Biological Psychiatry - Articles in Press

Evidence of Cortical Inhibitory Deficits in Major Depressive Disorder - Corrected Proof

2009-11-19

Background: Several lines of evidence suggest that major depressive disorder is associated with deficits in γ-aminobutyric acid (GABA) inhibitory neurotransmission. Transcranial magnetic stimulation represents a noninvasive technique to measure cortical inhibition. In this study, we endeavored to measure cortical inhibition in medicated patients with treatment resistant major depressive disorder (TRD), unmedicated patients with major depressive disorder, and medicated euthymic patients with a history of major depressive disorder and compare them with healthy subjects.Methods: Twenty-five patients with TRD, 16 unmedicated patients with major depressive disorder, 19 medicated euthymic patients with previous major depressive disorder (i.e., 17-item Hamilton Rating Scale for Depression < 8), and 25 healthy subjects were enrolled. Cortical inhibition was measured with transcranial magnetic stimulation paradigms known as short-interval cortical inhibition and the cortical silent period, which index GABAA and GABAB receptor-mediated inhibitory neurotransmission, respectively.Results: All major depressive disorder patient groups demonstrated significant cortical silent period deficits compared with healthy subjects. By contrast, only TRD patients demonstrated significant deficits in short-interval cortical inhibition compared with healthy subjects, medicated euthymic major depressive disorder patients, and unmedicated major depressive disorder patients. The TRD patients also demonstrated a significantly greater resting motor threshold compared with all other clinical subgroups and healthy subjects, suggesting that TRD was also associated with hypoexcitability of the frontal cortex.Conclusions: Our findings suggest that GABAB neurophysiological deficits are closely related to pathophysiology of major depressive disorder. Our findings also suggest that more severe illness is selectively associated with GABAA receptor-mediated inhibitory deficits.

Replication of Association Between Working Memory and Reelin, a Potential Modifier Gene in Schizophrenia - Corrected Proof

2009-11-19

Background: The challenges in gene identification for psychiatric disorders have awakened interest toward quantitative traits and endophenotypes that are potentially more closely related to the underlying biology and provide more power in the linkage and association analyses. Previously, we successfully replicated schizophrenia linkage on chromosome 7q21-32 in Finnish families and demonstrated that an intragenic short tandem repeat (STR) allele of the regional Reelin (RELN) gene is associated with multiple cognitive traits representing central cognitive functions regarded as valid endophenotypes for schizophrenia.Methods: Here, we used an extended sample of 290 Finnish families with schizophrenia and 375 control subjects in an association analysis between 96 SNPs and three STRs in RELN and diagnostic categories, clinical disorder features, as well as central cognitive functions impaired in schizophrenia.Results: We replicated the original association between RELN intragenic STR allele and working memory in individuals (n = 342) not overlapping with the previous study. This risk allele remained central in the whole study sample by being associated with impaired cognitive functioning and more severe positive and negative symptoms of schizophrenia (p = .0005–.00002). Additionally, multiple SNPs indicated association with the severity of positive symptoms of schizophrenia and together showed potential additive effect on the severity of the symptoms (p = .0000001). However, no significant associations with clinical diagnostic categories emerged.Conclusions: The strongest effects on cognitive functions were detected among the affected individuals. We thus propose a particular role for RELN as a modifier gene of the pathogenesis of schizophrenia.

Nucleus Accumbens Deep Brain Stimulation Decreases Ratings of Depression and Anxiety in Treatment-Resistant Depression - Corrected Proof

2009-11-18

Background: While most patients with depression respond to combinations of pharmacotherapy, psychotherapy, and electroconvulsive therapy (ECT), there are patients requiring other treatments. Deep brain stimulation (DBS) allows modulation of brain regions that are dysfunctional in depression. Since anhedonia is a feature of depression and there is evidence of dysfunction of the reward system, DBS to the nucleus accumbens (NAcc) might be promising.Methods: Ten patients suffering from very resistant forms of depression (treatment-resistant depression [TRD]), not responding to pharmacotherapy, psychotherapy, or ECT, were implanted with bilateral DBS electrodes in the NAcc. The mean (±SD) length of the current episode was 10.8 (±7.5) years; the number of past treatment courses was 20.8 (±8.4); and the mean Hamilton Depression Rating Scale (HDRS) was 32.5 (±5.3).Results: Twelve months following initiation of DBS treatment, five patients reached 50% reduction of the HDRS (responders, HDRS = 15.4 [±2.8]). The number of hedonic activities increased significantly. Interestingly, ratings of anxiety (Hamilton Anxiety Scale) were reduced in the whole group but more pronounced in the responders. The [18F]-2-fluoro-2-deoxy-D-glucose positron emission tomography data revealed that NAcc-DBS decreased metabolism in the subgenual cingulate and in prefrontal regions including orbital prefrontal cortex. A volume of interest analysis comparing responders and nonresponders identified metabolic decreases in the amygdala.Conclusions: We demonstrate antidepressant and antianhedonic effects of DBS to NAcc in patients suffering from TRD. In contrast to other DBS depression studies, there was also an antianxiety effect. These effects are correlated with localized metabolic changes.

5-Hydroxytryptamine 2C Receptors in the Basolateral Amygdala Are Involved in the Expression of Anxiety After Uncontrollable Traumatic Stress - Corrected Proof

2009-11-16

Background: Exposure to uncontrollable stressors often increases anxiety-like behavior in both humans and rodents. In rat, this effect depends on stress-induced activity within the dorsal raphe nucleus (DRN). However, the role of serotonin in DRN projection regions is largely unknown. The goals of this study were to 1) assess the effect of uncontrollable stress on extracellular serotonin in the basolateral amygdala during the anxiety test, 2) determine whether DRN activity during a poststress anxiety test is involved in anxiety-like behavior, and 3) determine the role of the serotonin 2C receptor (5-HT2C) in uncontrollable stress-induced anxiety.Method: Rats were exposed to tail shocks that were either controllable or uncontrollable. On the following day, anxiety-like behavior was assessed in a Juvenile Social Exploration (JSE) test. Basolateral amygdala (BLA) extracellular serotonin concentrations were assessed during JSE by in vivo microdialysis 24 hours after uncontrollable stress, controllable stress, or no stress. In separate experiments, drugs were administered before the JSE test to inhibit the DRN or to block 5-HT2C receptors.Results: Exposure to uncontrollable shock reduced later social exploration. Prior uncontrollable stress potentiated serotonin efflux in the BLA during social exploration, but controllable stress did not. Intra-DRN 8-OH-DPAT and systemic and intra-BLA 5-HT2C receptor antagonist SB 242,084 prevented the expression of potentiated anxiety in uncontrollably stressed rats. Intra-BLA injection of the 5-HT2C agonist CP 809,101 mimicked the effect of stress.Conclusions: These results suggest that the anxiety-like behavior observed after uncontrollable stress is mediated by exaggerated 5-HT acting at BLA 5-HT2C receptors.

Dopamine Receptor D4 Polymorphism Predicts the Effect of L-DOPA on Gambling Behavior - Corrected Proof

2009-11-16

Background: There is ample evidence that a subgroup of Parkinson's disease patients who are treated with dopaminergic drugs develop certain behavioral addictions such as pathological gambling. The fact that only a subgroup of these patients develops pathological gambling suggests an interaction between dopaminergic drug treatment and individual susceptibility factors. These are potentially of genetic origin, since research in healthy subjects suggests that vulnerability for pathological gambling may be linked to variation in the dopamine receptor D4 (DRD4) gene. Using a pharmacogenetic approach, we investigated how variation in this gene modulates the impact of dopaminergic stimulation on gambling behavior in healthy subjects.Methods: We administered 300 mg of L-dihydroxyphenylalanine (L-DOPA) or placebo to 200 healthy male subjects who were all genotyped for their DRD4 polymorphism. Subjects played a gambling task 60 minutes after L-DOPA administration.Results: Without considering genetic information, L-DOPA administration did not lead to an increase in gambling propensity compared with placebo. As expected, however, an individual's DRD4 polymorphism accounted for variation in gambling behavior after the administration of L-DOPA. Subjects who carry at least one copy of the 7-repeat allele showed an increased gambling propensity after dopaminergic stimulation.Conclusions: These findings demonstrate that genetic variation in the DRD4 gene determines an individual's gambling behavior in response to a dopaminergic drug challenge. They may have implications for the treatment of Parkinson's disease patients by offering a genotype approach for determining individual susceptibilities for pathological gambling and may also afford insights into the vulnerability mechanisms underlying addictive behavior.

