Biological Psychiatry - Articles in Press

Neurotrophic Tyrosine Kinase Polymorphism Impacts White Matter Connections in Patients with Major Depressive Disorder - Corrected Proof

2012-05-21

Background: Polymorphisms in the brain-derived neurotrophic factor (BDNF) gene and its receptor neurotrophic tyrosine kinase receptor type 2 (NTRK2) have been implicated in mood disorders. The aim of this study was to examine whether the NTRK2 and BDNF polymorphisms impact brain white matter connections in major depressive disorder and whether they may also have an interactive effect with environmental stress in the form of early life adversity. Methods: The study group comprised 45 depressed patients and 45 age- and gender-matched control subjects. High angular resolution diffusion images were obtained and analyzed using tract-based spatial statistics. Analysis of a single nucleotide polymorphism in the BDNF (rs6265/Valine66Methionine) and NTRK2 (rs11140714) genes was performed. Results: An interactive effect was found between NTRK2 and depression diagnosis maximally affecting the cingulum. Depressed patients homozygous for the A allele of NTRK2 showed significantly reduced fractional anisotropy compared with depressed patients with at least one copy of the G allele or control subjects with either the A/A or G carrier genotypes in the left and right corona radiata, left uncinate fasciculus, left inferior fronto-occipital fasciculus, left cerebral peduncle, posterior thalamic radiation, and middle cerebral peduncle. Significantly smaller gray matter volume was seen in frontal lobe regions in patients homozygous for the A allele. Conclusions: Polymorphisms in NTRK2 gene increase risk of architectural changes in several brain regions involved in emotional regulation.

Distinct Age-Dependent Effects of Methylphenidate on Developing and Adult Prefrontal Neurons - Corrected Proof

Kimberly R. Urban, Barry D. Waterhouse, Wen-Jun Gao — 2012-05-21

Background: Methylphenidate (MPH) has long been used to treat attention-deficit/hyperactivity disorder (ADHD); however, its cellular mechanisms of action and potential effects on prefrontal cortical circuitry are not well understood, particularly in the developing brain system. A clinically relevant dose range for rodents has been established in the adult animal; however, how this range will translate to juvenile animals has not been established. Methods: Juvenile (postnatal day [PD] 15) and adult (PD90) Sprague Dawley rats were treated with MPH or saline. Whole-cell patch clamp recording was used to examine the neuronal excitability and synaptic transmission in pyramidal neurons of prefrontal cortex. Recovery from MPH treatment was also examined at 1, 5, and 10 weeks following drug cessation. Results: A dose of 1 mg/kg intraperitoneal MPH, either single dose or chronic treatment (well within the accepted therapeutic range for adults), produced significant depressive effects on pyramidal neurons by increasing hyperpolarization-activated currents in juvenile rat prefrontal cortex, while exerting excitatory effects in adult rats. Minimum clinically-relevant doses (.03 to .3 mg/kg) also produced depressive effects in juvenile rats, in a linear dose-dependent manner. Function recovered within 1 week from chronic 1 mg/kg treatment, chronic treatment with 3 and 9 mg/kg resulted in depression of prefrontal neurons lasting 10 weeks and beyond. Conclusions: These results suggest that the juvenile prefrontal cortex is supersensitive to methylphenidate, and the accepted therapeutic range for adults is an overshoot. Juvenile treatment with MPH may result in long-lasting, potentially permanent, changes to excitatory neuron function in the prefrontal cortex of juvenile rats.

High Versus Low Level of Response to Alcohol: Evidence of Differential Reactivity to Emotional Stimuli - Corrected Proof

2012-05-18

Background: The low level of response (LR) or sensitivity to alcohol is genetically influenced and predicts heavy drinking and alcohol problems. Functional magnetic resonance imaging (fMRI) studies using cognitive tasks suggest that subjects with a low-LR process cognitive information differently after placebo and alcohol than those with a high LR, but no studies have evaluated whether similar LR group differences are seen during an emotional processing task. Methods: The fMRI data were gathered from 116 nonalcoholic subjects (60 women) after oral placebo or approximately .7 mL/kg of ethanol while performing a modified emotional faces processing task. These included 58 low- and high-LR pairs matched on demography and aspects of substance use. Results: Blood alcohol levels and task performance were similar across LR groups, but low-LR subjects consumed approximately .8 drinks more/occasion. Thirteen brain regions (mostly the middle and inferior frontal gyri, cingulate, and insula) showed significant LR group or LR × placebo/alcohol condition interactions for emotional (mostly happy) faces relative to non-face trials. Low-LR subjects generally showed decreasing blood-oxygen level-dependent response contrasts across placebo to alcohol, whereas high LR showed increasing contrasts from placebo to alcohol, even after controlling for drinking quantities and alcohol-related changes in cerebral blood flow. Conclusions: Thus, LR group fMRI differences are as prominent during an emotional face task as during cognitive paradigms. Low-LR individuals processed both types of information in a manner that might contribute to an impaired ability to recognize modest levels of alcohol intoxication in a range of life situations.

Alzheimer's Disease Genes and Cognition in the Nondemented General Population - Corrected Proof

2012-05-17

Background: Genome-wide association studies have established 11 genes for late-onset Alzheimer's disease (AD). We investigated whether these genes jointly affect cognition in a nondemented population and improve prediction of AD. Methods: In 5171 nondemented people (age 45–99 years) from the population-based Rotterdam Study, we genotyped APOE-ε4 and single nucleotide polymorphisms from the genes CLU, PICALM, BIN1, CR1, ABCA7, MS4A6A, MS4A4E, CD2AP, EPHA1, and CD33. We constructed a genetic risk score by adding the risk alleles per individual weighted by the reported effect sizes. All people underwent cognitive testing. With linear regression we investigated the relationship between the genetic risk score and cognition, with and without APOE. In a subcohort, with more than 10 years of follow-up, we assessed whether the risk score predicted AD. Results: The genetic risk score was primarily associated with memory (standardized difference [95% confidence interval] per SD increase in genetic risk score: −.05[−.07; −.02], p = 1.5 * 10−4). This association attenuated when APOE was excluded from the genetic risk score (−.03[−.05; .00], p = .047) and would not survive a multiple-testing correction. Similarly, we found that although the genetic risk score without APOE was associated with the development of AD (p = .010), it only marginally improved prediction of AD beyond age, sex, APOE (area under the curve: .8159 vs. .8148). Conclusions: In nondemented people, there is only a marginal joint effect of AD genes on memory independent from APOE. Moreover, although associated with AD, these genes jointly hardly improve prediction of AD.

Deletion of CREB-Regulated Transcription Coactivator 1 Induces Pathological Aggression, Depression-Related Behaviors, and Neuroplasticity Genes Dysregulation in Mice - Corrected Proof

2012-05-17

Background: Mood disorders are polygenic disorders in which the alteration of several susceptibility genes results in dysfunctional mood regulation. However, the molecular mechanisms underlying their transcriptional dysregulation are still unclear. The transcription factor cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) and the neurotrophin brain-derived neurotrophic factor (BDNF) have been implicated in rodent models of depression. We previously provided evidence that Bdnf expression critically rely on a potent CREB coactivator called CREB-regulated transcription coactivator 1 (CRTC1). Methods: To further evaluate the role of CRTC1 in the brain, we generated a knockout mouse line and analyzed its behavioral and molecular phenotype. Results: We found that mice lacking CRTC1 associate neurobehavioral endophenotypes related to mood disorders. Crtc1–/– mice exhibit impulsive aggressiveness, social withdrawal, and decreased sexual motivation, together with increased behavioral despair, anhedonia, and anxiety-related behavior in the novelty-induced hypophagia test. They also present psychomotor retardation as well as increased emotional response to stressful events. Crtc1–/– mice have a blunted response to the antidepressant fluoxetine in behavioral despair paradigms, whereas fluoxetine normalizes their aggressiveness and their behavioral response in the novelty-induced hypophagia test. Crtc1−/− mice strikingly show, in addition to a reduced dopamine and serotonin turnover in the prefrontal cortex, a concomitant decreased expression of several susceptibility genes involved in neuroplasticity, including Bdnf, its receptor TrkB, the nuclear receptors Nr4a1-3, and several other CREB-regulated genes. Conclusions: Collectively, these findings support a role for the CRTC1-CREB pathway in mood disorders etiology and behavioral response to antidepressants and identify CRTC1 as an essential coactivator of genes involved in mood regulation.

