Association of Lower Rostral Anterior Cingulate GABA+ and Dysregulated Cortisol Stress Response With Altered Functional Connectivity in Young Adults With Lifetime Depression: A Multimodal Imaging Investigation of Trait and State Effects.

OBJECTIVE: Preclinical work suggests that excess glucocorticoids and reduced cortical γ-aminobutyric acid (GABA) may affect sex-dependent differences in brain regions implicated in stress regulation and depressive phenotypes. The authors sought to address a critical gap in knowledge, namely, how stress circuitry is functionally affected by glucocorticoids and GABA in current or remitted major depressive disorder (MDD). METHODS: Multimodal imaging data were collected from 130 young adults (ages 18-25), of whom 44 had current MDD, 42 had remitted MDD, and 44 were healthy comparison subjects. GABA+ (γ-aminobutyric acid and macromolecules) was assessed using magnetic resonance spectroscopy, and task-related functional MRI data were collected under acute stress and analyzed using data-driven network modeling. RESULTS: Across modalities, trait-related abnormalities emerged. Relative to healthy comparison subjects, both clinical groups were characterized by lower rostral anterior cingulate cortex (rACC) GABA+ and frontoparietal network amplitude but higher amplitude in salience and stress-related networks. For the remitted MDD group, differences from the healthy comparison group emerged in the context of elevated cortisol levels, whereas the MDD group had lower cortisol levels than the healthy comparison group. In the comparison group, frontoparietal and stress-related network connectivity was positively associated with cortisol level (highlighting putative top-down regulation of stress), but the opposite relationship emerged in the MDD and remitted MDD groups. Finally, rACC GABA+ was associated with stress-induced changes in connectivity between overlapping default mode and salience networks. CONCLUSIONS: Lifetime MDD was characterized by reduced rACC GABA+ as well as dysregulated cortisol-related interactions between top-down control (frontoparietal) and threat (task-related) networks. These findings warrant further investigation of the role of GABA in the vulnerability to and treatment of MDD.

Genomic Analysis of Haloarchaea from Diverse Environments, including Permian Halite, Reveals Diversity of Ultraviolet Radiation Survival and DNA Photolyase Gene Variants.

Ultraviolet (UV) radiation responses of extremophilic and archaeal microorganisms are of interest from evolutionary, physiological, and astrobiological perspectives. Previous studies determined that the halophilic archaeon, Halobacterium sp. NRC-1, which survives in multiple extremes, is highly tolerant of UV radiation. Here, Halobacterium sp. NRC-1 UV tolerance was compared to taxonomically diverse Haloarchaea isolated from high-elevation salt flats, surface warm and cold hypersaline lakes, and subsurface Permian halite deposits. Haloterrigena/Natrinema spp. from subsurface halite deposits were the least tolerant after exposure to photoreactivating light. This finding was attributed to deviation of amino acid residues in key positions in the DNA photolyase enzyme or to the complete absence of the photolyase gene. Several Halobacterium, Halorubrum and Salarchaeum species from surface environments exposed to high solar irradiance were found to be the most UV tolerant, and Halorubrum lacusprofundi from lake sediment was of intermediate character. These results indicate that high UV tolerance is not a uniform character trait of Haloarchaea and is likely reflective of UV exposure experienced in their environment. This is the first report correlating natural UV tolerance to photolyase gene functionality among Haloarchaea and provides insights into their survival in ancient halite deposits and potentially on the surface of Mars.

Reductions in rostral anterior cingulate GABA are associated with stress circuitry in females with major depression: a multimodal imaging investigation.