Brain Region Specific Actions of Regulator of G Protein Signaling 4 Oppose Morphine Reward and Dependence but Promote Analgesia - Corrected Proof

2009-11-16

Background: Regulator of G protein signaling 4 (RGS4) is one of the smaller members of the RGS family of proteins, which are known to control signaling amplitude and duration via interactions with G protein α subunits or other signaling molecules. Earlier evidence suggests dynamic regulation of RGS4 levels in neuronal networks mediating actions of opiates and other drugs of abuse, but the consequences of RGS4 actions in vivo are largely unknown.Methods: In this study, we use constitutive and nucleus accumbens-inducible RGS4 knockout mice as well as mice overexpressing RGS4 in the nucleus accumbens via viral mediated gene transfer, to examine the influence of RGS4 on behavioral responses to opiates. We also use electrophysiology and immunoprecipitation assays to further understand the mechanisms underlying the tissue-specific actions of RGS4.Results: Inducible knockout or selective overexpression of RGS4 in the nucleus accumbens reveals that, in this brain region, RGS4 acts as a negative regulator of morphine reward, whereas in the locus coeruleus RGS4 opposes morphine physical dependence. In contrast, we show that RGS4 does not affect morphine analgesia or tolerance but is a positive modulator of certain opiate analgesics, such as methadone and fentanyl.Conclusions: These findings provide fundamentally novel information concerning the role of RGS4 in the cellular mechanisms underlying the diverse actions of opiate drugs in the nervous system.

Neonatal Intrahippocampal Immune Challenge Alters Dopamine Modulation of Prefrontal Cortical Interneurons in Adult Rats - Corrected Proof

Carlos Feleder, Kuei Yuan Tseng, Gwendolyn G. Calhoon, Patricio O'Donnell — 2009-11-16

Background: Among the diverse animal models proposed for schizophrenia, the neonatal ventral hippocampal lesion (NVHL) is one of the most widely used. However, its construct validity can be questioned because there is no evidence of a lesion present in schizophrenia. Other approaches that have tried to capture environmental influences on development include diverse models of maternal infection.Methods: As the early postnatal days in rodents are equivalent to the third trimester of human pregnancy in terms of brain development, we decided to test whether a neonatal immune challenge with an injection of the bacterial endotoxin lipopolysaccharide (LPS) into the ventral hippocampus caused deficits in interneuron function similar to those reported for the NVHL.Results: Neonatal LPS injection caused a persistent elevation in cytokines in several brain regions, deficits in prepulse inhibition of the acoustic startle response, and a loss of the periadolescent maturation in the response of prefrontal cortical fast-spiking interneurons to dopamine.Conclusions: The same phenotypes elicited by a NVHL can be obtained with an intrahippocampal immune challenge, suggesting that perinatal environmental factors can affect adult prefrontal interneuron maturation during adolescence.

Effects of Motivation and Medication on Electrophysiological Markers of Response Inhibition in Children with Attention-Deficit/Hyperactivity Disorder - Corrected Proof

2009-11-16

Background: Theories of attention-deficit/hyperactivity disorder (ADHD) posit either executive deficits and/or alterations in motivational style and reward processing as core to the disorder. Effects of motivational incentives on electrophysiological correlates of inhibitory control and relationships between motivation and stimulant medication have not been explicitly tested.Methods: Children (9–15 years) with combined-type ADHD (n = 28) and matched typically developing children (CTRL) (n = 28) performed a go/no-go task. Electroencephalogram data were recorded. Amplitude of two event-related potentials, the N2 and P3 (markers of response conflict and attention), were measured. The ADHD children were all stimulant responders tested on and off their usual dose of methylphenidate; CTRLs were never medicated. All children performed the task under three motivational conditions: reward; response cost; and baseline, in which points awarded/deducted for inhibitory performance varied.Results: There were effects of diagnosis (CTRL > ADHD unmedicated), medication (on > off), and motivation (reward and/or response cost > baseline) on N2 and P3 amplitude, although the N2 diagnosis effect did not reach statistical significance (p = .1). Interactions between motivation and diagnosis/medication were nonsignificant (p > .1).Conclusions: Motivational incentives increased amplitudes of electrophysiological correlates of response conflict and attention in children with ADHD, towards the baseline (low motivation) amplitudes of control subjects. These results suggest that, on these measures, motivational incentives have similar effects in children with ADHD as typically developing CTRLs and have additive effects with stimulant medication, enhancing stimulus salience and allocation of attentional resources during response inhibition.

The Role of Acetaldehyde in Human Psychomotor Function: A Double-Blind Placebo-Controlled Crossover Study - Corrected Proof

2009-11-16

Background: Acetaldehyde, the first product of ethanol metabolization, is a biologically active compound, but the behavioral properties of acetaldehyde in humans are largely undefined. We investigated the acute effects of both alcohol and acetaldehyde on psychomotor functions related to automobile driving skills.Methods: Twenty-four men were selected through genotyping; one-half had the ALDH2*1/*1 (active form) genotype and one-half had the ALDH2*1/*2 (inactive form) genotype. In a double-blind placebo-controlled crossover design, each subject was administered one of the following doses of alcohol: .25 g/kg, .5 g/kg, or .75 g/kg or a placebo in four trials that took place at 1-week intervals. Blood ethanol concentration (BEC) and blood acetaldehyde concentration (BAAC) were measured nine times, and psychomotor function tests (critical flicker fusion threshold, choice reaction time, compensatory tracking task, and digit symbol substitution test) were assessed seven times in total over 4 hours after study drug ingestion.Results: After the consumption of alcohol, BEC was comparable in the two subject groups, whereas BAAC was significantly higher in subjects with ALDH2 *1/*2 than in those with ALDH2 *1/*1. The psychomotor performance of subjects with ALDH2*1/*2 was significantly poorer than that of subjects with ALDH2*1/*1. Significant correlations between psychomotor performance and both BEC and BAAC were observed. However, in the linear regression analysis, BAAC significantly predicted poorer psychomotor performance, whereas BEC was not associated with any measure of psychomotor function.Conclusions: Acetaldehyde might be more important than alcohol in determining the effects on human psychomotor function and skills.

Reply Regarding “Efficacy and Safety of Transcranial Magnetic Stimulation in the Acute Treatment of Major Depression: A Multisite Randomized Controlled Trial” - Corrected Proof

2009-11-16

We appreciate the comments from Yu and Lurie (). They, however, make several errors of interpretation regarding the results of the study and in that regard, unfortunately, do a disservice to the article and your readers.

Changes of Brain Morphometry in First-Episode, Drug-Naïve, Non–Late-Life Adult Patients with Major Depression: An Optimized Voxel-Based Morphometry Study - Corrected Proof

2009-11-09

Background: Previous structural imaging studies found evidence of brain morphometric changes in major depression (MD) patients, but they rarely excluded compounding effects of some important factors, such as medication and brain degeneration. This study sought to explore the brain morphometric changes of first-episode, drug-naïve, non–late-life adult MD patients with optimized voxel-based morphometry (VBM) method.Methods: Twenty-three first-episode, drug-naïve, non–late-life adult depressed patients and 23 healthy control subjects were enrolled in this study. Subjects underwent high-resolution magnetic resonance imaging, and optimized VBM was performed to analyze the morphometric data. A partial correlation model was used to analyze associations of morphometric changes with Hamilton Depression Rating Scale scores and illness duration.Results: Depressed patients showed significant gray matter volume reduction in the bilateral limbic system, especially in hippocampus. These changes did not significantly correlate with symptom severity or illness duration.Conclusions: Our findings provided new evidence of gray matter deficits in first-episode, drug-naïve, non–late-life adult MD patients. It supported that the reduction of hippocampal volume is a trait for MD patients and further highlighted the important role of the limbic system, particularly hippocampus in the pathophysiology of MD.

Safety and Efficacy of Repeated-Dose Intravenous Ketamine for Treatment-Resistant Depression - Corrected Proof

2009-11-09

Background: A single subanesthetic (intravenous) IV dose of ketamine might have rapid but transient antidepressant effects in patients with treatment-resistant depression (TRD). Here we tested the tolerability, safety, and efficacy of repeated-dose open-label IV ketamine (six infusions over 12 days) in 10 medication-free symptomatic patients with TRD who had previously shown a meaningful antidepressant response to a single dose.Methods: On day 1, patients received a 40-min IV infusion of ketamine (.5 mg/kg) in an inpatient setting with continuous vital-sign monitoring. Psychotomimetic effects and adverse events were recorded repeatedly. The primary efficacy measure was change from baseline in the Montgomery-Åsberg Depression Rating Scale (MADRS) score. If patients showed a ≥50% reduction in MADRS scores on day 2, they received five additional infusions on an outpatient basis (days 3, 5, 8, 10, and 12). Follow-up visits were conducted twice-weekly for ≥4 weeks or until relapse.Results: Ketamine elicited minimal positive psychotic symptoms. Three patients experienced significant but transient dissociative symptoms. Side effects during and after each ketamine infusion were generally mild. The response criterion was met by nine patients after the first infusion as well as after the sixth infusion. The mean (SD) reduction in MADRS scores after the sixth infusion was 85% (12%). Postketamine, eight of nine patients relapsed, on average, 19 days after the sixth infusion (range 6 days–45 days). One patient remained antidepressant-free with minimal depressive symptoms for >3 months.Conclusions: These pilot findings suggest feasibility of repeated-dose IV ketamine for the acute treatment of TRD.