Reduced Dorsal Anterior Cingulate Cortical Activity During Emotional Regulation and Top-Down Attentional Control in Generalized Social Phobia, Generalized Anxiety Disorder, and Comorbid Generalized Social Phobia/Generalized Anxiety Disorder - Corrected Proof

2012-05-17

Background: Generalized social phobia (GSP) and generalized anxiety disorder (GAD) are both associated with emotion dysregulation. Research implicates dorsal anterior cingulate cortex in both explicit emotion regulation (EER) and top-down attentional control (TAC). Although studies have examined these processes in GSP or GAD, no work compares findings across the two disorders or examines functioning in cases comorbid for both disorders (GSP/GAD). Here we compare the neural correlates of EER and TAC in GSP, GAD, and GSP/GAD. Methods: Medication-free adults with GSP (EER n = 19; TAC n = 18), GAD (EER n = 17; TAC n = 17), GSP/GAD (EER n = 17; TAC n = 15), and no psychopathology (EER n = 18; TAC n = 18) participated. During EER, individuals alternatively viewed and upregulated and downregulated responses to emotional pictures. During TAC, they performed an emotional Stroop task. Results: For both tasks, significant group × condition interactions emerged in dorsal anterior cingulate cortex 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 groups differing from healthy adults but not from each other. Evidence of emotion-related disorder-specificity emerged in medial prefrontal cortex and amygdala. This disorder-specific responding varied as a function of emotion content but not emotion-regulatory demands. Conclusions: GSP and GAD both involve reduced capacity for engaging emotion-regulation brain networks, whether explicitly or via TAC. A reduced ability to recruit regions implicated in top-down attention might represent a general risk factor for anxiety disorders.

Understanding Interpersonal Function in Psychiatric Illness Through Multiplayer Economic Games - Corrected Proof

Brooks King-Casas, Pearl H. Chiu — 2012-05-14

Interpersonal factors play significant roles in the onset, maintenance, and remission of psychiatric conditions. In the current major diagnostic classification systems for psychiatric disorders, some conditions are defined by the presence of impairments in social interaction or maintaining interpersonal relationships; these include autism, social phobia, and the personality disorders. Other psychopathologies confer significant difficulties in the social domain, including major depression, posttraumatic stress disorder, and psychotic disorders. Still other mental health conditions, including substance abuse and eating disorders, seem to be exacerbated or triggered in part by the influence of social peers. For each of these and other psychiatric conditions, the extent and quality of social support is a strong determinant of outcome such that high social support predicts symptom improvement and remission. Despite the central role of interpersonal factors in psychiatric illness, the neurobiology of social impairments remains largely unexplored, in part due to difficulties eliciting and quantifying interpersonal processes in a parametric manner. Recent advances in functional neuroimaging, combined with multiplayer exchange games drawn from behavioral economics, and computational/quantitative approaches more generally, provide a fitting paradigm within which to study interpersonal function and dysfunction in psychiatric conditions. In this review, we outline the importance of interpersonal factors in psychiatric illness and discuss ways in which neuroeconomics provides a tractable framework within which to examine the neurobiology of social dysfunction.

Psilocybin Biases Facial Recognition, Goal-Directed Behavior, and Mood State Toward Positive Relative to Negative Emotions Through Different Serotonergic Subreceptors - Corrected Proof

2012-05-14

Background: Serotonin (5-HT) 1A and 2A receptors have been associated with dysfunctional emotional processing biases in mood disorders. These receptors further predominantly mediate the subjective and behavioral effects of psilocybin and might be important for its recently suggested antidepressive effects. However, the effect of psilocybin on emotional processing biases and the specific contribution of 5-HT2A receptors across different emotional domains is unknown. Methods: In a randomized, double-blind study, 17 healthy human subjects received on 4 separate days placebo, psilocybin (215 μg/kg), the preferential 5-HT2A antagonist ketanserin (50 mg), or psilocybin plus ketanserin. Mood states were assessed by self-report ratings, and behavioral and event-related potential measurements were used to quantify facial emotional recognition and goal-directed behavior toward emotional cues. Results: Psilocybin enhanced positive mood and attenuated recognition of negative facial expression. Furthermore, psilocybin increased goal-directed behavior toward positive compared with negative cues, facilitated positive but inhibited negative sequential emotional effects, and valence-dependently attenuated the P300 component. Ketanserin alone had no effects but blocked the psilocybin-induced mood enhancement and decreased recognition of negative facial expression. Conclusions: This study shows that psilocybin shifts the emotional bias across various psychological domains and that activation of 5-HT2A receptors is central in mood regulation and emotional face recognition in healthy subjects. These findings may not only have implications for the pathophysiology of dysfunctional emotional biases but may also provide a framework to delineate the mechanisms underlying psylocybin's putative antidepressant effects.

Using Attentional Bias Modification as a Cognitive Vaccine Against Depression - Corrected Proof

2012-05-14

Background: Negative attentional biases are thought to increase the risk of recurrence in depression, suggesting that reduction of such biases may be a plausible strategy in the secondary prevention of the illness. However, no previous study has tested whether reducing negative attentional bias causally affects risk factors for depressive recurrence. The current experimental medicine study reports the effects of a computerized attentional bias modification (ABM) procedure on intermediate measures of the risk of depressive recurrence (residual depressive symptoms and the cortisol awakening response) in patients with recurrent depression. Methods: Sixty-one patients with at least two previous episodes of depression who were currently in remission were randomized to receive either an active (positive) or placebo computer-based ABM regime. The ABM regime presented either pictures of faces or words. Residual depressive symptoms, measured using the Beck Depression Inventory and the cortisol awakening response were measured immediately before and after completion of the bias modification and then again after 4 weeks' follow-up. Results: Positive, face-based ABM reduced both measures of recurrence risk (Beck Depression Inventory and cortisol awakening response). This effect occurred during the month following completion of bias modification. Word-based modification did not influence the outcome measures. Conclusions: Positive face-based ABM was able to reduce intermediate measures of recurrence risk in previously depressed patients. These results suggest that ABM may provide a “cognitive vaccine” against depression and offer a useful strategy in the secondary prevention of the illness.

Neural Activations During Auditory Oddball Processing Discriminating Schizophrenia and Psychotic Bipolar Disorder - Corrected Proof

2012-05-10

Background: Reduced amplitude of the P300 event-related potential in auditory oddball tasks may characterize schizophrenia (SZ) but is also reported in bipolar disorder. Similarity of auditory processing abnormalities between these diagnoses is uncertain, given the frequent combination of both psychotic and nonpsychotic patients in bipolar samples; abnormalities may be restricted to psychosis. In addition, typically only latency and amplitude of brain responses at selected sensors and singular time points are used to characterize neural responses. Comprehensive quantification of brain activations involving both spatiotemporal and time-frequency analyses could better identify unique auditory oddball responses among patients with different psychotic disorders. Methods: Sixty SZ, 60 bipolar I with psychosis (BPP), and 60 healthy subjects (H) were compared on neural responses during an auditory oddball task using multisensor electroencephalography. Principal components analysis was used to reduce multisensor data before evaluating group differences on voltage and frequency of neural responses over time. Results: Linear discriminant analysis revealed five variables that best differentiated groups: 1) late beta activity to standard stimuli; 2) late beta/gamma activity to targets discriminated BPP from other groups; 3) midlatency theta/alpha activity to standards; 4) target-related voltage at the late N2 response discriminated both psychosis groups from H; and 5) target-related voltage during early N2 discriminated BPP from H. Conclusions: Although the P300 significantly differentiated psychotic groups from H, it did not uniquely discriminate groups beyond the above variables. No variable uniquely discriminated SZ, perhaps indicating utility of this task for studying psychosis-associated neurophysiology generally and BPP specifically.

Glucocorticoids Protect Against the Delayed Behavioral and Cellular Effects of Acute Stress on the Amygdala - Corrected Proof

Rajnish P. Rao, Shobha Anilkumar, Bruce S. McEwen, Sumantra Chattarji — 2012-05-10

Background: A single episode of acute immobilization stress has previously been shown to trigger a delayed onset of anxiety-like behavior and spinogenesis in the basolateral amygdala (BLA) of rats. Spurred on by a seemingly paradoxical observation in which even a modest increase in corticosterone (CORT), caused by a single vehicle injection before stress, could dampen the delayed effects of stress, we hypothesized a protective role for glucocorticoids against stress. Methods: We tested this hypothesis by analyzing how manipulations in CORT levels modulate delayed increase in anxiety-like behavior of rats on the elevated plus-maze 10 days after acute stress. We also investigated the cellular correlates of different levels of anxiety under different CORT conditions by quantifying spine density on Golgi-stained BLA principal neurons. Results: CORT in drinking water for 12 hours preceding acute stress prevented delayed increase in anxiety rather than exacerbating it. Conversely, vehicle injection failed to prevent the anxiogenic effect of stress in bilaterally adrenalectomized rats. However, when CORT was restored in adrenalectomized rats by injection, the delayed anxiogenic effect of stress was once again blocked. Finally, high and low anxiety states were accompanied by high and low levels of BLA spine density. Conclusions: Our findings suggest that the presence of elevated levels of CORT at the time of acute stress confers protection against the delayed enhancing effect of stress on BLA synaptic connectivity and anxiety-like behavior. These observations are consistent with clinical reports on the protective effects of glucocorticoids against the development of posttraumatic symptoms triggered by traumatic stress.

