Genome-wide association (GWA) studies of psychiatric disorders have been criticized for their lack in explaining a considerable proportion of the heritability established in twin and family studies. GWA studies of Major Depressive Disorder (MDD) in particular have so far been unsuccessful in detecting genome-wide significant SNPs. Using two different recently proposed methods designed to estimate the heritability of a phenotype that is attributable to genome-wide SNPs, we show that SNPs on current platforms contain substantial information concerning the additive genetic variance of MDD. To assess the consistency of these two different methods we analyzed four other complex phenotypes from different domains. The pattern of results is consistent with estimates of heritability obtained in twin studies carried out in the same population.
Obsessive compulsive disorder (OCD) has a complex etiology involving both genetic and environmental factors. However, the genetic causes of OCD are largely unknown, despite the identification of several promising candidate genes and linkage regions.
Our objective was to conduct genetic linkage studies of the type of OCD thought to have the strongest genetic etiology (i.e., childhood-onset OCD), in 33 Caucasian families with ≥2 childhood-onset OCD-affected individuals from the United States (US) (N=245 individuals with genotype data). Parametric and non-parametric genome-wide linkage analyses were conducted with Morgan and Merlin in these families using a selected panel of single nucleotide repeat polymorphisms (SNPs) from the Illumina 610-Quad Bead Chip. The initial analyses were followed by fine-mapping analyses in genomic regions with initial heterogeneity LOD (HLOD) scores of ≥2.0.
We identified five areas of interest (HLOD score ≥2) on chromosomes 1p36, 2p14, 5q13, 6p25, and 10p13. The strongest result was on chromosome 1p36.33-p36.32 (HLOD=3.77, suggestive evidence for linkage after fine-mapping). At this location, several of the families showed haplotypes co-segregating with OCD.
The results of this study represent the strongest linkage finding for OCD in a primary analysis to date, and suggest that chromosome 1p36, and possibly several other genomic regions, may harbor susceptibility loci for OCD. Multiple brain-expressed genes lie under the primary linkage peak (approximately 4 mb in size). Follow-up studies, including replication in additional samples and targeted sequencing of the areas of interest, are needed to confirm these findings and to identify specific OCD risk variants.
linkage; genomewide; pedigree; obsessive-compulsive; genetics; multigenerational
Chromosome 22q11.2 deletion syndrome (22q11DS), the most common microdeletion in humans, is associated with multiple medical features, almost universal cognitive deficits, and a high-risk of schizophrenia. The metabolic basis of the psychological/psychiatric features is not well understood. Volumetric brain imaging studies have shown that gray matter abnormalities in the dorsolateral prefrontal cortex (DLPFC), an area that is believed to be integral for higher neurocognition, as well as being involved in schizophrenia, are associated with the psychological manifestations. However, studies have not characterized any possible metabolite alterations within the DLPFC of children with 22q11DS and their correlations with the psychological findings.
We conducted a short echo-time, single-voxel, in vivo 1H spectroscopy study involving children with 22q11DS (n=26) and matched control subjects (n=23).
Absolute N-acetyl-aspartate (NAA) levels from the DLPFC were significantly elevated in children with 22q11DS compared to control subjects and the elevations were associated with poor global functioning and higher rates of comorbid attention deficit hyperactivity disorder. Children with 22q11DS had a lack of an age-associated decrease in NAA levels, a trend seen in the control subjects. However, the results did not remain statistically significant after corrections for multiple comparisons were made.
These findings represent the first report of 1H spectroscopy in children with 22q11DS. The elevated DLPFC NAA levels and the lack of decreasing trends in NAA with age in the 22q11DS group relative to controls suggest an alteration in cortical development. Also, such neuronal dysmaturation is associated with psychopathology in children with 22q11DS.
Chromosome 22q11.2 deletion syndrome; velocardiofacial syndrome; DiGeorge syndrome; neuropsychology; ADHD; 1H MRS; spectroscopy; N-acetyl-aspartate; NAA
To examine the relationship between autism spectrum disorders (ASD) and specific language impairment (SLI), family studies typically take a comparative approach where families with one disease are examined for traits of the other disease. In contrast, the present report is the first study with both disorders required to be present in each family to provide a more direct test of the hypothesis of shared genetic etiology.