Metabotropic Glutamate Receptor 5 Activity in the Nucleus Accumbens Is Required for the Maintenance of Ethanol Self-Administration in a Rat Genetic Model of High Alcohol Intake - Corrected Proof

2009-11-09

Background: Systemic modulation of Group I and II metabotropic glutamate receptors (mGluRs) regulate ethanol self-administration in a variety of animal models. Although these receptors are expressed in reward-related brain regions, the anatomical specificity of their functional involvement in ethanol self-administration remains to be characterized. This study sought to evaluate the functional role of Group I (mGluR5) and Group II (mGluR2/3) in mesocorticolimbic brain regions in ethanol self-administration.Methods: Alcohol-preferring (P) rats, a genetic model of high alcohol drinking, were trained to self-administer ethanol (15% v/v) versus water in operant conditioning chambers. Effects of brain site-specific infusion of the mGluR5 antagonist 2-methyl-6-(phenylethynyl)pyridine hydrochloride (MPEP) and the mGluR2/3 agonist were then assessed on the maintenance of self-administration.Results: Microinjection of the mGluR5 antagonist MPEP in the nucleus accumbens reduced ethanol self-administration at a dose that did not alter locomotor activity. By contrast, infusion of the mGluR2/3 agonist LY379268 in the nucleus accumbens reduced self-administration and produced nonspecific reductions in locomotor activity. The mGluR5 involvement showed anatomical specificity as evidenced by lack of effect of MPEP infusion in the dorsomedial caudate or medial prefrontal cortex on ethanol self-administration. To determine reinforcer specificity, P-rats were trained to self-administer sucrose (.4% w/v) versus water, and effects of intra-accumbens MPEP were tested. The MPEP did not alter sucrose self-administration or motor behavior.Conclusions: These results suggest that mGluR5 activity specifically in the nucleus accumbens is required for the maintenance of ethanol self-administration in individuals with genetic risk for high alcohol consumption.

Intranasal Oxytocin Improves Emotion Recognition for Youth with Autism Spectrum Disorders - Corrected Proof

2009-11-09

Background: A diagnostic hallmark of autism spectrum disorders is a qualitative impairment in social communication and interaction. Deficits in the ability to recognize the emotions of others are believed to contribute to this. There is currently no effective treatment for these problems.Methods: In a double-blind, randomized, placebo-controlled, crossover design, we administered oxytocin nasal spray (18 or 24 IU) or a placebo to 16 male youth aged 12 to 19 who were diagnosed with Autistic or Asperger's Disorder. Participants then completed the Reading the Mind in the Eyes Task, a widely used and reliable test of emotion recognition.Results: In comparison with placebo, oxytocin administration improved performance on the Reading the Mind in the Eyes Task. This effect was also shown when analysis was restricted to the younger participants aged 12 to 15 who received the lower dose.Conclusions: This study provides the first evidence that oxytocin nasal spray improves emotion recognition in young people diagnosed with autism spectrum disorders. Findings suggest the potential of earlier intervention and further evaluation of oxytocin nasal spray as a treatment to improve social communication and interaction in young people with autism spectrum disorders.

Antipsychotic Dose Equivalents and Dose-Years: A Standardized Method for Comparing Exposure to Different Drugs - Corrected Proof

Nancy C. Andreasen, Marcus Pressler, Peg Nopoulos, Del Miller, Beng-Choon Ho — 2009-11-09

Background: A standardized quantitative method for comparing dosages of different drugs is a useful tool for designing clinical trials and for examining the effects of long-term medication side effects such as tardive dyskinesia. Such a method requires establishing dose equivalents. An expert consensus group has published charts of equivalent doses for various antipsychotic medications for first- and second-generation medications. These charts were used in this study.Methods: Regression was used to compare each drug in the experts' charts to chlorpromazine and haloperidol and to create formulas for each relationship. The formulas were solved for chlorpromazine 100 mg and haloperidol 2 mg to derive new chlorpromazine and haloperidol equivalents. The formulas were incorporated into our definition of dose-years such that 100 mg/day of chlorpromazine equivalent or 2 mg/day of haloperidol equivalent taken for 1 year is equal to one dose-year.Results: All comparisons to chlorpromazine and haloperidol were highly linear with R2 values greater than .9. A power transformation further improved linearity.Conclusions: By deriving a unique formula that converts doses to chlorpromazine or haloperidol equivalents, we can compare otherwise dissimilar drugs. These equivalents can be multiplied by the time an individual has been on a given dose to derive a cumulative value measured in dose-years in the form of (chlorpromazine equivalent in mg) × (time on dose measured in years). After each dose has been converted to dose-years, the results can be summed to provide a cumulative quantitative measure of lifetime exposure.

Cortical Binding of Pittsburgh Compound B, an Endophenotype for Genetic Studies of Alzheimer's Disease - Corrected Proof

2009-11-06

Background: To date, all known Alzheimer's disease genes influence amyloid beta (Aβ). Imaging of Aβ deposition in the human brain using Pittsburgh Compound B (PIB) offers the possibility of using cortical PIB binding as a quantitative endophenotype for genetic studies of late-onset Alzheimer's disease (LOAD).Methods: Heritability of Aβ deposition was determined using 82 elderly siblings from 35 families. Correlation with other Aβ related traits was determined using an unrelated sample of 112 individuals. For both samples, apolipoprotein E (APOE) ε4 was genotyped and positron emission tomography imaging was performed using the PIB ligand. Mean cortical binding potential (MCBP) was computed from several regions of interest.Results: MCBP has a high heritability (.61, p = .043). Furthermore, 74% of the heritable component cannot be explained by APOE ε4 genotype. The unrelated sample reveals that a third of the variance of MCBP cannot be predicted by other biological traits, including cerebrospinal fluid (CSF) amyloid beta 42 (Aβ42) levels.Conclusions: These findings demonstrate that MCBP is a genetic trait and that other more easily measured Aβ related traits such as CSF Aβ42 do not fully explain the variance in MCBP. Thus, MCBP is a useful trait for large-scale genetic studies of LOAD.

Synaptic Adaptations of CA1 Pyramidal Neurons Induced by a Highly Effective Combinational Antidepressant Therapy - Corrected Proof

2009-11-06

Background: Antidepressants (AD) need to be chronically administered (weeks to months) to provide beneficial effects. Evidence suggests that combined administration of inhibitors of monoamine reuptake and phosphodiesterase type 4 allows a highly effective therapeutic action. Also, this coadministration more rapidly boosts the cyclic adenosine monophosphate (cAMP) pathway, which is normally activated during chronic treatment of single compounds. Little is known, however, about how this augmentation therapy affects the core mechanism of glutamatergic plasticity. We therefore investigated how in vivo combinational subchronic rolipram and imipramine (scRI) treatment affects depressive behavior, cAMP-dependent transcription, and glutamatergic transmission in the hippocampus, a region critically implicated in depression.Methods: Antidepressant properties of scRI were investigated through the forced swim test. Changes in cAMP-dependent transcription and synaptic transmission of CA1 pyramidal cells were explored with green fluorescent protein, enzyme-linked immunosorbent assay, electrophysiology recordings, and Golgi-Cox staining.Results: We demonstrate that scRI displays robust antidepressant properties compared with single-drug treatments and increases hippocampal c-Fos expression and brain-derived neurotrophic factor protein levels. These effects are accompanied by a specific increase in alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and N-methyl-D-aspartate receptors in already existing synapses. Finally, both acute and subchronic treatments led to enhancement of long-term potentiation but differently affected spine density and morphology, with scRI administration specifically resulting in a large increase in stubby spines.Conclusions: We conclude that scRI is highly effective in providing antidepressive effects, including the hippocampal transcriptional alterations normally observed with longer single-drug treatments. Furthermore, we identified scRI-induced modifications in glutamatergic transmission that probably underlie the beneficial action of this combinational therapy.

Fasting Glucose, Diagnosis of Type 2 Diabetes, and Depression: The Vietnam Experience Study - Corrected Proof

2009-11-06

Background: Recent findings suggest that both low and very high fasting blood glucose concentrations may be linked with depression, though whether type 2 diabetes is associated with depression may depend on awareness of the diagnosis. We explored the association between fasting glucose and type 2 diabetes (undiagnosed and diagnosed) and depression in middle-aged men.Methods: Participants were 4293 US veterans who underwent an examination during which fasting blood glucose was measured, major depression diagnosed using DSM-III criteria, and depressive symptoms assessed with Minnesota Multiphasic Personality Inventory (MMPI) clinical scale for depression.Results: Compared with those with normal fasting glucose, men with undiagnosed type 2 diabetes had nearly double the odds of major depression, odds ratio (95% confidence interval) 1.80 (1.01, 3.22), and men with diagnosed diabetes had triple the odds of major depression, 3.82 (1.68, 8.70), after adjustment for confounding variables. Men with undiagnosed or diagnosed diabetes had higher MMPI depression scores. There was no curvilinear association between fasting glucose and depression (p > .45).Conclusions: These findings do not support a U-shaped association between fasting glucose and depression. They suggest that the positive association between type 2 diabetes and depression extends beyond those who are aware they have the disease.