Replication Study and Meta-Analysis in European Samples Supports Association of the 3p21.1 Locus with Bipolar Disorder - Corrected Proof

2012-05-07

Background: Common genetic polymorphisms at chromosome 3p21.1, including rs2251219 in polybromo 1 (PBRM1), have been implicated in susceptibility to bipolar affective disorder (BP) through genome-wide association studies. Subsequent studies have suggested that this is also a risk locus for other psychiatric phenotypes, including major depression and schizophrenia. Methods: To replicate the association, we studied 2562 cases with BP and 25,439 control subjects collected from seven cohorts with either genome-wide association or individual genotyping of rs2251219 and tagging single nucleotide polymorphisms across the PBRM1 gene. Results from the different case-control groups were combined with the inverse variance weighting method. Results: In our dataset, rs2251219 was associated with BP (odds ratio [OR] = .89, p = .003), and meta-analysis of previously published data with our nonoverlapping new data confirmed genome-wide significant association (OR = .875, p = 2.68 × 10−9). Genotypic data from the SGENE-plus consortium were used to examine the association of the same variant with schizophrenia in an overall sample of 8794 cases and 25,457 control subjects, but this was not statistically significant (OR = .97, p = .21). Conclusions: There is strong evidence of association of rs2251219 with BP. However, our data do not support association of this marker with schizophrenia. Because the region of association has high linkage disequilibrium, forming a large haplotype block across many genes, it is not clear which gene is causally implicated in the disorder.

Potentiated Amygdala Response to Repeated Emotional Pictures in Borderline Personality Disorder - Corrected Proof

2012-05-07

Background: 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 functions abnormally in BPD. Methods: Event-related functional magnetic resonance imaging (MRI) was employed in three groups: unmedicated BPD (n = 33) and schizotypal personality disorder (n = 28) participants and healthy control subjects (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 and co-registered to their MRI scan. Amygdala responses were examined with a mixed-model multivariate analysis of variance. Results: 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 blood oxygen level-dependent response averaged across all pictures. Despite amygdala overactivation, BPD patients showed blunted 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. Conclusions: The increased amygdala response to the repeated emotional pictures observed in BPD was not observed in schizotypal 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 targeting emotion recognition.

Neuroeconomics of Attention-Deficit/Hyperactivity Disorder: Differential Influences of Medial, Dorsal, and Ventral Prefrontal Brain Networks on Suboptimal Decision Making? - Corrected Proof

Edmund J.S. Sonuga-Barke, Graeme Fairchild — 2012-05-07

Psychiatric neuroeconomics offers an alternative approach to understanding mental disorders by studying the way disorder-related neurobiological alterations constrain economic agency, as revealed through decisions about choices between future goods. In this article, we apply this perspective to understand suboptimal decision making in attention-deficit/hyperactivity disorder (ADHD) by integrating recent advances in the neuroscience of decision making and studies of the pathophysiology of ADHD. We identify three brain networks as candidates for further study and develop specific hypotheses about how these could be implicated in ADHD. First, we postulate that altered patterns of connectivity within a network linking medial prefrontal cortex and posterior cingulate cortex (i.e., the default mode network) disrupts ordering of utilities, prospection about desired future states, setting of future goals, and implementation of aims. Second, we hypothesize that deficits in dorsal frontostriatal networks, including the dorsolateral prefrontal cortex and dorsal striatum, produce executive dysfunction-mediated impairments in the ability to compare outcome options and make choices. Third, we propose that dopaminergic dysregulation in a ventral frontostriatal network encompassing the orbitofrontal cortex, ventral striatum, and amygdala disrupts processing of cues of future utility, evaluation of experienced outcomes (feedback), and learning of associations between cues and outcomes. Finally, we extend this perspective to consider three contemporary themes in ADHD research.

Reply to: Lithium and the Expanding Brain - Corrected Proof

2012-05-07

We thank Dr Regenold for his interest and comment on our recent article, in which we demonstrated that chronic lithium (Li) treatment increased both whole-brain volume and total cortical gray matter (GM) volume, relative to vehicle-treated controls, the latter effect being reversible upon drug withdrawal, confirmed postmortem (). Dr Regenold suggests the osmotic effects of Li () may provide a plausible explanation for the apparently transitory increases in cortical GM volume.

Predictive Pursuit Association with Deficits in Working Memory in Psychosis - Corrected Proof

2012-05-04

Background: Deficits in smooth pursuit eye movements are an established phenotype for schizophrenia (SZ) and are being investigated as a potential liability marker for bipolar disorder. Although the molecular determinants of this deficit are still unclear, research has verified deficits in predictive pursuit mechanisms in SZ. Because predictive pursuit might depend on the working memory system, we have hypothesized a relationship between the two in healthy control subjects (HC) and SZ and here examine whether it extends to psychotic bipolar disorder (BDP). Methods: Volunteers with SZ (n = 38), BDP (n = 31), and HC (n = 32) performed a novel eye movement task to assess predictive pursuit as well as a standard visuospatial measure of working memory. Results: Individuals with SZ and BDP both showed reduced predictive pursuit gain compared with HC (p < .05). Moreover, each patient group showed worse performance in visuospatial working memory compared with control subjects (p < .05). A strong correlation (r = .53, p = .007) was found between predictive pursuit gain and working memory in HC, a relationship that showed a trend correlation within the BDP group but not among SZ. Conclusions: Individuals with SZ and BDP showed similar deficits in predictive pursuit, suggesting that this alteration could be a characteristic trait of the psychosis domain. The correlation between predictive pursuit and working memory in HC supports the assumption that working memory is related to predictive pursuit eye movements; however, the degradation of working memory in people with psychosis disrupts its association with eye-tracking behavior.

Tumor Necrosis Factor Gene Variation Predicts Hippocampus Volume in Healthy Individuals - Corrected Proof

2012-05-04

Background: Cytokines such as tumor necrosis factor (TNF) α have been implicated in neurodegeneration relevant to various neuropsychiatric disorders. Little is known about the genetic predisposition to neurodegenerative properties of cytokine genes on brain function and on hippocampus (HC) function in particular. In this study we investigate the neurodegenerative role of TNF polymorphisms on brain morphology in healthy individuals. Methods: Voxel-based morphometry was used in a large sample of healthy individuals (n = 303) to analyze the associations between genetic variants of TNF (rs1800629; rs361525) and brain morphology (gray matter concentration). Results: In a region of interest analysis of the HC, for rs1800629, we observed a strong genotype effect on bilateral HC gray matter concentration. Carriers of one or two A-alleles had significantly smaller volumes compared with GG-homozygotes. For rs361525, a similar effect was observed at almost the same location, with the A-allele resulting in smaller HC volumes compared with GG homozygotes. Conclusions: The findings suggest a neurodegenerative role of the A-alleles of the TNF single nucleotide polymorphisms rs1800629 (-308G/A) and rs361525 (-238G/A) on hippocampal volumes in healthy individuals. Future imaging studies on the role of these single nucleotide polymorphisms in psychiatric populations of diseases with neurodegenerative components are warranted.

Lithium and the Expanding Brain - Corrected Proof

William T. Regenold — 2012-05-04

I read with great interest the article by Vernon et al. () entitled, “Contrasting Effects of Haloperidol and Lithium on Rodent Brain Structure: A Magnetic Resonance Imaging Study with Postmortem Confirmation,” describing their elegant imaging and postmortem study that showed lithium-related increases and haloperidol-related decreases in whole brain and cortical gray matter volume in rats. Their inclusion of postmortem histological confirmation of in vivo brain volume imaging data is a significant advancement over previous human studies limited to imaging ().