We behaviorally assessed fifty-one families including at least one person with ASD and at least one person with SLI (without ASD). Pedigree members were tested using 22 standardized measures of language and intelligence. Since these extended families include a non-shared environmental contrast, we calculated heritability, not just familiality, for each measure twice: 1) baseline heritability analysis compared to 2) heritability estimates after statistically removing ASD subjects from pedigrees.
Significant increases in heritability on four supra-linguistic measures (including Pragmatic Judgment) and a composite language score, but not on any other measures, were observed when removing ASD subjects from the analysis indicating differential genetic effects that are unique to ASD. Non-genetic explanations such as effects of ASD severity or measurement error or low score variability in ASD subjects were systematically ruled out, leaving the hypothesis of non-additive genetics effects as the potential source of the heritability change caused by ASD.
While the data suggest genetic risk factors common to both SLI and ASD, there are effects that appear unique to ASD, possibly caused by non-additive gene-gene interactions of shared risk loci.
autism; specific language impairment; heritability; epistasis; gene-gene; interaction; shared etiology
Clinical studies have identified several regions of the genome with copy number variations (CNVs) associated with diverse neurodevelopmental behavioral disorders.
We analyzed 1M SNP genotype arrays (Illumina BeadArrays) for evidence of previously reported recurrent CNVs and enriched genome wide CNV burden in DNA from 600 brains, including 441 individuals with various psychiatric diagnoses. We explored gene expression in the dorsolateral prefrontal cortex in selected cases with CNVs and in other subjects using Illumina BeadArrays (568 subjects in total), and additionally in 66–92 subjects using quantitative real-time PCR.
CNVs in previously reported genomic regions were identified in 4/193 patients with the diagnosis of schizophrenia (1q21.1, 11q25, 15q11.2, 22q11), 4/238 patients with mood disorders (11q25, 15q11.2, 22q11), and 1/10 patients with autism (2p16.3). No evidence of increased genome wide CNV burden was observed in cases with schizophrenia or mood disorders although the study is underpowered to observe rare events. mRNA expression patterns suggested incomplete molecular penetrance of observed CNVs.
Our data confirm in brain DNA the presence of certain recurrent CNVs in a small percentage of patients with psychiatric diagnoses.
copy number variations; major depressive disorder; schizophrenia; autism; gene expression; postmortem brain; prefrontal cortex
Dysregulation of excitatory synaptic input to nucleus accumbens (NAc) medium spiny neurons (MSNs) underlies a key pathophysiology of drug addiction and addiction-associated emotional and motivational alterations. Dynorphin peptides, which exhibit higher affinity to kappa type opioid receptors, are up-regulated within the NAc upon exposure to cocaine administration, and the increased dynorphin-signaling in NAc has been critically implicated in negative mood observed in cocaine- or stress-exposed animals. Despite such apparent behavioral significance of the NAc dynorphins, understanding of how dynorphins regulate excitatory synaptic transmission in NAc remains incomplete. Here, we focused on two key dynorphins, dynorphin A and B. Our current results show that dynorphin A and B differentially regulated excitatory postsynaptic currents (EPSCs) in NAc MSNs. Whereas perfusions of both dynorphin A and B to NAc slices decreased EPSCs in MSNs, the effect of dynorphin A, but not dynorphin B, was completely reversed by the kappa receptor-selective antagonist nor-Binaltorphimine. These results implicate kappa receptor-independent mechanisms in dynorphin B-mediated synaptic effect in NAc. Furthermore, repeated exposure to cocaine (15 mg/kg/day via intraperitoneal injection for 5 days, with 1 or 2 days withdrawal) completely abolished dynorphin A-mediated modulation of EPSCs in NAc MSNs, whereas the effect of dynorphin B remained largely unchanged. Given the quantitatively higher abundance of dynorphin B in the NAc, our present results suggest that the dynorphin B-mediated, kappa receptor-independent pathways predominate in the overall effect of dynorphins in cocaine-pretreated animals, and potentially in cocaine-induced alterations in mood.
membrane excitability; cocaine; nucleus accumbens; action potential; withdrawal
Parental bereavement is associated with increased risk for psychiatric illness and functional impairment in youth. Dysregulated hypothalamic-pituitary-adrenal (HPA) axis functioning may be one pathway through which bereaved children experience increased risk for poor outcomes. However, few studies have prospectively examined the association between parental bereavement and cortisol response while accounting for psychiatric disorders in both youth and their caregivers.