Catechol-O-Methyltransferase Valine158Methionine Genotype and Resting Regional Cerebral Blood Flow in Medication-Free Patients with Schizophrenia - Corrected Proof

2009-11-06

Background: A valine158methionine (val158met) polymorphism in catechol-O-methyltransferase (COMT) modulates cortical dopaminergic catabolism and has been associated with schizophrenia. Consistent with schizophrenia itself, during cognitive tasks, the risk (val) allele predicts less efficient prefrontal cortex (PFC) physiology and worse performance, while during aversive stimuli viewing, this allele predicts less limbic activation. Task-independent effects of this polymorphism in schizophrenia have not yet been characterized.Methods: Twenty-five medication-free patients (28 ± 6 years; 19 male patients) and 47 healthy individuals (29 ± 8 years; 33 male individuals) were genotyped for the COMT val158met polymorphism and underwent two 60-second radiolabeled water ([15O]H2O) regional cerebral blood flow (rCBF) positron emission tomography scans (10 mCi/scan) during rest. Data were analyzed with a random-effects general linear model using COMT genotype as a covariate.Results: In patients, but not healthy individuals, val (risk) allele load predicted less regional cerebral blood flow in the right dorsolateral PFC, right superior temporal gyrus, and left precuneus, but greater rCBF in the amygdala and parahippocampal gyrus.Conclusions: In schizophrenia, brain structures important for executive and affective processing show activity that is differentially predicted by COMT allelic variation in an opposing manner even at rest, providing evidence for the salience of prefrontal dopaminergic tone in task-independent, basal-level neural activity.

Cortical-Striatal Integration of Cocaine History and Prefrontal Dysfunction in Animal Modeling of Dual Diagnosis - Corrected Proof

2009-11-02

Background: High rates of substance disorders in schizophrenia and other mental illnesses may reflect biological vulnerabilities to the addiction process. Interactions between addictive drug effects and mental illness involving circuits that generate motivated behavior may underpin this vulnerability.Methods: We examined separate and combined effects of neonatal ventral hippocampal lesions (NVHLs)—a neurodevelopmental model of schizophrenia (vs. SHAM-operated control animals)—and a behaviorally sensitizing cocaine history (15 mg/kg/day × 5 days vs. saline injections) on acute cocaine-induced neural activation signaled by c-Fos expression. Stereological assessment of activation densities spanned six ventral to dorsal cortical-striatal compartments.Results: Cortically, NVHLs showed hypoactivation and decreased volume of the ventral medial prefrontal cortex. In contrast, cocaine history was only expressed subcortically and as a hyperactivating effect in the dorsal striatum where significant NVHL-induced hyperactivation also emerged. Across all subjects and brain regions, only dorsal striatal activation was correlated with differences in sensitized locomotion. However, this activation was tightly correlated to a simple multiplicative function of ventral medial prefrontal hypoactivation and cocaine history-related increases in striatal activation.Conclusions: These findings suggest drug history and developmental temporal limbic abnormalities associated with prefrontal dysfunction produce compounding effects within cortical-striatal circuits as mechanistic basis for dual diagnosis.

Copy Number Variation in Schizophrenia in the Japanese Population - Corrected Proof

2009-11-02

Background: Copy number variants (CNVs) have been shown to increase the risk to develop schizophrenia. The best supported findings are at 1q21.1, 15q11.2, 15q13.3, and 22q11.2 and deletions at the gene neurexin 1 (NRXN1).Methods: In this study, we used Affymetrix 5.0 arrays to investigate the role of rare CNVs in 575 patients with schizophrenia and 564 control subjects from Japan.Results: There was a nonsignificant trend for excess of rare CNVs in schizophrenia (p = .087); however, we did not confirm the previously implicated association for very large CNVs (>500 kilobase [kb]) in this population. We provide support for three previous findings in schizophrenia, as we identified one deletion in a case at 1q21.1, one deletion within NRXN1, and four duplications in cases and one in a control subject at 16p13.1, a locus first implicated in autism and later in schizophrenia.Conclusions: In this population, we support some of the previous findings in schizophrenia but could not find an increased burden of very large (>500 kb) CNVs, which was proposed recently. However, we provide support for the role of CNVs at 16p13.1, 1q21.1, and NRXN1.

Baseline Brain Perfusion and the Serotonin Transporter Promoter Polymorphism - Corrected Proof

2009-11-02

Background: The serotonin transporter length repeat polymorphism (5-HTTLPR) in the promoter region of the serotonin transporter gene (SLC6A4) has been associated in healthy subjects with changes in basal perfusion levels in the limbic system and ventral prefrontal areas, regions involved in the pathophysiology of depression and anxiety, suggesting the existence of a neurobiological trait predisposing to these disorders. We reassess the findings of an increased baseline perfusion in the amygdala and ventral prefrontal areas in healthy carriers of the risk genotype in a much larger sample than in previous studies.Methods: A cohort of 183 healthy European individuals underwent perfusion imaging with continuous arterial spin-labeling (CASL) while resting quietly in the scanner for 8 minutes. Participants were genotyped to assess the occurrence of the short allele and the Lg and La variants of the long repeat.Results: No association between the 5-HTTLPR polymorphism and baseline brain perfusion was detected in the regions of interest or elsewhere in the brain. In the amygdala, variability in baseline perfusion was explained in large part by global cerebral flow levels (between 50% and 55%), in minor part by sex (between 4% and 5%), but not by genotype (less than .5%). Power analyses showed that the study was of sufficient size to be informative.Conclusions: The findings did not confirm the existence of a biological marker of the effect of 5-HTTLPR polymorphism in the amygdala or in the orbitofrontal cortex.

A Computational Model for Cerebral Cortical Dysfunction in Autism Spectrum Disorders - Corrected Proof

Shashaank Vattikuti, Carson C. Chow — 2009-11-02

Background: Perturbations to the microscopic level balance between synaptic excitation and inhibition and neuron organization in the cerebral cortex are suggested to underlie autism spectrum disorder (ASD) traits. The mechanism linking these perturbations to cognitive behaviors in ASD is unknown. This study strives to bridge this gap by generating clinically testable diagnostic and pharmacological predictions based on the effect of synaptic imbalance and neuron distribution on a computational local circuit model of the cerebral cortex.Methods: We use a computational microscopic model of the cerebral cortex that incorporates N-methyl-D-aspartate and gamma-aminobutyric acid synaptic kinetics. We employ the model circuit during model tasks similar to visually guided and gap oculomotor saccade tasks and interpret qualitative model predictions of saccade hypometria and dysmetria. We consider the effects of varying the excitatory to inhibitory synaptic balance, neuron density, and neuron clustering in this model.Results: An increase of synaptic excitation over synaptic inhibition results in increased hypometria and dysmetria. Similar effects by either reduced inhibition or increased excitation suggest that a variety of pharmacological compounds can be used for both screening and medical management. On the other hand, any change to the microscopic neuron anatomy that increases the effective maximum distance between excitatory neurons decreases hypometria but has no affect on dysmetria.Conclusions: Perturbations to a computational model of a local cerebral cortical circuit can account for saccade hypometria and dysmetria reported in ASD studies. This approach may provide a direct link between cerebral cortical function and ASD behaviors.

Site-Specific Antidepressant Effects of Repeated Subconvulsive Electrical Stimulation: Potential Role of Brain-Derived Neurotrophic Factor - Corrected Proof

Roman Gersner, Erika Toth, Moshe Isserles, Abraham Zangen — 2009-11-02

Background: Electroconvulsive therapy (ECT) is a very effective treatment for major depression. This method involves robust nonfocal stimulation of the brain and can normalize both neurochemical alterations and depressive behavior in animal models. We hypothesized that short stimulation sessions of specific reward-related brain sites might induce similar effects.Methods: In the present study we compared behavioral and neurochemical effects produced by ECT and by repeated stimulation of reward-related brain sites, in a widely used rat model for depressive behavior induced by chronic mild stress (CMS). Different groups of rats received 10 sessions of either electroconvulsive shocks or subconvulsive electrical stimulation (SCES) of specific brain sites with an implanted electrode. The SCES temporal parameters were similar to those used in transcranial magnetic stimulation studies in humans. A battery of behavioral tests and measurements of brain-derived neurotrophic factor (BDNF) levels were used to assess the effectiveness of these treatments relative to sham treatments.Results: Repeated SCES of either the nucleus accumbens (NAC) or the ventral but not the dorsal prelimbic cortex (PLC) reversed the main behavioral deficit and the reduction of BDNF levels in the hippocampus that were induced by CMS. The ECT was more effective because it also normalized a behavioral deficit associated with anxiety but produced a learning and memory impairment.Conclusions: This study implicates the ventral PLC and the NAC in the pathophysiology of depressive behavior and suggests that local intermittent SCES can induce an antidepressant effect similar to that of ECT, without the cognitive impairment caused by the convulsive treatment.