Methylphenidate Effects on Prefrontal Functioning During Attentional-Capture and Response Inhibition - Corrected Proof

2012-05-03

Background: Methylphenidate improves motor response inhibition, typically assessed with the stop-signal task. The exact underlying mechanism for this, however, remains unknown. In addition, recent studies highlight that stop signals can have a confounding attentional-capture effect because of their low frequency in the task. In the current study, we assessed the effects of methylphenidate on neural networks of inhibitory control and attentional-capture within the context of two inhibitory control tasks. Methods: The effects of methylphenidate (40 mg) were assessed using functional magnetic resonance imaging in 16 healthy volunteers in a within-subject, double-blind, placebo-controlled design. Results: Methylphenidate significantly reduced activation of different regions within the right inferior frontal gyrus/insula to infrequent stimuli associated with successful inhibition, failed inhibition, and attentional capture. These inferior frontal gyrus regions showed different interregional connections with inhibitory and attention networks. For failed inhibitions, methylphenidate increased activation within performance-monitoring regions, including the superior frontal, anterior cingulate, and parietal-occipital cortices, but only after controlling for attentional capture. Conclusions: Our findings suggest that the improvement of response inhibition seen following methylphenidate administration is due to its influence on underlying attentional mechanisms linked to response control requirements.

Variant Brain Derived Neurotrophic Factor (Valine66Methionine) Polymorphism Contributes to Developmental and Estrous Stage–Specific Expression of Anxiety-Like Behavior in Female Mice - Corrected Proof

2012-05-03

Background: Most anxiety and depressive disorders are twice as common in women compared with men, and the sex difference in prevalence typically emerges during adolescence. Hormonal changes across the menstrual cycle and during the postpartum and perimenopausal 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 Valine66Methionine [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. Methods: 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. Results: 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. Conclusions: 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.

Learning and Memory Depend on Fibroblast Growth Factor Receptor 2 Functioning in Hippocampus - Corrected Proof

Hanna E. Stevens, Ginger Y. Jiang, Michael L. Schwartz, Flora M. Vaccarino — 2012-04-30

Background: Fibroblast growth factor (FGF) signaling controls self-renewal of neural stem cells during embryonic telencephalic development. FGF receptor 2 (FGFR2) has a significant role in the production of cortical neurons during embryogenesis, but its role in the hippocampus during development and in adulthood has not been described. Methods: Here we dissociate the role of FGFR2 in the hippocampus during development and during adulthood with the use of embryonic knockout and inducible knockout mice. Results: Embryonic knockout of FGFR2 causes a reduction of hippocampal volume and impairment in adult spatial memory in mice. Spatial reference memory, as assessed by performance on the water maze probe trial, was correlated with reduced hippocampal parvalbumin+ cells, whereas short-term learning was correlated with reduction in immature neurons in the dentate gyrus. Furthermore, short-term learning and newly generated neurons in the dentate gyrus were deficient even when FGFR2 was lacking only in adulthood. Conclusions: Taken together, these findings support a dual role for FGFR2 in hippocampal short-term learning and long-term reference memory, which appear to depend on the abundance of two separate cellular components, parvalbumin interneurons and newly generated granule cells in the hippocampus.

Vocal Acoustic Biomarkers of Depression Severity and Treatment Response - Corrected Proof

James C. Mundt, Adam P. Vogel, Douglas E. Feltner, William R. Lenderking — 2012-04-30

Background: 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. Methods: One hundred five adults with major depression were recruited into a 4-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. Results: Regression models of speech pattern changes associated with clinical outcomes in a 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. Conclusions: 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.

Cigarette Smoking Predicts Differential Benefit from Naltrexone for Alcohol Dependence - Corrected Proof

2012-04-30

Background: Identifying factors that modify responsiveness to pharmacotherapies for alcohol dependence is important for treatment planning. Cigarette smoking predicts more severe alcohol dependence and poorer treatment response in general. Nevertheless, there is limited research on cigarette smoking as a potential predictor of differential response to pharmacological treatment of alcoholism. Methods: We examined the association between cigarette smoking and drinking outcomes in the COMBINE (Combined Pharmacotherapies and Behavioral Interventions for Alcohol Dependence) study, a randomized, double-blind placebo-controlled 16-week trial comparing combinations of medications (i.e., acamprosate and naltrexone) and behavioral interventions (i.e., medical management, combined behavioral therapy) in 1383 alcohol-dependent individuals. Results: Smokers (i.e., more than one half the sample) significantly differed from nonsmokers on several demographic and drinking-related variables at baseline and generally had poorer treatment outcomes than nonsmokers. However, smokers who received naltrexone had better drinking outcomes than smokers who received placebo, whereas alcohol use among nonsmokers did not vary by naltrexone assignment. This pattern of findings occurred independent of whether patients received combined behavioral intervention or medical management and remained after controlling for alcoholism typology and baseline demographic differences. Approximately 9% of smokers quit smoking, and an additional 10% reduced their cigarette intake during treatment. Reductions in smoking did not vary by treatment assignment. Conclusions: These results suggest that naltrexone might be particularly beneficial for improving alcohol use outcomes in alcohol-dependent smokers.

Protracted Withdrawal from Cocaine Self-Administration Flips the Switch on 5-HT1B Receptor Modulation of Cocaine Abuse-Related Behaviors - Corrected Proof

2012-04-30

Background: The role of serotonin-1B receptors (5-HT1BRs) in modulating cocaine abuse-related behaviors has been controversial due to discrepancies between pharmacological and gene knockout approaches and opposite influences on cocaine self-administration versus cocaine-seeking behavior. We hypothesized that modulation of these behaviors via 5-HT1BRs in the mesolimbic pathway may vary depending on the stage of the addiction cycle. Methods: To test this hypothesis, we examined the effects of increasing 5-HT1BR production by microinfusing a viral vector expressing either green fluorescent protein and 5-HT1BR or green fluorescent protein alone into the medial nucleus accumbens shell of rats either during maintenance of cocaine self-administration (i.e., active drug use) or during protracted withdrawal. Results: 5-HT1BR receptor gene transfer during maintenance shifted the dose-response curve for cocaine self-administration upward and to the left and increased breakpoints and cocaine intake on a progressive ratio schedule, consistent with enhanced reinforcing effects of cocaine. In contrast, following 21 days of forced abstinence, 5-HT1BR gene transfer attenuated breakpoints and cocaine intake on a progressive ratio schedule of reinforcement, as well as cue- and cocaine-primed reinstatement of cocaine-seeking behavior. Conclusions: This unique pattern of effects suggests that mesolimbic 5-HT1BRs differentially modulate cocaine abuse-related behaviors, with a facilitative influence during periods of active drug use, in striking contrast to an inhibitory influence during protracted withdrawal. These findings suggest that targeting 5-HT1BRs may lead to a novel treatment for cocaine dependence and that the therapeutic efficacy of these treatments may vary depending on the stage of the addiction cycle.

R-Modafinil (Armodafinil): A Unique Dopamine Uptake Inhibitor and Potential Medication for Psychostimulant Abuse - Corrected Proof

2012-04-27

Background: (±)-Modafinil has piqued interest as a treatment for attention-deficit/hyperactivity disorder and stimulant dependence. The R-enantiomer of modafinil might have unique pharmacological properties that should be further investigated. Methods: (±)-Modafinil and its R-(−)- and S-(+)-enantiomers were synthesized and tested for inhibition of [3H] dopamine (DA) uptake and [3H]WIN 35428 binding in human dopamine transporter (DAT) wild-type and mutants with altered conformational equilibria. Data were compared with cocaine and the atypical DA uptake inhibitor, JHW 007. R- and S-modafinil were also evaluated in microdialysis studies in the mouse nucleus accumbens shell and in a cocaine discrimination procedure. Results: (±)-, R-, and S-modafinil bind to the DAT and inhibit DA uptake less potently than cocaine, with R-modafinil having approximately threefold higher affinity than its S-enantiomer. Molecular docking studies revealed subtle differences in binding modes for the enantiomers. R-modafinil was significantly less potent in the DAT Y156F mutant compared with wild-type DAT, whereas S-modafinil was affected less. Studies with the Y335A DAT mutant showed that the R- and S-enantiomers tolerated the inward-facing conformation better than cocaine, which was further supported by [2-(trimethylammonium)ethyl]-methanethiosulfonate reactivity on the DAT E2C I159C. Microdialysis studies demonstrated that both R- and S-modafinil produced increases in extracellular DA concentrations in the nucleus accumbens shell less efficaciously than cocaine and with a longer duration of action. Both enantiomers fully substituted in mice trained to discriminate cocaine from saline. Conclusions: R-modafinil displays an in vitro profile different from cocaine. Future trials with R-modafinil as a substitute therapy with the potential benefit of cognitive enhancement for psychostimulant addiction are warranted.