The interplay between cortical and limbic regions in stress circuitry calls for a neural systems approach to investigations of acute stress responses in major depressive disorder (MDD). Advances in multimodal imaging allow inferences between regional neurotransmitter function and activation in circuits linked to MDD, which could inform treatment development. The current study investigated the role of the inhibitory neurotransmitter GABA in stress circuitry in females with current and remitted MDD. Multimodal imaging data were analyzed from 49 young female adults across three groups (current MDD, remitted MDD (rMDD), and healthy controls). GABA was assessed at baseline using magnetic resonance spectroscopy, and functional MRI data were collected before, during, and after an acute stressor and analyzed using a network modeling approach. The MDD group showed an overall lower cortisol response than the rMDD group and lower rostral anterior cingulate cortex (ACC) GABA than healthy controls. Across groups, stress decreased activation in the frontoparietal network (FPN) but increased activation in the default mode network (DMN) and a network encompassing the ventromedial prefrontal cortex-striatum-anterior cingulate cortex (vmPFC-Str-ACC). Relative to controls, the MDD and rMDD groups were characterized by decreased FPN and salience network (SN) activation overall. Rostral ACC GABA was positively associated with connectivity between an overlapping limbic network (Temporal-Insula-Amygdala) and two other circuits (FPN and DMN). Collectively, these findings indicate that reduced GABA in females with MDD was associated with connectivity differences within and across key networks implicated in depression. GABAergic treatments for MDD might alleviate stress circuitry abnormalities in females.

Repeatability and reliability of GABA measurements with magnetic resonance spectroscopy in healthy young adults.

PURPOSE: Gamma-aminobutyric acid (GABA) abnormalities have been implicated in a range of neuropsychiatric disorders. Despite substantial interest in probing GABA in vivo, human imaging studies relying on magnetic resonance spectroscopy (MRS) have generally been hindered by technical challenges, including GABA's relatively low concentration and spectral overlap with other metabolites. Although past studies have shown moderate-to-strong test-retest repeatability and reliability of GABA within certain brain regions, many of these studies have been limited by small sample sizes. METHODS: GABA+ (macromolecular-contaminated) test-retest reliability and repeatability were assessed via a Meshcher-Garwood point resolved spectroscopy (MEGA-PRESS) MRS sequence in the rostral anterior cingulate cortex (rACC; n = 21) and dorsolateral prefrontal cortex (dlPFC; n = 20) in healthy young adults. Data were collected on a 3T scanner (Siemens Prisma, Siemens Healthcare, Erlangen, Germany) and GABA+ results were reported in reference to both total creatine (GABA+/tCr) and water (GABA+/water). RESULTS: Results showed strong test-retest repeatability (mean GABA+/tCr coefficient of variation [CV] = 4.6%; mean GABA+/water CV = 4.0%) and reliability (GABA+/tCr intraclass correlation coefficient [ICC] = 0.77; GABA+/water ICC = 0.87) in the dlPFC. The rACC showed acceptable (but comparatively lower) repeatability (mean GABA+/tCr CV = 8.0%; mean GABA+/water CV = 7.5%), yet low-moderate reliability (GABA+/tCr ICC = 0.40; GABA+/water ICC = 0.44). CONCLUSION: The present study found excellent GABA+ MRS repeatability and reliability in the dlPFC. The rACC showed inferior results, possibly because of a combination of shimming impedance and measurement error. These data suggest that MEGA-PRESS can be utilized to reliably distinguish participants based on dlPFC GABA+ levels, whereas the mixed results in the rACC merit further investigation.

Preventing Neurodegeneration by Controlling Oxidative Stress: The Role of OXR1.

Parkinson's disease, diabetic retinopathy, hyperoxia induced retinopathy, and neuronal damage resulting from ischemia are among the notable neurodegenerative diseases in which oxidative stress occurs shortly before the onset of neurodegeneration. A shared feature of these diseases is the depletion of OXR1 (oxidation resistance 1) gene products shortly before the onset of neurodegeneration. In animal models of these diseases, restoration of OXR1 has been shown to reduce or eliminate the deleterious effects of oxidative stress induced cell death, delay the onset of symptoms, and reduce overall severity. Moreover, increasing OXR1 expression in cells further increases oxidative stress resistance and delays onset of disease while showing no detectable side effects. Thus, restoring or increasing OXR1 function shows promise as a therapeutic for multiple neurodegenerative diseases. This review examines the role of OXR1 in oxidative stress resistance and its impact on neurodegenerative diseases. We describe the potential of OXR1 as a therapeutic in light of our current understanding of its function at the cellular and molecular level and propose a possible cascade of molecular events linked to OXR1's regulatory functions.