Aversive Imagery in Posttraumatic Stress Disorder: Trauma Recurrence, Comorbidity, and Physiological Reactivity - Corrected Proof

2009-10-30

Background: Posttraumatic stress disorder (PTSD) is characterized as a disorder of exaggerated defensive physiological arousal. The novel aim of the present research was to investigate within PTSD a potential dose-response relationship between past trauma recurrence and current comorbidity and intensity of physiological reactions to imagery of trauma and other aversive scenarios.Methods: A community sample of principal PTSD (n = 49; 22 single-trauma exposed, 27 multiple-trauma exposed) and control (n = 76; 46 never-trauma exposed, 30 trauma exposed) participants imagined threatening and neutral events while acoustic startle probes were presented and the eye-blink response (orbicularis occuli) was recorded. Changes in heart rate, skin conductance level, and facial expressivity were also indexed.Results: Overall, PTSD patients exceeded control participants in startle reflex, autonomic responding, and facial expressivity during idiographic trauma imagery and, though less pronounced, showed heightened reactivity to standard anger, panic, and physical danger imagery. Concerning subgroups, control participants with and without trauma exposure showed isomorphic patterns. Within PTSD, only the single-trauma patients evinced robust startle and autonomic responses, exceeding both control participants and multiple-trauma PTSD. Despite greater reported arousal, the multiple-trauma relative to single-trauma PTSD group showed blunted defensive reactivity associated with more chronic and severe PTSD, greater mood and anxiety disorder comorbidity, and more pervasive dimensional dysphoria (e.g., depression, trait anxiety).Conclusions: Whereas PTSD patients generally show marked physiological arousal during aversive imagery, concordant with self-reported distress, the most symptomatic patients with histories of severe, cumulative traumatization show discordant physiological hyporeactivity, perhaps attributable to sustained high stress and an egregious, persistent negative affectivity that ultimately compromises defensive responding.

Genomewide Association Study of Movement-Related Adverse Antipsychotic Effects - Corrected Proof

2009-10-30

Background: Understanding individual differences in the development of extrapyramidal side effects (EPS) as a response to antipsychotic therapy is essential to individualize treatment.Methods: We performed genomewide association studies to search for genetic susceptibility to EPS. Our sample consisted of 738 schizophrenia patients, genotyped for 492K single nucleotide polymorphisms (SNPs). We studied three quantitative measures of antipsychotic adverse drug reactions—the Simpson-Angus Scale (SAS) for Parkinsonism, the Barnes Akathisia Rating Scale, and the Abnormal Involuntary Movement Scale (AIMS)—as well as a clinical diagnosis of probable tardive dyskinesia.Results: Two SNPs for SAS, rs17022444 and rs2126709 with p = 1.2 × 10−10 and p = 3.8 × 10−7, respectively, and one for AIMS, rs7669317 with p = 7.7 × 10−8, reached genomewide significance (Q value < .1). rs17022444 and rs7669317 were located in intergenic regions and rs2126709 was located in ZNF202 on 11q24. Fourteen additional signals were potentially interesting (Q value < .5). The ZNF202 is a transcriptional repressor controlling, among other genes, PLP1, which is the major protein in myelin. Mutations in PLP1 cause Pelizaeus-Merzbacher disease, which has Parkinsonism as an occurring symptom. Altered mRNA expression of PLP1 is associated with schizophrenia.Conclusions: Although our findings require replication and validation, this study demonstrates the potential of genomewide association studies to discover genes and pathways that mediate adverse effects of antipsychotics.

The ANKK1 Gene Associated with Addictions Is Expressed in Astroglial Cells and Upregulated by Apomorphine - Corrected Proof

2009-10-26

Background: TaqIA, the most widely analyzed genetic polymorphism in addictions, has traditionally been considered a gene marker for association with D2 dopamine receptor gene (DRD2). TaqIA is located in the coding region of the ANKK1 gene that overlaps DRD2 and encodes a predicted kinase ANKK1. The ANKK1 protein nonetheless had yet to be identified. This study examined the ANKK1 expression pattern as a first step to uncover the biological bases of TaqIA-associated phenotypes.Methods: Northern blot and quantitative reverse-transcriptase polymerase chain reaction analyses were performed to analyze the ANKK1 mRNA. To study ANKK1 protein expression, we developed two polyclonal antibodies to a synthetic peptides contained in the putative Ser/Thr kinase domain.Results: We demonstrate that ANKK1 mRNA and protein were expressed in the adult central nervous system (CNS) in human and rodents, exclusively in astrocytes. Ankk1 mRNA level in mouse astrocyte cultures was upregulated by apomorphine, suggesting a potential relationship with the dopaminergic system. Developmental studies in mice showed that ANKK1 protein was ubiquitously located in radial glia in the CNS, with an mRNA expression pick around embryonic Day 15. This time expression pattern coincided with that of the Drd2 mRNA. On induction of differentiation by retinoic acid, a sequential expression was found in human neuroblastoma, where ANKK1 was expressed first, followed by that of DRD2. An opposite time expression pattern was found in rat glioma.Conclusions: Spatial and temporal regulation of the expression of ANKK1 suggest an involvement of astroglial cells in TaqIA-related neuropsychiatric phenotypes both during development and adult life.

Comment on “Decreased Neurokinin-1 (Substance P) Receptor Binding in Patients with Panic Disorder: Positron Emission Tomographic Study With [18F]SPA-RQ” - Corrected Proof

2009-10-26

In a recent and interesting study, Fujimura et al. () reported decreased resting state neurokinin-1 (NK1) (substance P) receptor binding in patients with panic disorder compared with healthy subjects using positron emission tomography (PET) with [18F]SPA-RQ. Fujimura et al. also attempted to measure in vivo substance P release as a result of an anxiety challenge using doxapram, which elicited panic attacks in 6 of 7 patients and in 2 of 10 healthy subjects. However, doxapram challenge caused no significant change of [18F]SPA-RQ binding. We recently reported () that anxiety provocation in patients with specific phobia is associated with a decreased NK1 receptor binding in the right amygdala using [11C]GR205171 as a PET tracer, indicating a reduced availability of NK1-receptors, possibly reflecting an endogenous release of substance P.

Identification of Novel Candidate Genes for Treatment Response to Risperidone and Susceptibility for Schizophrenia: Integrated Analysis Among Pharmacogenomics, Mouse Expression, and Genetic Case-Control Association Approaches - Corrected Proof

2009-10-23

Background: Pharmacogenomic approaches based on genomewide sets of single nucleotide polymorphisms (SNPs) are now feasible and offer the potential to uncover variants that influence drug response.Methods: To detect potential predictor gene variants for risperidone response in schizophrenic subjects, we performed a convergent analysis based on 1) a genomewide (100K SNP) SNP pharmacogenetic study of risperidone response and 2) a global transcriptome study of genes with mRNA levels influenced by risperidone exposure in mouse prefrontal cortex.Results: Fourteen genes were highlighted as of potential relevance to risperidone activity in both studies: ATP2B2, HS3ST2, UNC5C, BAG3, PDE7B, PAICS, PTGFRN, NR3C2, ZBTB20, ST6GAL2, PIP5K1B, EPHA6, KCNH5, and AJAP1. The SNPs related to these genes that were associated in the pharmacogenetic study were further assessed for evidence for association with schizophrenia in up to three case-control series comprising 1564 cases and 3862 controls in total (Japanese [JPN] 1st and 2nd samples and UK sample). Of 14 SNPs tested, one (rs9389370) in PDE7B showed significant evidence for association with schizophrenia in a discovery sample (pallele = .026 in JPN_1st, two-tailed). This finding replicated in a joint analysis of two independent case-control samples (pJPN_2nd+UK = .008, one-tailed, uncorrected) and in all combined data sets (pall = .0014, two-tailed, uncorrected and pall = .018, two-tailed, Bonferroni correction).Conclusions: We identified novel candidate genes for treatment response to risperidone and provide evidence that one of these additionally may confer susceptibility to schizophrenia. Specifically, PDE7B is an attractive candidate gene, although evidence from integrated methodology, including pharmacogenomics, pharmacotranscriptomic, and case-control association approaches.

One Hormonal System for Love and Envy: A Reply to Tops - Corrected Proof

Simone G. Shamay-Tsoory — 2009-10-23

We appreciate the commentary offered by Tops (). Interestingly, the alternative interpretation offered by Tops follows many earlier commentators suggesting that because the oxytocinergic system is engaged mainly in positive prosocial behavior, it must never be involved in negative social behaviors.

Oxytocin: Envy or Engagement in Others? - Corrected Proof

Mattie Tops — 2009-10-23

Shamay-Tsoory et al. () reported that intranasal oxytocin administration to healthy participants increased ratings of negative interpersonal emotions. In their double-blind, placebo-controlled, within-subject study, 56 participants played a game of chance with another (fake) participant who either won more money (relative gain; envy manipulation), lost more money (relative loss; gloating manipulation), or won/lost equal amounts of money (equal gain). In comparison with the placebo, oxytocin increased the envy ratings in the relative loss conditions and increased ratings of gloating during relative gain conditions. The results seem to suggest that oxytocin facilitates negative social emotions, such as envy and gloating, and thus contrast with the prevailing belief that the oxytocinergic system is specifically involved in positive prosocial behaviors. However, although the results of Shamay-Tsoory et al. are interesting and provocative, a closer look at their results suggests an alternative interpretation. And even though the alternative interpretation is more in line with prevailing beliefs about oxytocin function, it would nevertheless be very relevant and consequential to studies of oxytocin, empathy, and game playing and informative about mechanisms of psychopathological disorders.

