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• Enhancing prolonged exposure therapy for posttraumatic stress disorder with d-cycloserine: further support for treatments that promote experience-dependent neuroplasticity.

  Authors: John H Krystal

  Biological psychiatry. 71(11):932-4.

• N-acetylcysteine for the treatment of glutathione deficiency and oxidative stress in schizophrenia.

  Authors: Dikoma C Shungu

  Biological psychiatry. 71(11):937-8.

• Translating the rosetta stone of N-acetylcysteine.

  Authors: Olivia M Dean, Ashley I Bush, Michael Berk

  Biological psychiatry. 71(11):935-6.

• D-cycloserine effects on extinction of conditioned responses to drug-related cues.

  Authors: Karyn M Myers, William A Carlezon

  Biological psychiatry. 71(11):947-55.

  D-cycloserine (DCS) is an N-methyl-D-aspartate (NMDA) receptor partial agonist that facilitates extinction of conditioned fear in animals and cue exposure therapy (CET) for fear and anxiety disordersD-cycloserine (DCS) is an N-methyl-D-aspartate (NMDA) receptor partial agonist that facilitates extinction of conditioned fear in animals and cue exposure therapy (CET) for fear and anxiety disorders in people. Recent preclinical and clinical studies have examined the effect of DCS on extinction of conditioned responses elicited by cues paired with administration of or withdrawal from drugs of abuse, including physiological responses, craving, withdrawal, and drug-seeking behavior. DCS facilitates extinction and blunts postextinction recovery of these responses in animal models, including place conditioning and drug self-administration, but DCS effects on CET in substance users/abusers are less robust. Some of the null effects in the clinical literature might be attributable to issues related to sample size, data characteristics, DCS administration, and participant characteristics, among others. In this review we describe the preclinical and clinical literatures on DCS modulation of extinction of addiction-related conditioned responses, consider possible limitations of the clinical studies that have been published to date, and propose ways of designing future clinical studies so as to maximize the probability of detecting a DCS effect. We also discuss concerns with regard to potential harmful effects of DCS-coupled CET in addicts and describe how these concerns might be mitigated. We conclude that it is as yet unclear whether DCS-coupled CET might be a useful approach in the treatment of addiction.

• A Step-by-Step Guide to Dopamine.

  Authors: Peter Dayan, Mark E Walton

  Biological psychiatry. 71(10):842-3.

• 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.

  Authors: Karina S Blair, Marilla Geraci, Bruce W Smith, Nick Hollon, Jeffrey Devido, Marcela Otero, James R Blair, Daniel S Pine

  Biological psychiatry.

  BACKGROUND: Generalized social phobia (GSP) and generalized anxiety disorder (GAD) are both associated with emotion dysregulation. Research implicates dorsal anterior cingulate cortex in bothBACKGROUND: 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.

• Functional network endophenotypes of psychotic disorders.

  Authors: Ed Bullmore

  Biological psychiatry. 71(10):844-5.

• Alzheimer's Disease Genes and Cognition in the Nondemented General Population.

  Authors: Benjamin F J Verhaaren, Meike W Vernooij, Peter J Koudstaal, André G Uitterlinden, Cornelia M van Duijn, Albert Hofman, Monique M B Breteler, M Arfan Ikram

  Biological psychiatry.

  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 populationBACKGROUND: 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.

  Authors: Lionel Breuillaud, Clara Rossetti, Elsa M Meylan, Christophe Mérinat, Olivier Halfon, Pierre J Magistretti, Jean-René Cardinaux

  Biological psychiatry.

  BACKGROUND: Mood disorders are polygenic disorders in which the alteration of several susceptibility genes results in dysfunctional mood regulation. However, the molecular mechanisms underlying theirBACKGROUND: 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.

• Using Attentional Bias Modification as a Cognitive Vaccine Against Depression.

  Authors: Michael Browning, Emily A Holmes, Matthew Charles, Philip J Cowen, Catherine J Harmer

  Biological psychiatry.