Disrupted Functional Brain Connectome in Individuals at Risk for Alzheimer's Disease - Corrected Proof

2012-04-27

Background: Alzheimer's disease disrupts the topological architecture of whole-brain connectivity (i.e., the connectome); however, whether this disruption is present in amnestic mild cognitive impairment (aMCI), the prodromal stage of Alzheimer's disease, remains largely unknown. Methods: We employed resting-state functional magnetic resonance imaging and graph theory approaches to systematically investigate the topological organization of the functional connectome of 37 patients with aMCI and 47 healthy control subjects. Frequency-dependent brain networks were derived from wavelet-based correlations of both high- and low-resolution parcellation units. Results: In the frequency interval .031–.063 Hz, the aMCI patients showed an overall decreased functional connectivity of their brain connectome compared with control subjects. Further graph theory analyses of this frequency band revealed an increased path length of the connectome in the aMCI group. Moreover, the disease targeted several key nodes predominantly in the default-mode regions and key links primarily in the intramodule connections within the default-mode network and the intermodule connections among different functional systems. Intriguingly, the topological aberrations correlated with the patients' memory performance and differentiated individuals with aMCI from healthy elderly individuals with a sensitivity of 86.5% and a specificity of 85.1%. Finally, we demonstrated a high reproducibility of our findings across different large-scale parcellation schemes and validated the test-retest reliability of our network-based approaches. Conclusions: This study demonstrates a disruption of whole-brain topological organization of the functional connectome in aMCI. Our finding provides novel insights into the pathophysiological mechanism of aMCI and highlights the potential for using connectome-based metrics as a disease biomarker.

Ventral Striatum Reactivity to Reward and Recent Life Stress Interact to Predict Positive Affect - Corrected Proof

Yuliya S. Nikolova, Ryan Bogdan, Bartholomew D. Brigidi, Ahmad R. Hariri — 2012-04-26

Background: Stressful life events are among the most reliable precipitants of major depressive disorder; yet, not everyone exposed to stress develops depression. It has been hypothesized that robust neural reactivity to reward and associated stable levels of positive affect (PA) may protect against major depressive disorder in the context of environmental adversity. However, little empirical data exist to confirm this postulation. Here, we test the hypothesis that individuals with relatively low ventral striatum (VS) reactivity to reward will show low PA levels in the context of recent life stress, while those with relatively high VS reactivity will be protected against these potentially depressogenic effects. Methods: Differential VS reactivity to positive feedback was assessed using blood oxygen level-dependent functional magnetic resonance imaging in a sample of 200 nonpatient young adults. Recent life stress, current depressive symptoms, and PA were assessed via self-report. Linear regression models were used to investigate the moderating effects of VS reactivity on the relationship between recent stress and state PA across participants. Results: Recent life stress interacted with VS reactivity to predict self-reported state PA, such that higher levels of life stress were associated with lower PA for participants with relatively low, but not for those with high, VS reactivity. These effects were independent of age, gender, race/ethnicity, trait PA, and early childhood trauma. Conclusions: The current results provide empirical evidence for the potentially protective role of robust reward-related neural responsiveness against reductions in PA that may occur in the wake of life stress and possibly vulnerability to depression precipitated by stressful life events.

SCN1A Affects Brain Structure and the Neural Activity of the Aging Brain - Corrected Proof

2012-04-26

Background: The aging of the human brain is accompanied by changes in cortical structure as well as functional activity and variable degrees of cognitive decline. One-third of the observable inter-individual differences in cognitive decline are thought to be heritable. SCN1A encodes the sodium channel α subunit and is considered to be a susceptibility gene for several neurological disorders with prominent cognitive deficits. In a recent genome-wide association study the C allele of the SCN1A variant rs10930201 was observed to be significantly associated with poor short-term memory performance. rs10930201 was further observed to be related to differences in neural activity during a working memory task. Methods: The aim of the present study was to explore whether SCN1A modifies the vulnerability to aging processes of the human brain. Therefore we assessed the interacting effects of the SCN1A vulnerability allele rs10930201 and age in terms of brain activity and brain morphology in 62 healthy volunteers between 21 and 82 years of age. Results: In C allele carriers, activity in the right inferior frontal cortex and the posterior cingulate cortex increased with age. Moreover, exploratory analysis revealed regional effects of rs10930201 on brain structure, indicating reduced gray matter densities in the frontal and insular regions in the C allele carriers. Conclusions: Collectively, the present results suggest that the SCN1A polymorphism has modulatory effects on brain morphology and vulnerability to age-related alterations in brain activity of cortical regions that subserve working memory.

Linkage Analysis Followed by Association Show NRG1 Associated with Cannabis Dependence in African Americans - Corrected Proof

2012-04-23

Background: A genetic contribution to cannabis dependence (CaD) has been established but susceptibility genes for CaD remain largely unknown. Methods: We employed a multistage design to identify genetic variants underlying CaD. We first performed a genome-wide linkage scan for CaD in 384 African American (AA) and 354 European American families ascertained for genetic studies of cocaine and opioid dependence. We then conducted association analysis under the linkage peak, first using data from a genome-wide association study from the Study of Addiction: Genetics and Environment, followed by replication studies of prioritized single nucleotide polymorphisms (SNPs) in independent samples. Results: We identified the strongest linkage evidence with CaD (logarithm of odds = 2.9) on chromosome 8p21.1 in AAs. In the association analysis of the Study of Addiction: Genetics and Environment sample under the linkage peak, we identified one SNP (rs17664708) associated with CaD in both AAs (odds ratio [OR] = 2.93, p = .0022) and European Americans (OR = 1.38, p = .02). This SNP, located at NRG1, a susceptibility gene for schizophrenia, was prioritized for further study. We replicated the association of rs17664708 with CaD in an independent AAs sample (OR = 2.81, p = .0068). The joint analysis of the two AA samples demonstrated highly significant association between rs17664708 and CaD with adjustment for either global (p = .00044) or local ancestry (p = .00075). Conclusions: Our study shows that NRG1 is probably a susceptibility gene for CaD, based on convergent evidence of linkage and replicated associations in two independent AA samples.

Early-Life Mental Disorders and Adult Household Income in the World Mental Health Surveys - Corrected Proof

2012-04-23

Background: Better information on the human capital costs of early-onset mental disorders could increase sensitivity of policy makers to the value of expanding initiatives for early detection and treatment. Data are presented on one important aspect of these costs: the associations of early-onset mental disorders with adult household income. Methods: Data come from the World Health Organization (WHO) World Mental Health Surveys in 11 high-income, five upper-middle income, and six low/lower-middle income countries. Information about 15 lifetime DSM-IV mental disorders as of age of completing education, retrospectively assessed with the WHO Composite International Diagnostic Interview, was used to predict current household income among respondents aged 18 to 64 (n = 37,741) controlling for level of education. Gross associations were decomposed to evaluate mediating effects through major components of household income. Results: Early-onset mental disorders are associated with significantly reduced household income in high and upper-middle income countries but not low/lower-middle income countries, with associations consistently stronger among women than men. Total associations are largely due to low personal earnings (increased unemployment, decreased earnings among the employed) and spouse earnings (decreased probabilities of marriage and, if married, spouse employment and low earnings of employed spouses). Individual-level effect sizes are equivalent to 16% to 33% of median within-country household income, and population-level effect sizes are in the range 1.0% to 1.4% of gross household income. Conclusions: Early mental disorders are associated with substantial decrements in income net of education at both individual and societal levels. Policy makers should take these associations into consideration in making health care research and treatment resource allocation decisions.

Ghrelin Regulates the Hypothalamic-Pituitary-Adrenal Axis and Restricts Anxiety After Acute Stress - Corrected Proof

2012-04-23

Background: Ghrelin plays important roles in glucose metabolism, appetite, and body weight regulation, and recent evidence suggests ghrelin prevents excessive anxiety under conditions of chronic stress. Methods: We used ghrelin knockout (ghr−/−) mice to examine the role of endogenous ghrelin in anxious behavior and hypothalamic-pituitary-adrenal axis (HPA) responses to acute stress. Results: Ghr−/− mice are more anxious after acute restraint stress, compared with wild-type (WT) mice, with three independent behavioral tests. Acute restraint stress exacerbated neuronal activation in the hypothalamic paraventricular nucleus and medial nucleus of the amygdala in ghr−/− mice compared with WT, and exogenous ghrelin reversed this effect. Acute stress increased neuronal activation in the centrally projecting Edinger-Westphal nucleus in WT but not ghr−/− mice. Ghr−/− mice exhibited a lower corticosterone response after stress, suggesting dysfunctional glucocorticoid negative feedback in the absence of ghrelin. We found no differences in dexamethasone-induced Fos expression between ghr−/− and WT mice, suggesting central feedback was not impaired. Adrenocorticotropic hormone replacement elevated plasma corticosterone in ghr−/−, compared with WT mice, indicating increased adrenal sensitivity. The adrenocorticotropic hormone response to acute stress was significantly reduced in ghr−/− mice, compared with control subjects. Pro-opiomelanocortin anterior pituitary cells express significant growth hormone secretagogue receptor. Conclusions: Ghrelin reduces anxiety after acute stress by stimulating the HPA axis at the level of the anterior pituitary. A novel neuronal growth hormone secretagogue receptor circuit involving urocortin 1 neurons in the centrally projecting Edinger-Westphal nucleus promotes an appropriate stress response. Thus, ghrelin regulates acute stress and offers potential therapeutic efficacy in human mood and stress disorders.