One-hundred and eighty-one bereaved and nonbereaved offspring and their caregivers were assessed at multiple time points over a 5-year period after parental death. Offspring participated in an adaptation of the Trier Social Stress Task (TSST), and salivary cortisol samples were collected before and after exposure to social stressors. Mixed models for repeated measures were used to analyze the effects of bereavement status, psychiatric disorder in both offspring and caregiver, and demographic indices on trajectories of cortisol response.
After controlling for demographic variables and offspring depression, bereaved offspring demonstrated significantly different trajectories of cortisol response compared with nonbereaved offspring, characterized by higher total cortisol output and an absence of cortisol reactivity to acute social stress. Within the bereaved group, offspring of parents who died by sudden natural death demonstrated significant cortisol reactivity to social stress compared with offspring whose parents died by suicide, who demonstrated more blunted trajectory of cortisol response.
Parentally bereaved youth demonstrate higher cortisol output than nonbereaved youth but are less able to mount an acute response in the face of social stressors.
Adolescent; bereavement; cortisol; depression; HPA axis; TSST
Nicotinic signaling in prefrontal layer VI pyramidal neurons is important to the function of mature attention systems. The normal incorporation of α5 subunits into α4β2* nicotinic acetylcholine receptors augments nicotinic signaling in these neurons and is required for normal attention performance in adult mice. However, the role of α5 subunits in the development of the prefrontal cortex is not known.
We sought to answer this question by examining nicotinic currents and neuronal morphology in layer VI neurons of medial prefrontal cortex of wild-type and α5 subunit knockout (α5−/−) mice during postnatal development and in adulthood.
In wild-type but not in α5−/− mice, there is a developmental peak in nicotinic acetylcholine currents in the third postnatal week. At this juvenile time period, the majority of neurons in all mice have long apical dendrites extending into cortical layer I. Yet, by early adulthood, wild-type but not α5−/− mice show a pronounced shift toward shorter apical dendrites. This cellular difference occurs in the absence of genotype differences in overall cortical morphology.
Normal developmental changes in nicotinic signaling and dendritic morphology in prefrontal cortex depend on α5-comprising nicotinic acetylcholine receptors. It appears that these receptors mediate a specific developmental retraction of apical dendrites in layer VI neurons. This finding provides novel insight into the cellular mechanisms underlying the known attention deficits in α5−/− mice and potentially also into the pathophysiology of developmental neuropsychiatric disorders such as attention-deficit disorder and autism.
α5 subunit; CHRNA5; layer VI; neuronal morphology; nicotinic acetylcholine receptor; prefrontal cortex
Clinical evidence that ketamine, a nonselective N-methyl-D-aspartate receptor (NMDAR) antagonist, has therapeutic effects within hours in people suffering from depression suggests that modulating glutamatergic neurotransmission is a fundamental step in alleviating the debilitating symptoms of mood disorders. Acutely, ketamine increases extracellular glutamate levels, neuronal excitability and spontaneous gamma oscillations, but it is unknown whether these effects are key to ketamine's mechanism of antidepressant action.
Twenty drug-free MDD patients received a single, open-label intravenous infusion of ketamine hydrochloride (.5 mg/kg). Magnetoencephalographic recordings were made ≈3 d before and ≈6.5 h after the infusion while patients passively received tactile stimulation to the right and left index fingers, and also while they rested (eyes-closed). Antidepressant response was assessed by percent change in Montgomery-Åsberg Depression Rating Scale scores.