Uncoupling the D1-N-Methyl-D-Aspartate (NMDA) Receptor Complex Promotes NMDA-Dependent Long-Term Potentiation and Working Memory - Corrected Proof

2009-10-21

Background: Although dopamine D1 receptors are involved in working memory, how D1 receptors contribute to this process remains unclear. Numerous studies have shown that D1 receptors have extensive functional interaction with N-methyl-D-aspartate (NMDA) receptor. Our group previously demonstrated that D1 receptors were able to regulate NMDA receptor functions through direct protein–protein interactions involving the carboxyl terminals of D1 receptors and NMDA receptor NR1a and NR2A subunits respectively. In this study, we explored the effects of the D1–NR1 interaction on NMDA receptor-dependent long-term potentiation (LTP) and working memory by using the TAT-conjugated interfering peptide (TAT-D1-t2).Methods: Miniature excitatory postsynaptic currents are recorded in rat hippocampal primary cultures. Coimmunoprecipitation and calcium/calmodulin-dependent protein kinase II (CaMKII) activity are measured in hippocampal slices and hippocampal neurons under the specified experimental conditions, respectively. Working memory was assessed using a delayed match-to-place protocol in the Morris Water Maze following administration of the TAT-D1-t2 peptide.Results: Electrophysiology experiments showed that activation of D1 receptor upregulates NMDA receptor-mediated LTP in a CaMKII-dependent manner. Furthermore, D1 receptor agonist stimulation promotes the NR1-CaMKII coupling and enhances the CaMKII activity; and the D1 receptor-mediated effects can be blocked by the application of the TAT-D1-t2 peptide. Interestingly, animals injected with TAT-D1-t2 peptide exhibited significantly impaired working memory.Conclusions: Our study showed a critical role of NMDA-D1 direct protein–protein interaction in NMDA receptor–mediated LTP and working memory and implicated the involvement of CaMKII in this process.

Subgenual Prefrontal Cortex Activity Predicts Individual Differences in Hypothalamic-Pituitary-Adrenal Activity Across Different Contexts - Corrected Proof

2009-10-21

Background: Hypothalamic-pituitary-adrenal (HPA) system activation is adaptive in response to stress, and HPA dysregulation occurs in stress-related psychopathology. It is important to understand the mechanisms that modulate HPA output, yet few studies have addressed the neural circuitry associated with HPA regulation in primates and humans. Using high-resolution F-18-fluorodeoxyglucose positron emission tomography (FDG-PET) in rhesus monkeys, we assessed the relation between individual differences in brain activity and HPA function across multiple contexts that varied in stressfulness.Methods: Using a logical AND conjunctions analysis, we assessed cortisol and brain metabolic activity with FDG-PET in 35 adolescent rhesus monkeys exposed to two threat and two home-cage conditions. To test the robustness of our findings, we used similar methods in an archival data set. In this data set, brain metabolic activity and cortisol were assessed in 17 adolescent male rhesus monkeys that were exposed to three stress-related contexts.Results: Results from the two studies revealed that subgenual prefrontal cortex (PFC) metabolism (Brodmann's area 25/24) consistently predicted individual differences in plasma cortisol concentrations regardless of the context in which brain activity and cortisol were assessed.Conclusions: These findings suggest that activation in subgenual PFC may be related to HPA output across a variety of contexts (including familiar settings and novel or threatening situations). Individuals prone to elevated subgenual PFC activity across multiple contexts may be individuals who consistently show heightened cortisol and may be at risk for stress-related HPA dysregulation.

Remission of Major Depression Under Deep Brain Stimulation of the Lateral Habenula in a Therapy-Refractory Patient - Corrected Proof

2009-10-21

Depression is a severe, common psychiatric illness with limited therapeutic options. Only approximately two-thirds of patients treated respond to standard antidepressants. Even with electroconvulsive therapy (ECT), a significant fraction remains therapy refractory.

A Genomewide Association Study of Citalopram Response in Major Depressive Disorder - Corrected Proof

2009-10-21

Background: Antidepressant response is likely influenced by genetic constitution, but the actual genes involved have yet to be determined. We have carried out a genomewide association study to determine whether common DNA variation influences antidepressant response.Methods: Our sample is derived from Level 1 participants in the Sequenced Treatment Alternatives to Relieve Depression (STAR⁎D) study, all treated with citalopram. Association for the response phenotype included 883 responders and 608 nonresponders. For the remission phenotype, 743 subjects that achieved remission were compared with 608 nonresponders. We used a subset of single nucleotide polymorphisms (SNPs; n = 430,198) from the Affymetrix 500K and 5.0 Human SNP Arrays, and association analysis was carried out after correcting for population stratification.Results: We identified three SNPs associated with response with p values less than 1 × 10−5 near the UBE3C gene (rs6966038, p = 4.65 × 10−7), another 100 kb away from BMP7 (rs6127921, p = 3.45 × 10−6), and a third that is intronic in the RORA gene (rs809736, p = 8.19 × 10−6). These same SNPs were also associated with remission. Thirty-nine additional SNPs are of interest with p values ≤ .0001 for the response and remission phenotypes.Conclusions: Although the findings reported here do not meet a genomewide threshold for significance, the regions identified from this study provide targets for independent replication and novel pathways to investigate mechanisms of antidepressant response. This study was not placebo controlled, making it possible that we are also observing associations to nonspecific aspects of drug treatment of depression.

Cocaine-Specific Antibodies Blunt the Subjective Effects of Smoked Cocaine in Humans - Corrected Proof

2009-10-21

Background: Rates of relapse among cocaine-dependent patients are high, and new treatment approaches are needed. Clinical data demonstrate that a cocaine vaccine (TA-CD) produces selective anticocaine antibodies, yet the impact of these antibodies on cocaine's direct effects is unknown. The objective of this human laboratory study was to measure the relationship between antibody titers and the effects of smoked cocaine on ratings of intoxication, craving, and cardiovascular effects.Methods: Ten cocaine-dependent men not seeking drug treatment spent 2 nights per week for 13 weeks inpatient where the effects of cocaine (0 mg, 25 mg, 50 mg) were determined before vaccination and at weekly intervals thereafter. Two doses of TA-CD (82 μg, n = 4; 360 μg, n = 6) were administered at weeks 1, 3, 5, and 9.Results: Peak plasma antibody levels, which were highly variable, significantly predicted cocaine's effects. Those individuals in the upper half of antibody production had an immediate (within 4 minutes of cocaine smoking) and robust (55%–81%) reduction in ratings of good drug effect and cocaine quality, while those in the lower half showed only a nonsignificant attenuation (6%–26%). Self-reported cocaine use while participants were outpatient tended to decrease as a function of antibody titer (p < .12). By contrast, higher antibody levels predicted significantly greater cocaine-induced tachycardia.Conclusions: The TA-CD vaccine substantially decreased smoked cocaine's intoxicating effects in those generating sufficient antibody. These data support further testing of cocaine immunotherapy as a treatment for cocaine dependence.

New Findings on Extinction of Conditioned Fear Early in Development: Theoretical and Clinical Implications - Corrected Proof

Jee Hyun Kim, Rick Richardson — 2009-10-21

Research with adult animals suggests that extinction depends, at least partly, on new inhibitory learning that is specific to the context in which it is learned. However, several recent studies show that extinction processes are dissociated across development. The present article reviews research on the behavioral and neurobiological mechanisms underlying extinction in developing rats. To summarize, postweanling aged rats (i.e., 24-day-olds) display adult-like extinction in that they show renewal, reinstatement, spontaneous recovery, and compound summation of extinguished stimuli. However, preweanling aged rats (i.e., 17-day-olds) do not show any of those behavioral phenomena. Pharmacological studies also show that reducing N-methyl-D-aspartate, γ-aminobutryic acid, and opioid neurotransmission impairs extinction in 24-day-old rats, but extinction in P17 rats is only affected by the blocking of opioid neurotransmission. Lastly, extinction in 24-day-old rats involves the amygdala and the ventromedial prefrontal cortex (vmPFC), which are critical brain areas in the neural circuitry of extinction in adult rats. Interestingly, extinction in 17-day-old rats involves the amygdala but not the vmPFC. The existing models of extinction cannot account for these developmental differences. These findings showing that distinct processes mediate extinction at different stages of development may have significant clinical implications, which are discussed in this review.

Functional Magnetic Resonance Imaging of Inner Speech in Schizophrenia - Corrected Proof

2009-10-21

Background: Auditory verbal hallucinations in schizophrenia have been linked to defective monitoring of one's own verbal thoughts. Previous studies have shown that patients with auditory verbal hallucinations show attenuated activation of brain regions involved with auditory processing during the monitoring of inner speech. However, there are no functional magnetic resonance imaging studies explicitly comparing the perception of external speech with internal speech in the same patients with schizophrenia. The present study investigated the functional neuroanatomy of inner and external speech in both patients with schizophrenia and healthy control subjects.Methods: Fifteen patients with schizophrenia and 12 healthy control subjects were studied using functional magnetic resonance imaging while listening to sentences or imagining sentences.Results: Significant interactions between group (control subjects vs. patients) and task (listening vs. inner speech) were seen for the left superior temporal gyrus, as well as regions within the cingulate gyrus.Conclusions: Attenuated deactivation of the left superior temporal gyrus in schizophrenia patients during the processing of inner speech may reflect deficits in the forward models subserving self-monitoring.