Estimating the Genetic Variance of Major Depressive Disorder Due to All Single Nucleotide Polymorphisms - Corrected Proof

2012-04-23

Genome-wide association studies of psychiatric disorders have been criticized for their lack of explaining a considerable proportion of the heritability established in twin and family studies. Genome-wide association studies of major depressive disorder in particular have so far been unsuccessful in detecting genome-wide significant single nucleotide polymorphisms (SNPs). Using two 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 major depressive disorder. To assess the consistency of these two 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.

Neuroeconomics and the Study of Addiction - Corrected Proof

John Monterosso, Payam Piray, Shan Luo — 2012-04-23

We review the key findings in the application of neuroeconomics to the study of addiction. Although there are not “bright line” boundaries between neuroeconomics and other areas of behavioral science, neuroeconomics coheres around the topic of the neural representations of “Value” (synonymous with the “decision utility” of behavioral economics). Neuroeconomics parameterizes distinct features of Valuation, going beyond the general construct of “reward sensitivity” widely used in addiction research. We argue that its modeling refinements might facilitate the identification of neural substrates that contribute to addiction. We highlight two areas of neuroeconomics that have been particularly productive. The first is research on neural correlates of delay discounting (reduced Valuation of rewards as a function of their delay). The second is work that models how Value is learned as a function of “prediction-error” signaling. Although both areas are part of the neuroeconomic program, delay discounting research grows directly out of behavioral economics, whereas prediction-error work is grounded in models of learning. We also consider efforts to apply neuroeconomics to the study of self-control and discuss challenges for this area. We argue that neuroeconomic work has the potential to generate breakthrough research in addiction science.

Maternal Care Influences Hippocampal N-Methyl-D-Aspartate Receptor Function and Dynamic Regulation by Corticosterone in Adulthood - Corrected Proof

2012-04-23

Background: Variations in maternal care in the rat associate with robust differences in hippocampal development and synaptic plasticity in the offspring. Maternal care also influences pituitary-adrenal stress responses and corticosterone (CORT) regulation of hippocampal plasticity. N-methyl-D-aspartate receptors (NMDAR) regulate synaptic plasticity, and NMDAR function is modulated by stress and CORT. We hypothesized that altered NMDAR function underlies the interaction of maternal and stress effects on hippocampal synaptic plasticity. Methods: We used electrophysiology and western blot to examine NMDAR synaptic function/expression and NMDAR-dependent long-term potentiation (LTP) in adult offspring of mothers that varied in the frequency of pup licking/grooming (LG) (i.e., High or Low LG). Results: Basal NMDAR synaptic function was enhanced in the hippocampal dentate gyrus (DG) of adult Low LG offspring. Synaptic expression of NMDAR but not α-amino-3-hydroxy-methyl-4-isoxazole propionic acid receptors was also increased. Stress level CORT (100 nmol/L) rapidly (<20 min) and robustly increased NMDAR function in High LG offspring, eliminating the maternal effect. Corticosterone did not affect NMDAR function in Low LG offspring. Bovine serum albumin-conjugated CORT reproduced the CORT effect in High LG offspring, implicating a membrane-bound corticosteroid receptor. NMDAR hyperfunction might impair synaptic plasticity. Partial NMDAR antagonism by low concentration DL-2-Amino-5-phosphonopentanoic acid rescued a basal LTP deficit in Low LG offspring and inhibited LTP in High LG offspring. Conclusions: Low LG offspring exhibit basally elevated NMDAR function coupled with insensitivity to CORT modulation indicative of a chronic alteration of NMDAR function. Elevated NMDAR function in the hippocampus might underlie impaired LTP in Low LG offspring.

Posttraumatic Stress Disorder Across Two Generations: Concordance and Mechanisms in a Population-Based Sample - Corrected Proof

2012-04-23

Background: 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. Methods: 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. Results: Mother's lifetime posttraumatic stress symptoms were associated with child's PTSD in dose–response fashion (mother's 1–3 symptoms, child's RR = 1.2; mother's 4–5 symptoms, RR = 1.3; mother's 6–7 symptoms, RR = 1.6, compared with children of mothers with no symptoms, p < .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 < .001). Conclusions: 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.

Reducing Behavioral Inhibition to Novelty via Systematic Neonatal Novelty Exposure: The Influence of Maternal Hypothalamic-Pituitary-Adrenal Regulation - Corrected Proof

Akaysha C. Tang, Bethany C. Reeb-Sutherland, Russell D. Romeo, Bruce S. McEwen — 2012-04-23

Background: Behavioral inhibition (BI) to novelty is thought to be a stable temperament type that appears early in life and is a major risk factor for anxiety disorders. In the rat, habituation of such inhibition can be facilitated via neonatal novelty exposure (NNE), thus reducing BI to novelty. Here, we tested the hypothesis that this early intervention effect is modulated by the context of maternal self-stress regulation. Methods: The NNE was carried out during postnatal days 1–21, in which one half of each litter was exposed to a relatively novel nonhome environment for 3-min daily while the remaining one half stayed in the home cage. After weaning, BI to novelty was assessed in an open field with a measure of disinhibition defined as a greater increase in exploration across two brief trials. Maternal context was characterized by trait measures of hypothalamic-pituitary-adrenal (HPA) axis reactivity, including basal and stress-evoked corticosterone (CORT) responses. Results: Family-to-family variations in the NNE effect were associated with variations in maternal HPA function—a low-basal CORT and high-evoked CORT response profile constituting the context for a novelty-induced facilitation of disinhibition (i.e., a greater increase in exploratory activity over repeated trials) and an opposite HPA profile constituting the context for a novelty-induced reduction of disinhibition. Conclusions: This result is consistent with the hypothesis that maternal self-stress regulation modulates the effect of early life intervention on BI to novelty and suggests that effective interventions should include strategies to help mothers improve their self-stress regulation.

Synaptic Potentiation Is Critical for Rapid Antidepressant Response to Ketamine in Treatment-Resistant Major Depression - Corrected Proof

2012-04-23

Background: 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 γ oscillations, but it is unknown whether these effects are key to the mechanism of antidepressant action of ketamine. Methods: Twenty drug-free major depressive disorder patients received a single, open-label intravenous infusion of ketamine hydrochloride (.5 mg/kg). Magnetoencephalographic recordings were made approximately 3 days before and approximately 6.5 hours after the infusion, whereas patients passively received tactile stimulation to the right and left index fingers and also while they rested (eyes-closed). Antidepressant response was assessed by percentage change in Montgomery-Åsberg Depression Rating Scale scores. Results: Patients with robust improvements in depressive symptoms 230 min after infusion (responders) exhibited increased cortical excitability within this antidepressant response window. Specifically, we found that stimulus-evoked somatosensory cortical responses increase after infusion, relative to pretreatment responses in responders but not in treatment nonresponders. Spontaneous somatosensory cortical γ-band activity during rest did not change within the same timeframe after ketamine in either responders or nonresponders. Conclusions: These findings suggest NMDAR antagonism does not lead directly to increased cortical excitability hours later and thus might 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 the antidepressant effect of ketamine.