Patients with robust improvements in depressive symptoms 230 m post-infusion (responders) exhibited increased cortical excitability within this antidepressant response window. Specifically, we found that stimulus-evoked somatosensory cortical (SS ctx) responses increase post-infusion relative to pretreatment responses in responders but not in treatment non-responders. Spontaneous SS ctx gamma-band activity during rest did not change within the same timeframe following ketamine in either responders or non-responders.
These findings suggest NMDAR antagonism does not lead directly to increased cortical excitability hours later, and, thus, may not be sufficient for therapeutic effects of ketamine to take hold. Rather, increased cortical excitability as depressive symptoms improve is consistent with the hypothesis that enhanced non-NMDAR-mediated glutamatergic neurotransmission via synaptic potentiation is central to ketamine's antidepressant effect.
cortical excitability; gamma oscillation; ketamine; major depression; magnetoencephalography; NMDA antagonist
Valid, reliable biomarkers of depression severity and treatment response would provide new targets for clinical research. Noticeable differences in speech production between depressed and nondepressed patients have been suggested as a potential biomarker.
One hundred and five adults with Major Depression were recruited into a four-week, randomized, double-blind, placebo-controlled research methodology study. An exploratory objective of the study was to evaluate the generalizability and repeatability of prior study results indicating vocal acoustic properties in speech may serve as biomarkers for depression severity and response to treatment. Speech samples, collected at baseline and study end-point using an automated telephone system, were analyzed as a function of clinician-rated and patient-reported measures of depression severity and treatment response.
Regression models of speech pattern changes associated with clinical outcomes in the prior study were found to be reliable and significant predictors of outcome in the current study despite differences in the methodological design and implementation of the two studies. Results of the current study replicate and support findings from the prior study. Clinical changes in depressive symptoms among patients responding to the treatments provided also reflected significant differences in speech production patterns. Depressed patients who did not improve clinically showed smaller vocal acoustic changes and/or changes that were directionally opposite to treatment responders.
This study supports the feasibility and validity of obtaining clinically important, biologically-based vocal acoustic measures of depression severity and treatment response using an automated telephone system. National Institutes of Health Clinical Trials Registry: http://clinicaltrials.gov Identifier: NCT00406952.
Depression assessment; methodology; speech; voice acoustics; telephone; interactive voice response (IVR)
Adult neurogenesis is coupled to angiogenesis in neurogenic niches in the dentate gyrus (DG) and increased by antidepressants in rodents. We hypothesized that, in major depressive disorder (MDD), antidepressants increase neural progenitor cells (NPCs) and capillaries in the human DG.
NPCs and capillaries, detected on hippocampal sections by immunohistochemistry for nestin, were quantified by stereology in matched MDDs (untreated, n=12), MDD treated with selective serotonin reuptake inhibitors (MDD*SSRI, n=6) or tricyclic antidepressants (MDD*TCA, n=6) and nonpsychiatric controls (n=12), all confirmed by psychological autopsy.
MDD*SSRI had a larger capillary area and more NPCs versus MDDs (p=.034 and p=.008, respectively) and controls (p=.010 and p=.002, respectively) in the whole DG, more NPCs in the anterior (pes, p=.042) and central (mid-body, p=.004) DG, and greater capillary area in the pes (p=.002) and mid-body (p=.021). NPC number and capillary area correlated positively in the whole sample (R2=.454, p<.001) and in treated subjects (R2=.749, p=.001). We found no NPCs or antidepressant-related angiogenesis in CA1 and parahippocampal gyrus. DG volume correlated positively with NPC number (p=.004) and capillary area (p<.001), and differed between groups in whole hippocampus (p=.013) and mid-body (p=.036). Age negatively correlated with NPC number (p=.042), capillary area (p=.037) and bifurcations (p=.030). No sex effect was detected.