Understanding the Relation Between Anorexia Nervosa and Bulimia Nervosa in a Swedish National Twin Sample - Corrected Proof

2009-10-15

Background: We present a bivariate twin analysis of anorexia nervosa and bulimia nervosa to determine the extent to which shared genetic and environmental factors contribute to liability to these disorders.Method: Focusing on females from the Swedish Twin study of Adults: Genes and Environment (n = 7000), we calculated heritability estimates for narrow and broad anorexia nervosa and bulimia nervosa and estimated their genetic correlation.Results: In the full model, the heritability estimate for narrow anorexia nervosa (AN) was (a2 = .57; 95% confidence interval [CI]: .00–.81) and for narrow bulimia nervosa (BN) (a2 = .62; 95% CI: .08–.70), with the remaining variance accounted for by unique environmental factors. Shared environmental factors estimates were (c2 = .00; 95% CI: .00–.67) for AN and (c2 = .00; 95% CI: .00–.40) for BN. Moderate additive genetic (.46) and unique environmental (.42) correlations between AN and BN were observed. Heritability estimates for broad AN were lower (a2 = .29; 95% CI: .04–.43) than for narrow AN, but estimates for broad BN were similar to narrow BN. The genetic correlation for broad AN and BN was .79, and the unique environmental correlation was .44.Conclusions: We highlight the contribution of additive genetic factors to both narrow and broad AN and BN and demonstrate a moderate overlap of both genetic and unique environmental factors that influence the two conditions. Common concurrent and sequential comorbidity of AN and BN can in part be accounted for by shared genetic and environmental influences on liability although independent factors also operative.

Childhood Maltreatment and Telomere Shortening: Preliminary Support for an Effect of Early Stress on Cellular Aging - Corrected Proof

2009-10-15

Background: Psychological stress and trauma are risk factors for several medical and psychiatric illnesses. Recent studies have implicated advanced cellular aging as a potential mechanism of this association. Telomeres, DNA repeats that cap the ends of chromosomes and promote stability, shorten progressively with each cell division; their length is a marker of biological aging. Based on previous evidence linking psychosocial stress to shorter telomere length, this study was designed to evaluate the effect of childhood adversity on telomere length.Methods: Thirty-one adults with no current or past major Axis I psychiatric disorder participated. Subjects reported on their history of childhood maltreatment and telomere length was measured from DNA extracted from frozen whole blood using quantitative polymerase chain reaction.Results: Participants reporting a history of childhood maltreatment had significantly shorter telomeres than those who did not report a history of maltreatment. This finding was not due to effects of age, sex, smoking, body mass index, or other demographic factors. Analysis of subscales showed that both physical neglect and emotional neglect were significantly linked to telomere length.Conclusions: These results extend previous reports linking shortened leukocyte telomere length and caregiver stress to more remote stressful experiences in childhood and suggest that childhood maltreatment could influence cellular aging.

Retinal Response to Light in Young Nonaffected Offspring at High Genetic Risk of Neuropsychiatric Brain Disorders - Corrected Proof

2009-10-15

Background: In neuropsychiatric brain disorders, such as schizophrenia (SZ) and bipolar disorder (BD), the biased effect of chronic drug therapy and the toxic effect of illness once installed constitute obstacles to the identification of valid biomarkers. Such biomarkers could lie at the level of retinal function where anomalies have already been reported in adults suffering from neuropsychiatric disorders. Here, we report a specific electroretinographic (ERG) anomaly in young nonaffected and nonmedicated offspring at high genetic risk (HR) of these disorders.Methods: Electroretinography was performed in 29 HR offspring having one parent affected by DSM-IV SZ or BD (mean age: 20.8 years, SD 4.4) and 29 healthy control subjects (mean age: 20.6 years, SD 4.2). The HRs' parents descended from multigenerational families affected by SZ or BD.Results: Rod ERG (b-wave amplitude at Vmax) in HRs was significantly lower than control subjects (p < .0001; effect size of −1.47), whereas the cone ERG Vmax showed no difference (p = .27). No effects of gender, age, and seasons of testing were observed. The anomaly in retinal response (rod Vmax b-wave amplitude) was observed independently of parents' diagnosis (SZ; p = .007, effect size of −1.09; BD: p < .0001, effect size of −1.88) and was present in both the younger and older HRs (effect size of −1.6 and −1.8, respectively).Conclusions: A rod retinal response anomaly before the age of the disease incidence may represent an early and specific biomarker of risk with meaning for further genetic and prevention research.

The Influence of GABRA2, Childhood Trauma, and Their Interaction on Alcohol, Heroin, and Cocaine Dependence - Corrected Proof

2009-10-15

Background: The GABRA2 gene has been implicated in addiction. Early life stress has been shown to alter GABRA2 expression in adult rodents. We hypothesized that childhood trauma, GABRA2 variation, and their interaction would influence addiction vulnerability.Methods: African-American men were recruited for this study: 577 patients with lifetime DSM-IV single and comorbid diagnoses of alcohol, cocaine, and heroin dependence, and 255 control subjects. The Childhood Trauma Questionnaire (CTQ) was administered. Ten GABRA2 haplotype-tagging single-nucleotide polymorphisms (SNPs) were genotyped.Results: We found that exposure to childhood trauma predicted substance dependence (p < .0001). Polysubstance dependence was associated with the highest CTQ scores (p < .0001). The African Americans had four common haplotypes (frequency: .11–.30) within the distal haplotype block: two that correspond to the Caucasian and Asian yin-yang haplotypes, and two not found in other ethnic groups. One of the unique haplotypes predicted heroin addiction, whereas the other haplotype was more common in control subjects and seemed to confer resilience to addiction after exposure to severe childhood trauma. The yin-yang haplotypes had no effects. Moreover, the intron 2 SNP rs11503014, not located in any haplotype block and potentially implicated in exon splicing, was independently associated with addiction, specifically heroin addiction (p < .005). Childhood trauma interacted with rs11503014 variation to influence addiction vulnerability, particularly to cocaine (p < .005).Conclusions: Our results suggest that at least in African-American men, childhood trauma, GABRA2 variation, and their interaction play a role in risk-resilience for substance dependence.

Streptococcal Upper Respiratory Tract Infections and Psychosocial Stress Predict Future Tic and Obsessive-Compulsive Symptom Severity in Children and Adolescents with Tourette Syndrome and Obsessive-Compulsive Disorder - Corrected Proof

2009-10-15

Background: One goal of this prospective longitudinal study was to identify new group A beta-hemolytic streptococcal infections (GABHS) in children and adolescents with Tourette syndrome (TS) and/or obsessive-compulsive disorder (OCD) compared with healthy control subjects. We then examined the power of GABHS infections and measures of psychosocial stress to predict future tic, obsessive-compulsive (OC), and depressive symptom severity.Methods: Consecutive ratings of tic, OC, and depressive symptom severity were obtained for 45 cases and 41 matched control subjects over a 2-year period. Clinical raters were blinded to the results of laboratory tests. Laboratory personnel were blinded to case or control status and clinical ratings. Structural equation modeling for unbalanced repeated measures was used to assess the sequence of new GABHS infections and psychosocial stress and their impact on future symptom severity.Results: Increases in tic and OC symptom severity did not occur after every new GABHS infection. However, the structural equation model found that these newly diagnosed infections were predictive of modest increases in future tic and OC symptom severity but did not predict future depressive symptom severity. In addition, the inclusion of new infections in the model greatly enhanced, by a factor of three, the power of psychosocial stress in predicting future tic and OC symptom severity.Conclusions: Our data suggest that a minority of children with TS and early-onset OCD were sensitive to antecedent GABHS infections. These infections also enhanced the predictive power of current psychosocial stress on future tic and OC symptom severity.

Amyloid Plaques Disrupt Resting State Default Mode Network Connectivity in Cognitively Normal Elderly - Corrected Proof

2009-10-15

Background: Important functional connections within the default mode network (DMN) are disrupted in Alzheimer's disease (AD), likely from amyloid-beta (Aβ) plaque-associated neuronal toxicity. Here, we sought to determine if pathological effects of Aβ amyloid plaques could be seen, even in the absence of a task, by examining functional connectivity in cognitively normal participants with and without preclinical amyloid deposition.Methods: Participants with Alzheimer's disease (AD) (n = 35) were compared with 68 cognitively normal participants who were further subdivided by positron emission tomography (PET) Pittsburgh Compound-B (PIB) imaging into those without evidence of brain amyloid (PIB−) and those with brain amyloid (PIB+) deposition.Results: Resting state functional magnetic resonance imaging (fMRI) demonstrated that, compared with the PIB− group, the PIB+ group differed significantly in functional connectivity of the precuneus to hippocampus, parahippocampus, anterior cingulate, dorsal cingulate, gyrus rectus, superior precuneus, and visual cortex. These differences were in the same regions and in the same direction as differences found in the AD group.Conclusions: Thus, before any manifestations of cognitive or behavioral changes, there were differences in resting state connectivity in cognitively normal subjects with brain amyloid deposition, suggesting that early manifestation of Aβ toxicity can be detected using resting state fMRI.