Relationship of Ketamine's Plasma Metabolites with Response, Diagnosis, and Side Effects in Major Depression - Corrected Proof

2012-04-20

Background: Ketamine has rapid antidepressant effects lasting as long as 1 week in patients with major depressive disorder (MDD) and bipolar depression (BD). Ketamine is extensively metabolized. This study examined the relationship between ketamine metabolites and response, diagnosis, and psychotomimetic symptoms in MDD and BD patients. Methods: Following a 40-minute ketamine infusion (.5 mg/kg), plasma samples were collected at 40, 80, 110, and 230 minutes and day 1 postinfusion in 67 patients currently experiencing a major depressive episode (MDD, n = 45; BD, n = 22). Concentrations of ketamine, norketamine (NK), dehydronorketamine (DHNK), six hydroxynorketamine metabolites (HNK), and hydroxyketamine (HK) were measured. Plasma concentrations were analyzed by diagnostic group and correlated with patients' depressive, psychotic, and dissociative symptoms. The relationship between cytochrome P450 gene polymorphisms and metabolites, response, and diagnosis was also examined. Results: Ketamine, NK, DHNK, four of six HNKs, and HK were present during the first 230 minutes postinfusion. Patients with BD had higher plasma concentrations of DHNK, (2S,6S;2R,6R)-HNK, (2S,6R;2R,6S)-HNK, and (2S,5S;2R,5R)-HNK than patients with MDD, who, in turn, had higher concentrations of (2S,6S;2R,6R)-HK. Higher (2S,5S;2R,5R)-HNK concentrations were associated with nonresponse to ketamine in BD patients. Dehydronorketamine, HNK4c, and HNK4f levels were significantly negatively correlated with psychotic and dissociative symptoms at 40 minutes. No relationship was found between cytochrome P450 genes and any of the parameters examined. Conclusions: A diagnostic difference was observed in the metabolism and disposition of ketamine. Concentrations of (2S,5S;2R,5R)-HNK were related to nonresponse to ketamine in BD. Some hydroxylated metabolites of ketamine correlated with psychotic and dissociative symptoms.

Antidepressant Effects of Fibroblast Growth Factor-2 in Behavioral and Cellular Models of Depression - Corrected Proof

2012-04-19

Background: Basic and clinical studies report that the expression of fibroblast growth factor-2 (FGF-2) is decreased in the prefrontal cortex (PFC) of depressed subjects or rodents exposed to stress and increased following antidepressant treatment. Here, we aim to determine if 1) FGF-2/fibroblast growth factor receptor (FGFR) signaling is sufficient and required for mediating an antidepressant response behaviorally and cellularly; and 2) if the antidepressant actions of FGF-2 are mediated specifically by the PFC. Methods: The role of FGF-2 signaling in behavioral models of depression and anxiety was tested using chronic unpredictable stress (CUS)/sucrose consumption test (SCT), forced swim test (FST), and novelty suppressed feeding test (NSFT). We also assessed the number of bromodeoxyuridine labeled dividing glial cells in the PFC as a cellular index relevant to depression (i.e., decreased by stress and increased by antidepressant treatment). Results: Chronic FGF-2 infusions (intracerebroventricular) blocked the deficit in SCT caused by CUS. Moreover, the response to antidepressant treatment in the CUS/SCT and FST was abolished upon administration of an inhibitor of FGFR activity, SU5402. These results are consistent with the regulation of proliferating cells in the PFC, a portion of which are of oligodendrocyte lineage. Lastly, subchronic infusions of FGF-2 into the PFC but not into the dorsal striatum produced antidepressant-like and anxiolytic-like effects on FST and NSFT respectively. Conclusions: These findings demonstrate that FGF-2/FGFR signaling is sufficient and necessary for the behavioral, as well as gliogenic, actions of antidepressants and highlight the PFC as a brain region sensitive to the antidepressant actions of FGF-2.

Optogenetics and Psychiatry: Applications, Challenges, and Opportunities - Corrected Proof

Karl Deisseroth — 2012-04-16

Achieving circuit-level insight into the fundamental nature of psychiatric symptoms has long proven elusive. Technological limitations have traditionally prevented cell type-targeted and temporally precise interventions into intact mammalian neural circuitry to elicit or ameliorate expression of disease symptom-related phenotypes. However, recent years have seen a growing wave of applications of optogenetics to questions in neuropsychiatric disease, with the deployment of millisecond-precision optical excitation or inhibition of specific circuit elements within behaving mammals. Indeed, optogenetic technology now exists in a special relationship with psychiatry because one of the unique and most versatile features of optogenetics (modulation of defined neural projections) is well aligned with what may be a core feature of psychiatric disease (altered function along pathways of neural communication). In this special issue, we collect perspectives from leading researchers at the convergence of psychiatry and optogenetics, highlighting the fundamental questions that have been addressed and many of the opportunities that remain.

Common Genetic Variants and Gene-Expression Changes Associated with Bipolar Disorder Are Over-Represented in Brain Signaling Pathway Genes - Corrected Proof

2012-04-16

Background: Despite high heritability, the genetic variants influencing bipolar disorder (BD) susceptibility remain largely unknown. Low statistical power to detect the small effect-size alleles believed to underlie much of the genetic risk and possible heterogeneity between cohorts are an increasing concern. Integrative biology approaches might offer advantages over genetic analysis alone by combining different genomic datasets at the higher level of biological processes rather than the level of specific genetic variants or genes. We employed this strategy to identify biological processes involved in BD etiopathology. Method: Three genome-wide association studies and a brain gene-expression study were combined with the Human Protein Reference Database protein–protein interaction network data. We used bioinformatic analysis to search for biological networks with evidence of association on the basis of enrichment among both genetic and differential-expression associations with BD. Results: We identified association with gene networks involved in transmission of nerve impulse, Wnt, and Notch signaling. Three features stand out among these genes: 1) they localized to the human postsynaptic density, which is crucial for neuronal function; 2) their mouse knockouts present altered behavioral phenotypes; and 3) some are known targets of the pharmacological treatments for BD. Conclusions: Genetic and gene-expression associations of BD cluster in discrete regions of the protein–protein interaction network. We found replicated evidence for association for networks involving several interlinked signaling pathways. These genes are promising candidates to generate animal models and pharmacological interventions. Our results demonstrate the potential advantage of integrative biology analyses of BD datasets.

Estrogen Levels Are Associated with Extinction Deficits in Women with Posttraumatic Stress Disorder - Corrected Proof

2012-04-16

Background: Women are twice as likely to develop posttraumatic stress disorder (PTSD) than men. As shown in our previous work, the inability to suppress fear responses in safe conditions may be a biomarker for PTSD. Low estrogen in naturally cycling women is associated with deficits in fear extinction. On the basis of these findings, we have now examined the influence of estrogen levels on fear extinction in women with and without PTSD. Methods: We measured fear-potentiated startle during fear conditioning and extinction in women. The study sample (N = 81) was recruited from an urban, highly traumatized civilian population at Grady Memorial Hospital in Atlanta, Georgia. We assayed serum estrogen levels and used a median split to divide the sample into high and low estradiol (E2) groups. Seventeen of 41 women (41.5%) in the low E2 group and 15 of 40 women (37.5%) met criteria for PTSD in the high E2 group. Results: The results showed that all groups had equivalent levels of fear conditioning. However, we found significant interaction effects between high versus low E2 groups and PTSD diagnosis [F(1,71) = 4.55, p < .05] on extinction. Among women with low estrogen levels, fear-potentiated startle was higher during extinction in the PTSD group compared with traumatized control women [F(1,38) = 5.04, p < .05]. This effect was absent in the High E2 group. Conclusion: This study suggests that low estrogen may be a vulnerability factor for development of PTSD in women with trauma histories. Research on the role of estrogen in fear regulation may provide insight into novel treatment strategies for PTSD.

Social Dominance in Female Monkeys: Dopamine Receptor Function and Cocaine Reinforcement - Corrected Proof

2012-04-16

Background: Brain imaging and behavioral studies suggest an inverse relationship between dopamine (DA) D2/D3 receptors and vulnerability to cocaine abuse, although most research has used males. For example, male monkeys that become dominant in a social group have significant elevations in D2/D3 receptor availability and are less vulnerable to cocaine reinforcement. Methods: DA D2/D3 receptor availability was assessed in female cynomolgus monkeys (n = 16) with positron emission tomography (PET) while they were individually housed, 3 months after stable social hierarchies had formed, and again when individually housed. In addition, PET was used to examine changes in dopamine transporter (DAT) availability after social hierarchy formation. After imaging studies were complete, monkeys received implantation with indwelling intravenous catheters and self-administered cocaine (.001–.1 mg/kg/injection) under a fixed-ratio 30 schedule of reinforcement. Acquisition of cocaine reinforcement occurred when response rates were significantly higher than when saline was self-administered. Results: Neither DAT nor D2/D3 receptor availability in the caudate nucleus and putamen was predictive of social rank, but both significantly changed after formation of social hierarchies. DA D2/D3 receptor availability significantly increased in females that became dominant, whereas DAT availability decreased in subordinate females. Dominant female monkeys acquired cocaine reinforcement at significantly lower doses than subordinate monkeys. Conclusions: The relationship between D2/D3 receptor availability and vulnerability to cocaine reinforcement seems, on the basis of these findings, opposite in females and males. These data indicate that the social environment profoundly affects the DA system but does so in ways that have different functional consequences for females than for males.