Antidepressants increase human hippocampal NPCs and angiogenesis selectively in the anterior and mid DG. These results raise the possibility of a causal relationship between angiogenesis and neurogenesis, as seen in other proliferating tissues, and support their possible role in the mechanism of action of antidepressants.
neural progenitor cells; nestin; dentate gyrus; postmortem; stereology; immunohistochemistry
Since publication of the first randomized controlled trial describing rapid antidepressant effects of ketamine, several reports have confirmed the potential utility of this dissociative anesthetic medication for treatment of major depressive episodes, including those associated with bipolar disorder and resistant to other medications and electroconvulsive therapy. These reports have generated several questions with respect to who might respond to ketamine, how, and for how long. To start answering these questions. We used PubMed.gov and ClinicalTrials.gov to perform a systematic review of all available published data on the antidepressant effects of ketamine and of all recently completed, ongoing, and planned studies. To date, 163 patients, primarily with treatment-resistant depression, have participated in case studies, open-label investigations, or controlled trials. All controlled trials have used a within-subject, crossover design with an inactive placebo as the control. Ketamine administration has usually involved an anaesthesiologist infusing a single, subanesthetic, intravenous dose, and required hospitalization for at least 24 hours postinfusion. Response rates in the open-label investigations and controlled trials have ranged from 25% to 85% at 24 hours postinfusion and from 14% to 70% at 72 hours postinfusion. Although adverse effects have generally been mild, some patients have experienced brief changes in blood pressure, heart rate, or respiratory rate. Risk–benefit analyses support further research of ketamine for individuals with severe mood disorders. However, given the paucity of randomized controlled trials, lack of an active placebo, limited data on long-term outcomes, and potential risks, ketamine administration is not recommended outside of the hospital setting.
Antidepressant; bipolar disorder; glutamate; ketamine; major depressive disorder; treatment-resistant depression
Phosphodiesterase type IV (PDE4), an important component of the cyclic adenosine monophosphate (cAMP) cascade, selectively metabolizes cAMP in the brain to the inactive monophosphate. Basic studies suggest that PDE4 mediates the effects of several antidepressants. This study sought to quantify the binding of 11C-(R)-rolipram, a PDE4 inhibitor, as an indirect measure of this enzyme’s activity in the brain of individuals with major depressive disorder (MDD) compared with healthy control subjects.
11C-(R)-Rolipram brain positron emission tomography scans were performed in 28 unmedicated MDD subjects and 25 age- and gender-matched healthy control subjects. Patients were moderately depressed and about one half were treatment-naive. 11C-(R)-Rolipram binding in the brain was measured using arterial 11C-(R)-rolipram levels to correct for the influence of cerebral blood flow.
Major depressive disorder subjects showed a widespread, approximately 20% reduction in 11C-(R)-rolipram binding (p = .002), which was not caused by different volumes of gray matter. Decreased rolipram binding of similar magnitudes was observed in most brain areas. Rolipram binding did not correlate with the severity of depressive or anxiety symptoms.
This study is the first to demonstrate that brain levels of PDE4, a critical enzyme that regulates cAMP, are decreased in unmedicated individuals with MDD in vivo. These results are in line with human postmortem and rodent studies demonstrating downregulation of the cAMP cascade in MDD and support the hypothesis that agents such as PDE4 inhibitors, which increase activity within the cAMP cascade, may have antidepressant effects.
cAMP; compartmental analysis; in vivo imaging; second messenger; unipolar depression; unmedicated
Most anxiety and depressive disorders are twice as common in women compared to men and the sex difference in prevalence typically emerges during adolescence. Hormonal changes across the menstrual cycle and during the postpartum and peri-menopausal periods are associated with increased risk for anxiety and depression symptoms. In humans and animals, reduced brain derived neurotrophic factor (BDNF) has been associated with increased expression of affective pathology. Recently, a single nucleotide polymorphism (SNP) in the BDNF gene (BDNF Val66Met), which reduces BDNF bioavailability, has been identified in humans and associated with a variety of neuropsychiatric disorders. Although BDNF expression can be directly influenced by estrogen and progesterone, the potential impact of the BDNF Val66Met SNP on sensitivity to reproductive hormone changes remains an open question.
As a predictive model, we used female mice in which the human SNP (BDNF Val66Met) was inserted into the mouse BDNF gene. Using standard behavioral paradigms, we tested the impact of this SNP on age and estrous-cycle specific expression of anxiety-like behaviors.