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.

Transcription-coupled repair of UV damage in the halophilic archaea.

Transcription-coupled repair (TCR) is a subpathway of nucleotide excision repair (NER) in which excision repair proteins are targeted to RNA polymerase-arresting lesions located in the transcribed strand of active genes. TCR has been documented in a variety of bacterial and eukaryotic organisms but has yet to be observed in the Archaea. We used Halobacterium sp. NRC-1 and Haloferax volcanii to determine if TCR occurs in the halophilic archaea. Following UV irradiation of exponentially growing cultures, we quantified the rate of repair of cyclobutane pyrimidine dimers in the two strands of the rpoB2B1A1A2 and the trpDFEG operons of Halobacterium sp. NRC-1 and the pts operon of H. volcanii through the use of a Southern blot assay and strand-specific probes. TCR was observed in all three operons and was dependent on the NER gene uvrA in Halobacterium sp. NRC-1, but not in H. volcanii. The halophilic archaea likely employ a novel mechanism for TCR in which an as yet unknown coupling factor recognizes the arrested archaeal RNA polymerase complex and recruits certain NER proteins to complete the process.

Blunted neural responses to reward in remitted major depression: A high-density event-related potential study.

BACKGROUND: Major depressive disorder (MDD) is a highly recurrent condition, and improving our understanding of the abnormalities that persist in remitted MDD (rMDD) may provide insight into mechanisms that contribute to relapse. MDD has been characterized by reward learning deficits linked to dysfunction in frontostriatal regions. Although initial behavioral evidence of reward learning deficits in rMDD has recently emerged, it is unclear whether these reflect impairments in neural reward processing that persist into remission. METHODS: We examined behavioral reward learning and 128-channel event-related potentials (ERP) during a well-validated probabilistic reward task in 26 rMDD individuals and 34 never-depressed controls. Temporo-spatial principal components analysis (PCA) was used to separate overlapping ERP components, and group differences in neural activity in a priori regions were examined using low-resolution electromagnetic tomography (LORETA). RESULTS: Individuals with rMDD displayed reduced behavioral reward learning, as well as blunted ERP amplitude to reward feedback. Importantly, the reduction in ERP amplitude occurred at a PCA factor that peaked during the time at which phasic reward feedback-related signaling - hypothesized to originate in the striatum and project to the anterior cingulate cortex (ACC) - are thought to modulate scalp-recorded activity. Consistent with this, LORETA analyses revealed reduced activity in the ACC in the rMDD group, and this blunting correlated with poorer reward learning. CONCLUSION: These findings suggest that the reward learning impairment observed in acute MDD persists into full remission and that these impairments may be attributable to abnormalities in the neural processes that support reward feedback monitoring, particularly within the ACC.

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.

Neuroimaging studies of individuals with family histories of alcoholism provide evidence suggesting neurobiological risk factors for alcoholism. Youth family history positive (FH+) for alcoholism exhibit increased impulsivity compared to family history negative (FH-) peers in conjunction with altered functional activation in prefrontal cortex, including anterior cingulate cortex (ACC). This study examined glutamate (Glu) and glutamine (Gln), amino acids vital to protein synthesis, cellular metabolism and neurotransmission, acquired from ACC and parieto-occipital cortex (POC) using magnetic resonance spectroscopy (MRS) at 4T. Participants were 28 adolescents (13 male, 12-14 yrs) and 31 emerging adults (16 male, 18-25 yrs), stratified into FH- and FH+ groups. Significantly higher ACC Gln/Glu was observed in emerging adults versus adolescents in FH- but not FH+ groups. In FH- adolescents, higher impulsivity was significantly associated with higher ACC Gln/Glu. In FH+ emerging adults, higher impulsivity was negatively associated with ACC Gln/Glu. No differences or associations were observed for POC. These findings provide preliminary evidence that family history of alcoholism is associated with a neurochemical profile that may influence normative age differences in glutamatergic metabolites and their association with impulse control, which together could confer greater genetic risk of addiction later in life.

