correlated with right Glu and right Glu/NAA. Trauma load was positively correlated with right Glu/NAA in PTSD patients. When re-experiencing symptoms and trauma load were examined together in relation to right Glu/NAA, only re-experiencing symptoms remained a significant correlate. This represents the first report that PTSD is associated with MRS markers of hippocampus Glu excess, together with indices of compromised neuron integrity. Their robust associations with re-experiencing symptoms affirm that MRS indices of hippocampus neuron integrity and glutamate metabolism may reflect biomarkers of clinically significant disease variation in PTSD.

Acute stress impairs frontocingulate activation during error monitoring in remitted depression

Deficits in cognitive control are a hallmark characteristic of depression, however less is known about the degree to which they persist beyond symptom remission and might contribute to symptom recurrence in remitted individuals (rMDD). Evidence indicates that stress interferes with cognitive control, highlighting a potential mechanism by which stress precipitates depression relapse. Therefore, this study examined whether stress exposure elicits deficits in error monitoring - a component of cognitive control thought to be particularly implicated in the ability to adaptively respond to negative feedback - in individuals with rMDD. Unmedicated individuals with rMDD (n=30) and healthy controls (n=34) performed an Eriksen Flanker task before and 45min after an acute stressor while 128-channel event-related potentials (ERPs) were recorded. Flanker interference effects and post-error adjustments were examined, and ERP analyses focused on the error-related negativity (ERN) and error positivity (Pe). Standardized low resolution electromagnetic tomography (sLORETA) was used to examine stress-induced changes in current source density. Individuals with rMDD showed blunted cortisol reactivity to the stressor, coupled with heightened self-reported stress reactivity. Although no significant effects of group or stress were observed in scalp-level ERPs, source-level analyses indicated that among the rMDD group only, stress caused a reduction in activation in frontocingulate regions critically implicated in error monitoring. The magnitude of stress-induced decreases in frontocingulate activation correlated with heightened self-reported stress reactivity, and also predicted heightened levels of stress and depression 18 months later in the entire sample. These findings suggest that individuals with rMDD show a stress-induced disruption in frontocingulate function that is linked to heightened stress reactivity, and this disruption prospectively predicts heightened levels of future stress and depressive symptomatology.