Mice homozygous for the BDNF Val66Met SNP begin to exhibit increased anxiety-like behaviors over prepubertal and early adult development, show significant fluctuations in anxiety-like behaviors over the estrous cycle, and as adults differ from wild-type mice by showing significant fluctuations in anxiety-like behaviors over the estrous cycle, specifically more anxiety-like behaviors during the estrus phase.
These findings have implications regarding the potential role of this SNP in contributing to developmental and reproductive hormone-dependent changes in affective disorders in humans.
BDNF Val66Met; Estrous; Female; Anxiety; Behavior; Development
Research conducted using small samples of persons exposed to extreme stressors has documented an association between parental and offspring posttraumatic stress disorder (PTSD), but it is unknown whether this association exists in the general population and whether trauma exposure mediates this association. We sought to determine whether mothers’ posttraumatic stress symptoms were associated with PTSD in their young adult children and whether this association was mediated by higher trauma exposure in children of women with PTSD.
Using data from a cohort of mothers (n=6924) and a cohort of their children (n=8453), we calculated risk ratios (RR) for child’s PTSD and examined mediation by trauma exposure.
Mother’s lifetime posttraumatic stress symptoms were associated with child’s PTSD in dose-response fashion (mother’s 1 to 3 symptoms, child’s RR=1.2; mother’s 4-5 symptoms, RR=1.3; mother’s 6-7 symptoms, RR=1.6, compared to children of mothers with no symptoms, p<0.001 for each). Mother’s lifetime symptoms were also associated with child’s trauma exposure in dose-response fashion. Elevated exposure to trauma substantially mediated elevated risk for PTSD in children of women with symptoms (mediation proportion, 74%, p<0.001).
Intergenerational association of PTSD is clearly present in a large population-based sample. Children of women who had PTSD were more likely than children of women without PTSD to experience traumatic events; this suggests, in part, why the disorder is associated across generations. Health care providers who treat mothers with PTSD should be aware of the higher risk for trauma exposure and PTSD in their children.
Posttraumatic stress disorder; trauma; childhood abuse; epidemiology; family studies; violence
Borderline personality disorder (BPD) is characterized by an inability to regulate emotional responses. The amygdala is important in learning about the valence (goodness and badness) of stimuli and has been reported to function abnormally in BPD.
Event-related functional MRI (fMRI) was employed in three groups: unmedicated BPD (n=33) and schizotypal personality disorder (SPD;n=28) participants and healthy controls (n=32) during a task involving an intermixed series of unpleasant, neutral, and pleasant pictures each presented twice within their respective trial block/run. The amygdala was hand-traced on each participant’s structural-MRI scan which was co-registered to their BOLD-scan. Amygdala responses were examined with a mixed-model MANOVA with repeated measures.
Compared with both control groups, BPD patients showed greater amygdala activation, particularly to the repeated emotional but not neutral pictures and a prolonged return to baseline for the overall BOLD response averaged across all pictures. Despite amygdala overactivation, BPD patients showed a blunted response on the self-report ratings of emotional but not neutral pictures. Fewer dissociative symptoms in both patient groups were associated with greater amygdala activation to repeated unpleasant pictures.
The increased amygdala response to the repeated emotional pictures observed in BPD was not observed in SPD patients suggesting diagnostic specificity. This BPD-related abnormality is consistent with the well-documented clinical feature of high sensitivity to emotional stimuli with unusually strong and long-lasting reactions. The finding of a mismatch between physiological and self-report measures of emotion reactivity in BPD patients suggests they may benefit from treatments which help them recognize emotions.
borderline personality disorder; schizotypal personality disorder; amygdala; emotion; fMRI; arousal; valence
Generalized Social Phobia (GSP) and Generalized Anxiety Disorder (GAD) are both associated with emotion dysregulation. In healthy subjects, research implicates dorsal anterior cingulate (dACC) in both explicit emotion regulation and top-down attentional control. While studies have examined these processes in GSP or GAD, no work compares findings across the two disorders. Moreover, no work examines functioning in cases comorbid for both disorders (GSP/GAD). Here we compare the neural correlates of explicit emotion regulation (EER) and top-down attentional control (TAC) in GSP, GAD, and GSP/GAD.