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.

Binge alcohol consumption in emerging adults: anterior cingulate cortical "thinness" is associated with alcohol use patterns.

BACKGROUND: The brain undergoes dynamic and requisite changes into the early 20s that are associated with improved cognitive efficiency, particularly in prefrontal regions that are still undergoing neuromaturation. As alcohol consumption is typically initiated and progresses to binge drinking (BD) during this time, the objective of the present study was to investigate the impact of binge alcohol consumption on frontal lobe cortical thickness in emerging adults. METHODS: Twenty-three binge drinking (11 females, mean age 22.0 ± 1.2) and 31 light drinking (15 females, mean age 21.5 ± 1.6) emerging adults underwent high-resolution magnetic resonance imaging at 3 Tesla. Cortical surface reconstruction and thickness estimation were performed using FreeSurfer for 3 a priori brain regions of interest: bilateral anterior cingulate cortex (ACC), posterior cingulate cortex (PCC), and parieto-occipital sulcus (POS). Cortical thickness measurements were then compared between binge drinker (BD) and light drinker (LD) groups. RESULTS: Cortical thickness was significantly lower in BD than LD in the right middle ACC (mid-ACC; p ≤ 0.05) and in the left dorsal PCC (dPCC; p ≤ 0.01). No significant differences in cortical thickness were observed in the POS. Cortical thickness in the mid-ACC correlated negatively with higher quantity and frequency of drinks consumed (p < 0.01) and positively with the number of days elapsed since most recent use (p < 0.05). Furthermore, less cortical thickness in the mid-ACC in the BD group alone correlated with reported patterns of high quantity and frequency of alcohol consumption (p ≤ 0.05). CONCLUSIONS: Findings suggest that past and recent patterns of intermittent heavy alcohol consumption are associated with less frontal cortical thickness (i.e., "thinness") of the right mid-ACC and left dPCC in emerging adults, but not the POS. While cortical thinness could have predated binge drinking, this pattern of maladaptive consumption may have acute neurotoxic effects that interfere with the finalization of neuromaturational processes in the vulnerable frontal cortex, resulting in increased microarchitectural pruning.

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.

Insula and anterior cingulate GABA levels in posttraumatic stress disorder: preliminary findings using magnetic resonance spectroscopy.

BACKGROUND: 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 ((1) H-MRS) to measure brain GABA in PTSD. METHODS: Thirteen adults with DSM-IV PTSD and 13 matched healthy control subjects underwent single voxel (1) H-MRS at 4 Tesla. GABA was measured in the right anterior insula and dorsal ACC, using Mescher-Garwood Point-Resolved Echo Spectroscopy Sequence (MEGAPRESS) spectral editing. Subjects were interviewed with the Structured Clinical Interview for DSM-IV and the Clinician Administered PTSD Scale, and also completed the State and Trait Anxiety Inventory. RESULTS: Insula GABA was significantly lower in PTSD subjects than in controls, and dorsal ACC GABA did not differ significantly between the groups. Insula GABA was not significantly associated with severity of PTSD symptoms. However, lower insula GABA was associated with significantly higher state and trait anxiety in the subject sample as a whole. CONCLUSIONS: PTSD is associated with reduced GABA in the right anterior insula. This preliminary evidence of the (1) H-MRS GABA metabolite as a possible biomarker of PTSD encourages replication in larger samples and examination of relations with symptom dimensions. Future studies also should examine whether insula GABA is a marker of anxiety proneness, cutting across clinical diagnostic categories.