Imaging Models of Valuation During Social Interaction in Humans - Corrected Proof

Kenneth T. Kishida, P. Read Montague — 2012-04-16

The role of dopamine neurons in value-guided behavior has been described in computationally explicit terms. These developments have motivated new model-based probes of reward processing in healthy humans, and in recent years these same models have also been used to design and understand neural responses during simple social exchange. These latter applications have opened up the possibility of identifying new endophenotypes characteristic of biological substrates underlying psychiatric disease. In this report, we review model-based approaches to functional magnetic resonance imaging in healthy individuals and the application of these paradigms to psychiatric disorders. We show early results from the application of model-based human interaction at three disparate levels: 1) interaction with a single human, 2) interaction within small groups, and 3) interaction with signals generated by large groups. In each case, we show how reward-prediction circuitry is engaged by abstract elements of each paradigm with blood oxygen level–dependent imaging as a read-out; and, in the last case (i.e., signals generated by large groups) we report on direct electrochemical dopamine measurements during decision making in humans. Lastly, we discuss how computational approaches can be used to objectively assess and quantify elements of complex and hidden social decision-making processes.

Deficient Inhibitory Cortical Networks in Antipsychotic-Naive Subjects at Risk of Developing First-Episode Psychosis and First-Episode Schizophrenia Patients: A Cross-Sectional Study - Corrected Proof

2012-04-16

Background: Impaired cortical inhibition is a well-established finding in schizophrenia patients and has been linked to dysfunctional gamma-aminobutyric acid (GABA)ergic transmission. However, there have been no previous studies investigating cortical excitability with particular regard to intracortical inhibitory networks in antipsychotic-naive subjects at risk of developing first-episode psychosis. Methods: A total of 18 subjects at risk, 18 first-episode schizophrenia patients, and 18 healthy control subjects were included in this study. Transcranial magnetic stimulation over the left primary motor cortex was used to determine short-latency intracortical inhibition, intracortical facilitation, and the contralateral silent period (CSP). Short-latency intracortical inhibition can be considered as a parameter of GABA type A (GABAA)-mediated inhibition and it has been proposed that CSP can test GABA type B (GABAB)-mediated inhibitory intracortical networks. Results: Subjects at risk and first-episode patients showed a reduced short-latency intracortical inhibition compared with healthy control subjects, suggesting reduced GABAA-mediated inhibition. First-episode patients had a prolonged CSP duration compared with the other two groups, implying a GABAB imbalance only in patients with full-blown psychosis. Analyses did not reveal group differences for intracortical facilitation. Conclusions: These results indicate specific alterations in inhibitory cortical networks in subjects at risk and in first-episode patients. It appears that there is already a cortical inhibitory deficit in at-risk individuals. These results suggest a possible GABAA dysfunction early in the disease course, whereas alterations in GABAB functionality seem to occur later in the disease's progression. Future longitudinal studies will be needed to clarify this inhibitory deficit and its relation to the transition to psychosis.

Reply To: Brain-Derived Neurotrophic Factor in Patients With Chronic Hepatitis C: Beyond Neurotrophic Support - Corrected Proof

Amirhossein Modabbernia, Mandana Ashrafi, Shervin Taslimi, Hossein Poustchi — 2012-04-13

We read with great interest the correspondence by Fabregas et al. () in response to our letter, “Brain-derived neurotrophic factor predicts physical health in untreated patients with hepatitis C,” which was published in September 2011 in Biological Psychiatry (). We found that brain-derived neurotrophic factor (BDNF) was lower in hepatitis C (HCV) than hepatitis B (HBV) patients and was related to the measures of physical health. Fabregas et al. () compared BDNF and other inflammatory markers between HCV and control subjects and found higher concentration of BDNF in HCV than the control group. They also found that BDNF correlated with some of the inflammatory markers but not with quality-of-life measures. They concluded that BDNF in HCV patients was probably related to inflammation rather than changes in the central nervous system.

On the Safety and Benefits of Repeated Intravenous Injections of Ketamine For Depression - Corrected Proof

Pierre Blier, Daniel Zigman, Jean Blier — 2012-04-13

The rapid and robust antidepressant effect of the intravenous infusion of a subanesthetic dose of ketamine in 2000 has triggered research endeavors in this novel mechanism of action (). Its drug abuse potential and early reports of neuronal toxicity in rats are likely contributing to slowing the clinical progress ().

Lesions of Ventrolateral Prefrontal or Anterior Orbitofrontal Cortex in Primates Heighten Negative Emotion - Corrected Proof

2012-04-13

Background: Heightened fear and anxiety are core symptoms of a variety of neuropsychiatric disorders. They are associated with structural and activity changes throughout neural circuitry that includes the ventral and medial prefrontal cortices (PFC), the amygdala, and hippocampus. Although the contributions of the medial PFC, amygdala, and hippocampus to fear and anxiety have been studied extensively with animal models, the selective roles of the ventral PFC—including the ventrolateral prefrontal cortex (vlPFC) and orbitofrontal cortex—are poorly understood. Methods: We investigated the effects of selective excitotoxic lesions of either the vlPFC or anterior orbitofrontal cortex (antOFC) on anxious behavior and Pavlovian conditioned autonomic and behavioral fear responses in the New World primate, the common marmoset. Results: Both vlPFC and antOFC lesions resulted in stronger, less adaptable conditioned fear responses. They also heightened the anxiety responses of a marmoset to a human intruder. In contrast, only a lesion of the vlPFC affected the coping style that a marmoset displayed in the presence of the human intruder, increasing the likelihood of proactive mobbing. Conclusions: These results suggest that both the antOFC and vlPFC can downregulate fear and anxiety and, together, provide necessary but independent contributions to the top-down control of negative emotion.

Clustering of Depression and Inflammation in Adolescents Previously Exposed to Childhood Adversity - Corrected Proof

Gregory E. Miller, Steve W. Cole — 2012-04-12

Background: There is mounting interest in the hypothesis that inflammation contributes to the pathogenesis of depression and underlies depressed patients' vulnerability to comorbid medical conditions. However, research on depression and inflammation has yielded conflicting findings, fostering speculation that these conditions associate only in certain subgroups, such as patients exposed to childhood adversity. Methods: We studied 147 female adolescents. All were in good health at baseline but at high risk for depression because of family history or cognitive vulnerability. Subjects were assessed every 6 months for 2.5 years, undergoing diagnostic interviews and venipuncture for measurement of two inflammatory biomarkers, C-reactive protein (CRP) and interleukin-6 (IL-6). Childhood adversity was indexed by parental separation, low socioeconomic status, and familial psychopathology. Results: Multilevel models indicated that childhood adversity promotes clustering of depression and inflammation. Among subjects exposed to high childhood adversity, the transition to depression was accompanied by increases in both CRP and IL-6. Higher CRP remained evident 6 months later, even after depressive symptoms had abated. These lingering effects were bidirectional, such that among subjects with childhood adversity, high IL-6 forecasted depression 6 months later, even after concurrent inflammation was considered. This coupling of depression and inflammation was not apparent in subjects without childhood adversity. Conclusions: These findings suggest that childhood adversity promotes the formation of a neuroimmune pipeline in which inflammatory signaling between the brain and periphery is amplified. Once established, this pipeline leads to a coupling of depression and inflammation, which may contribute to later affective difficulties and biomedical complications.

Interplay of Maternal Care and Genetic Influences in Programming Adult Hippocampal Neurogenesis - Corrected Proof

2012-04-09

Background: Adult hippocampal neurogenesis, which is involved in the physiopathology of hippocampal functions, is genetically determined and influenced by early life events. However, studies on the interaction of these determining forces are lacking. This prompted us to investigate whether adult hippocampal neurogenesis can be modulated by maternal care and whether this influence depends upon the genetic background of the individual. Methods: We used a model of fostering that allows singling out the influence of the genetic make-up of the pups on the outcome of maternal behavior. Mice from two different inbred strains (C57BL/6J and DBA/2J) known to differ in their baseline neurogenesis as well as in their sensitivity to the influence of environmental experiences were raised by nonrelated mothers from the AKR/Ola (AKR) and C3H/He (C3H) strains exhibiting low- and high-pup-oriented behavior, respectively. Neurogenesis was then assessed in the dentate gyrus of the adult adopted C57BL/6J and DBA/2J mice. Results: We show that both the number and the morphological features of newborn granule cells in the dentate gyrus are determined by the maternal environment to which mice were exposed as pups and that this sensitivity to maternal environment is observed only in genetically vulnerable subjects. Conclusions: Altogether, our data indicate interplay between early environment and the genetic envelop of an individual in determining adult hippocampal neurogenesis. Our experimental approach could thus contribute to the identification of factors determining the neurogenic potential of the adult hippocampus.