Medication-free adults with GSP (EER n=19; TAC n=18), GAD (EER n=17; TAC n =17), GSP/GAD (EER n=17; TAC=15), or no psychopathology (EER n=18; TAC n=18). During EER, individuals alternatively viewed, up-regulated, and down-regulated responses to emotional pictures. During TAC, they performed an emotional Stroop task.
For both tasks, significant group-by-condition interactions emerged in dACC and parietal cortices. Healthy adults showed significantly increased recruitment during emotion regulation, relative to emotion-picture viewing. GAD, GSP, and GSP/GAD subjects showed no such increases, with all three groups differing from healthy adults but not from each other. Evidence of emotion-related disorder-specificity emerged in medial prefrontal cortex (MPFC) and amygdala. This disorder-specific responding varied as a function of stimulus emotion content but not emotion-regulatory demands.
GSP and GAD both involve reduced capacity for engaging emotion-regulation brain networks, whether explicitly or via top-down attentional control. A reduced ability to recruit regions implicated in top-down attention might represent a general risk factor for anxiety disorders.
imaging; social anxiety; generalized anxiety; emotion regulation; anterior cingulate cortex; top-down attentional control
Accumulating evidence suggests that fetal exposure to maternal psychiatric symptoms is associated with future risk for psychopathology. One potential pathway is distress–linked constriction in uterine or umbilical blood flow (UBF). With approximately 6.6% of pregnant women taking an antidepressant, an ecologically valid investigation of this hypothesis must consider the potential concomitant influence of pharmacotherapy on UBF.
Pregnant women (n=101) with lifetime histories of mental illness were evaluated every 4–6 weeks during gestation for mood symptoms and medication use; women underwent an ultrasound examination for UBF at approximately 25 weeks gestation.
No associations were observed between UBF and three assessments of maternal prenatal depression and anxiety (acute: coincident with the UBF scan; proximal: within two weeks of the scan; chronic: serial symptom ratings). Chronic and acute use of bupropion was associated with reduced UBF even after controlling for pregnancy complications. Chronic use of atypical antipsychotics also was associated with decreased UBF. There were no associations between serotonergic antidepressant use and UBF.
Contrary to a popular hypothesis, depression and anxiety–associated reductions in UBF may not be a pathway by which risk is conferred during prenatal development. However, while requiring replication, our findings suggest that prenatal bupropion exposure may be associated with reductions in UBF.
pregnancy; depression; uterine blood flow; bupropion; SSRIs; neurobehavioral development; psychopathology
Alterations in arousal states are associated with multiple neuropsychiatric disorders including generalized anxiety disorders, addiction, schizophrenia, and depression. Therefore, elucidating the neurobiological mechanisms controlling the boundaries between arousal, hyperarousal, and hypoarousal is a crucial endeavor in biological psychiatry. Substantial research over several decades has identified distinct arousal-promoting neural populations in the brain; however, how these nuclei act individually and collectively to promote and maintain wakefulness and various arousal states is unknown. We have recently applied optogenetic technology to the repertoire of techniques used to study arousal. Here, we discuss the recent results of these experiments and propose future use of this approach as a way to understand the complex dynamics of neural circuits controlling arousal and arousal-related behaviors.
sleep; wakefulness; arousal; hypothalamus; locus coeruleus; optogenetics
Event-related oscillations (EROs) are increasingly being used to assess neuro-cognitive functioning in normal and clinical populations. The current study compares different frequency activities in offspring of alcoholics (OA) and in normal controls (NC) in order to examine whether the OA group exhibits any abnormality in oscillatory activity while performing a Go/NoGo task.
The S-Transform algorithm was employed to decompose the EEG signals into different time-frequency bands, and the oscillatory responses in the P300 time window (300–700 ms) was statistically analyzed in both groups.