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.

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.

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.

Relation of schizophrenia prevalence to latitude, climate, fish consumption, infant mortality, and skin color: a role for prenatal vitamin d deficiency and infections?

Previous surveys found a large (>10-fold) variation in schizophrenia prevalence at different geographic sites and a tendency for prevalence to increase with latitude. We conducted meta-analyses of prevalence studies to investigate whether these findings pointed to underlying etiologic factors in schizophrenia or were the result of methodological artifacts or the confounding of sites' latitude with level of healthcare at those sites. We found that these patterns were still present after controlling for an index of healthcare--infant mortality--and focusing on 49 studies that used similar diagnostic and ascertainment methods. The tendencies for schizophrenia prevalence to increase with both latitude and colder climate were still large and significant and present on several continents. The increase in prevalence with latitude was greater for groups with low fish consumption, darker skin, and higher infant mortality--consistent with a role of prenatal vitamin D deficiency in schizophrenia. Previous research indicates that poor prenatal healthcare and nutrition increase risk for schizophrenia within the same region. These adverse conditions are more prevalent in developing countries concentrated near the equator, but schizophrenia prevalence is lowest at sites near the equator. This suggests that schizophrenia-producing environmental factors associated with higher latitude may be so powerful they overwhelm protective effects of better healthcare in industrialized countries. The observed patterns of correlations of risk factors with prevalence are consistent with an etiologic role for prenatal vitamin D deficiency and exposure to certain infectious diseases. Research to elucidate environmental factors that underlie variations in schizophrenia prevalence deserves high priority.

Transcriptional responses to biologically relevant doses of UV-B radiation in the model archaeon, Halobacterium sp. NRC-1.

BACKGROUND: Most studies of the transcriptional response to UV radiation in living cells have used UV doses that are much higher than those encountered in the natural environment, and most focus on short-wave UV (UV-C) at 254 nm, a wavelength that never reaches the Earth's surface. We have studied the transcriptional response of the sunlight-tolerant model archaeon, Halobacterium sp. NRC-1, to low doses of mid-wave UV (UV-B) to assess its response to UV radiation that is likely to be more biologically relevant. RESULTS: Halobacterium NRC-1 cells were irradiated with UV-B at doses equivalent to 30 J/m2 and 5 J/m2 of UV-C. Transcriptional profiling showed that only 11 genes were up-regulated 1.5-fold or more by both UV-B doses. The most strongly up-regulated gene was radA1 (vng2473), the archaeal homologue of RAD51/recA recombinase. The others included arj1 (vng779) (recJ-like exonuclease), top6A (vng884) and top6B (vng885) (coding for Topoisomerase VI subunits), and nrdJ (vng1644) (which encodes a subunit of ribonucleotide reductase). We have found that four of the consistently UV-B up-regulated genes, radA1 (vng2473), vng17, top6B (vng885) and vng280, share a common 11-base pair motif in their promoter region, TTTCACTTTCA. Similar sequences were found in radA promoters in other halophilic archaea, as well as in the radA promoter of Methanospirillum hungatei. We analysed the transcriptional response of a repair-deficient DeltauvrA (vng2636) DeltauvrC (vng2381) double-deletion mutant and found common themes between it and the response in repair proficient cells. CONCLUSION: Our results show a core set of genes is consistently up-regulated after exposure to UV-B light at low, biologically relevant doses. Eleven genes were up-regulated, in wild-type cells, after two UV-B doses (comparable to UV-C doses of 30 J/m2 and 5 J/m2), and only four genes were up-regulated by all doses of UV-B and UV-C that we have used in this work and previously. These results suggest that high doses of UV-C radiation do not necessarily provide a good model for the natural response to environmental UV. We have found an 11-base pair motif upstream of the TATA box in four of the UV-B up-regulated genes and suggest that this motif is the binding site for a transcriptional regulator involved in their response to UV damage in this model archaeon.