Functional and Dysfunctional Synaptic Plasticity in Prefrontal Cortex: Roles in Psychiatric Disorders - Corrected Proof

Yukiori Goto, Charles R. Yang, Satoru Otani — 2009-10-15

Prefrontal cortex (PFC) mediates an assortment of cognitive functions including working memory, behavioral flexibility, attention, and future planning. Unlike the hippocampus, where induction of synaptic plasticity in the network is well-documented in relation to long-term memory, cognitive functions mediated by the PFC have been thought to be independent of long-lasting neuronal adaptation of the network. Nonetheless, accumulating evidence suggests that prefrontal cortical neurons possess the cellular machinery of synaptic plasticity and exhibit lasting changes of neural activity associated with various cognitive processes. Moreover, deficits in the mechanisms of synaptic plasticity induction in the PFC might be involved in the pathophysiology of psychiatric and neurological disorders such as schizophrenia, drug addiction, mood disorders, and Alzheimer's disease.

Bilateral Epidural Prefrontal Cortical Stimulation for Treatment-Resistant Depression - Corrected Proof

2009-10-12

Background: Treatment-resistant depression presents a serious challenge to both patients and clinicians. The anterior and midlateral prefrontal cortices play complementary roles in integrating emotional and cognitive experiences and in modulating subcortical regions. Both regions offer a distinct opportunity for targeted antidepressant treatments. We chose to pilot the safety and therapeutic benefits of chronic and intermittent epidural prefrontal cortical stimulation (EpCS) in patients with treatment-resistant depression.Methods: We enrolled five adults with an average of 5.8 failed antidepressant treatments in their current depressive episode. All subjects underwent comprehensive clinical assessments, detailed neuropsychological testing, and presurgical magnetic resonance imaging. Four cortical stimulation paddle leads were stereotactically placed bilaterally over the anterior frontal poles and midlateral prefrontal cortex. We also acquired a postsurgical computed tomography scan and repeatedly assessed clinical outcomes over time of EpCS as an adjunctive treatment to constant medications.Results: All patients tolerated the therapy. At 7-month follow-up, the average improvement from preimplant baseline on the Hamilton Rating Scale for Depression and the Inventory of Depressive Symptoms—Self-Report were 54.9% (± 37.7) and 60.1% (± 34.1), respectively. Three implanted subjects reached remission. One patient's left hemisphere leads were explanted 12 weeks postsurgery because of a scalp infection.Conclusions: Bilateral EpCS over anterior and midlateral frontal cortex is a promising new technology for treatment-resistant depression. Future double-blind studies are warranted.

Psychological and Somatic Symptoms of Anxiety and Risk of Coronary Heart Disease: The Health and Social Support Prospective Cohort Study - Corrected Proof

2009-10-12

Background: Despite evidence showing anxiety to be a negative emotion that can be accompanied by various psychological and somatic complaints, previous studies have rarely considered these two components of anxiety separately in relation to coronary heart disease (CHD) events. This study aims to examine the extent to which the psychological and somatic components of anxiety are predictive of CHD.Methods: This is a prospective population-based cohort study of 24,128 participants (9830 men, 14,298 women) aged 20 to 54 years. Psychological and somatic symptoms were assessed at study baseline in 1998. Fatal and nonfatal CHD events during the following 7 years were documented from data on hospitalizations from the National Hospital Discharge Register and mortality records from the Statistics Finland Register.Results: In men, unadjusted hazard ratios for CHD per one unit increase in mean score were 1.50 (95% confidence interval [CI], 1.21–1.87) for somatic symptoms and 1.04 (95% CI, .85–1.29) for psychological symptoms. After serial adjustment for sociodemographic characteristics, biobehavioral risk factors, and clinically significant symptoms of depression, these associations were completely attenuated. In women, the corresponding unadjusted hazard ratios were 2.25 (95% CI, 1.66–3.06) and 1.55 (95% CI, 1.12–2.13), respectively. The corresponding fully adjusted hazard ratios were 1.47 (95% CI, 1.04–2.06) and 1.24 (95% CI, .91–1.70).Conclusions: Somatic symptoms of anxiety were robustly associated with an increased risk of CHD in women. This finding lends support to the physiological pathway for the association between psychological factors, anxiety in particular, and CHD.

Antidepressant-Like Effects of Medial Prefrontal Cortex Deep Brain Stimulation in Rats - Corrected Proof

2009-10-12

Background: Subcallosal cingulate gyrus (SCG) deep brain stimulation (DBS) is being investigated as a treatment for major depression. We report on the effects of ventromedial prefrontal cortex (vmPFC) DBS in rats, focusing on possible mechanisms involved in an antidepressant-like response in the forced swim test (FST).Methods: The outcome of vmPFC stimulation alone or combined with different types of lesions, including serotonin (5-HT) or norepineprhine (NE) depletion, was characterized in the FST. We also explored the effects of DBS on novelty-suppressed feeding, learned helplessness, and sucrose consumption in animals predisposed to helplessness.Results: Stimulation at parameters approximating those used in clinical practice induced a significant antidepressant-like response in the FST. Ventromedial PFC lesions or local muscimol injections did not lead to a similar outcome. However, animals treated with vmPFC ibotenic acid lesions still responded to DBS, suggesting that the modulation of fiber near the electrodes could play a role in the antidepressant-like effects of stimulation. Also important was the integrity of the serotonergic system, as the effects of DBS in the FST were completely abolished in animals bearing 5-HT, but not NE, depleting lesions. In addition, vmPFC stimulation induced a sustained increase in hippocampal 5-HT levels. Preliminary work with other models showed that DBS was also able to influence specific aspects of depressive-like states in rodents, including anxiety and anhedonia, but not helplessness.Conclusions: Our study suggests that vmPFC DBS in rats may be useful to investigate mechanisms involved in the antidepressant effects of SCG DBS.

Meta-Analysis of 15 Genome-Wide Linkage Scans of Smoking Behavior - Corrected Proof

Shizhong Han, Joel Gelernter, Xingguang Luo, Bao-Zhu Yang — 2009-10-12

Background: A genetic contribution to smoking behavior is well-established. To identify loci that increase the risk for smoking behavior, many genome-wide linkage scans have been performed with various smoking behavior assessments. Numerous putative susceptibility loci have been identified, but only a few of these were replicated in independent studies.Methods: We used genome search meta-analysis (GSMA) to identify risk loci by pooling all available independent genome scan results on smoking behavior. Additionally, to minimize locus heterogeneity, subgroup analyses of the smoking behavior assessed by the Fagerstrom Test for Nicotine Dependence (FTND) and maximum number of cigarettes smoked in a 24-hour period (MaxCigs24) were carried out. Samples of European ancestry were also analyzed separately.Results: A total number of 15 genome scan results were available for analysis, including 3404 families with 10,253 subjects. Overall, the primary GSMA across all smoking behavior identified a genome-wide suggestive linkage in chromosome 17q24.3-q25.3 (pSR = .001). A secondary analysis of FTND in European-ancestry samples (625 families with 1878 subjects) detected a genome-wide suggestive linkage in 5q33.1–5q35.2 (pSR = .0076). Subgroup analysis of MaxCigs24 (966 families with 3273 subjects) identified a genome-wide significant linkage in 20q13.12-q13.32 (pSR = .00041, pOR = .048), where a strongly supported nicotine dependence candidate gene, CHRNA4, is located.Conclusions: The regions identified in the current study deserve close attention and will be helpful for candidate gene identification or target re-sequencing studies in the future.

Impaired Plasticity at Specific Subset of Striatal Synapses in the Ts65Dn Mouse Model of Down Syndrome - Corrected Proof

2009-10-09

Background: Trisomy 21 or Down syndrome (DS) is the most frequent genetic cause of mental retardation. There is limited insight into the biological basis for the cognitive and motor deficits in DS. Because the striatum plays a key role in the regulation and learning of voluntary movements and in cognitive processes, our study was aimed at investigating striatal synaptic transmission and plasticity in a well-accepted genetic model of DS.Methods: Electrophysiological recordings were performed in a corticostriatal slice preparation from trisomic (Ts65Dn) and wild-type mice. Synaptic properties and plasticity, long-term potentiation (LTP) and long-term depression (LTD), were investigated.Results: The basal electrophysiological properties of striatal principal spiny neurons and cholinergic interneurons were spared in the Ts65Dn mouse model of DS. Striatal principal spiny neurons from Ts65Dn mice maintained their ability to undergo LTP and LTD. Conversely, LTP was lost in striatal cholinergic interneurons of Ts65Dn mice. The loss of LTP in striatal cholinergic interneurons of Ts65Dn mice was accompanied by a severe impairment of endogenous cholinergic signaling within the striatum.Conclusions: The intrastriatal cholinergic system that was thought to be spared in DS is functionally altered in the Ts65Dn genetic model of DS. Altered cholinergic transmission might play a critical role in the pathophysiology of motor and cognitive deficits in DS, leading to an abnormal processing of neuronal inputs within the basal ganglia. Targeting striatal cholinergic transmission might represent a new therapeutic strategy in DS.