The OA group manifested significantly decreased activity in delta (1–3 Hz), theta (4–7 Hz), and alpha1 (8–9 Hz) bands during the NoGo condition as well as reduced delta and theta activity during the Go condition. This reduction was more prominent in the NoGo than in the Go condition.
The decreased response in delta, theta, and alpha1 oscillations, especially during the NoGo condition in high risk individuals is perhaps suggestive of cognitive and neural disinhibition, and may serve as an endophenotypic marker in the development of alcoholism and/or other disinhibitory disorders.
Event-related oscillations; Go/NoGo; Offspring of Alcoholics; Delta; Theta; Endophenotype
Disrupted neuroplasticity may be an important aspect of the neural basis of schizophrenia. We used event-related brain potentials (ERPs) to assay neuroplasticity after auditory conditioning in chronic schizophrenia patients (SZ) and matched healthy control subjects (HC).
Subjects (15 HC, 14 SZ) performed an auditory oddball task during electroencephalogram recording before and after auditory tetanic stimulation (Pre/Post Blocks). Each oddball block consisted of 1000-Hz and 1500-Hz standards and 400-Hz targets. During tetanic conditioning, 1000-Hz tones were presented at 11 Hz for 2.4 min. We analyzed the standard trials, comparing the ERPs evoked by the tetanized stimuli (1000 Hz tones: TS+) and untetanized stimuli (1500 Hz tones: TS−) in the Post Blocks with ERPs from the Pre Blocks (averaged into Baseline ERPs).
In Post Block 1 in HC, TS+ tones evoked a negative shift (60–350 msec) at right temporal electrodes relative to Baseline. No pre-/post-tetanus effects were found in SZ. In Post Block 2 in HC, TS+ tones evoked a positive shift (200–300 msec) at bilateral frontal electrodes. In SZ, TS+ tones evoked a positive shift (100–400 msec) at right frontotemporal electrodes. No pre-/post-tetanus effects were found in either subject group for the TS− tones. The right temporal Post Block 1 and 2 effects were correlated in SZ, suggesting a trade-off in the expression of these effects.
These results suggest that stimulus-specific auditory neuroplasticity is abnormal in schizophrenia. The electrophysiologic assessment of stimulus-specific plasticity may yield novel targets for drug treatment in schizophrenia.
Auditory processing; ERP; event-related brain potential; NMDA receptor; plasticity; schizophrenia
Complex behavioral traits such as coping strategies in response to stress are usually formed by genetic and environmental influences.
By exploiting the phenotypic and genotypic differences between the Wistar Kyoto (WKY) and Fischer 344 (F344) inbred rat strains, we recently identified three X chromosome-linked quantitative trait loci contributing to differences in coping strategies in the defensive burying (DB) paradigm. In this article we study the influence of postnatal maternal environment in these behaviors by characterizing the maternal behavior of these strains and the effect of cross-fostering on DB behavior of male offspring from reciprocal crossing (F1).
Maternal behavior of WKY rats can be quantitatively characterized by less contact and more periods of neglect of their F1 pups. In contrast, F344 mothers engaged in more active behaviors such as licking/grooming and arched-back nursing. Cross-fostering male F1 pups at birth did not influence the latency to bury measure in DB; however, duration of burying and prod approaches were influenced by both genotype and maternal environment in an additive manner.
These results demonstrate that different measures of behavioral coping in the DB paradigm are influenced by maternal environment to differing degrees and in addition by genetic factors.
Wistar-Kyoto; genetics; stress; cross-fostering; reciprocal breeding; Fischer 344
The peptide hormone ghrelin acts in the central nervous system as a potent orexigenic signal. Not only is ghrelin recognized as playing an important role in feeding circuits traditionally thought of as affecting body weight homeostasis, but an accumulating number of scientific studies now have identified ghrelin as being a key regulator of reward-based, hedonic eating behaviors. In the current article, we review ghrelin’s orexigenic actions, the evidence linking ghrelin to food reward behavior, potential mechanisms by which ghrelin mediates reward-based eating behavior, and those studies suggesting an obligatory role for ghrelin in the changed eating behaviors induced by stress.
Ghrelin; GHSR; hedonic; reward; eating; stress