  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 preventionBACKGROUND: 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.

• Understanding Interpersonal Function in Psychiatric Illness Through Multiplayer Economic Games.

  Authors: Brooks King-Casas, Pearl H Chiu

  Biological psychiatry.

  Interpersonal factors play significant roles in the onset, maintenance, and remission of psychiatric conditions. In the current major diagnostic classification systems for psychiatric disorders, someInterpersonal 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.

  Authors: Michael Kometer, André Schmidt, Rosilla Bachmann, Erich Studerus, Erich Seifritz, Franz X Vollenweider

  Biological psychiatry.

  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 subjectiveBACKGROUND: 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.

• Neural Activations During Auditory Oddball Processing Discriminating Schizophrenia and Psychotic Bipolar Disorder.

  Authors: Lauren E Ethridge, Jordan P Hamm, John R Shapiro, Ann T Summerfelt, Sarah K Keedy, Michael C Stevens, Godfrey Pearlson, Carol A Tamminga, Nash N Boutros, John A Sweeney, Matcheri S Keshavan, Gunvant Thaker, Brett A Clementz

  Biological psychiatry.

  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 auditoryBACKGROUND: 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.

  Authors: Rajnish P Rao, Shobha Anilkumar, Bruce S McEwen, Sumantra Chattarji

  Biological psychiatry.

  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.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.

  Authors: Evangelos Vassos, Stacy Steinberg, Sven Cichon, Gerome Breen, Engilbert Sigurdsson, Ole A Andreassen, Srdjan Djurovic, Gunnar Morken, Maria Grigoroiu-Serbanescu, Carmen C Diaconu [......] I Alex Rubino, Vera Golimbet, Lambertus A Kiemeney, Leonard H van den Berg, Barbara Franke, Erik G Jönsson, Anne Farmer, Hreinn Stefansson, Kari Stefansson, David A Collier

  Biological psychiatry.

  BACKGROUND: Common genetic polymorphisms at chromosome 3p21.1, including rs2251219 in polybromo 1 (PBRM1), have been implicated in susceptibility to bipolar affective disorder (BP) throughBACKGROUND: 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.

• Reply to: Lithium and the Expanding Brain.

  Authors: Anthony C Vernon, Sridhar Natesan, William R Crum, Michel Modo, Jonathan D Cooper, Steven C R Williams, Shitij Kapur

  Biological psychiatry.

• Potentiated Amygdala Response to Repeated Emotional Pictures in Borderline Personality Disorder.

  Authors: Erin A Hazlett, Jing Zhang, Antonia S New, Yuliya Zelmanova, Kim E Goldstein, M Mehmet Haznedar, David Meyerson, Marianne Goodman, Larry J Siever, King-Wai Chu

  Biological psychiatry.

  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) ofBACKGROUND: 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?

  Authors: Edmund J S Sonuga-Barke, Graeme Fairchild

  Biological psychiatry.

  Psychiatric neuroeconomics offers an alternative approach to understanding mental disorders by studying the way disorder-related neurobiological alterations constrain economic agency, as revealedPsychiatric 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.

• Tumor Necrosis Factor Gene Variation Predicts Hippocampus Volume in Healthy Individuals.

  Authors: Bernhard T Baune, Carsten Konrad, Dominik Grotegerd, Thomas Suslow, Patricia Ohrmann, Jochen Bauer, Volker Arolt, Walter Heindel, Katharina Domschke, Sonja Schöning, Astrid Veronika Rauch, Christina Sehlmeyer, Harald Kugel, Udo Dannlowski

  Biological psychiatry.

  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 predispositionBACKGROUND: 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.

• Predictive Pursuit Association with Deficits in Working Memory in Psychosis.

  Authors: Amanda F Moates, Elena I Ivleva, Hugh B O'Neill, Nithin Krishna, C Munro Cullum, Gunvant K Thaker, Carol A Tamminga

  Biological psychiatry.

  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 theBACKGROUND: 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.

• Lithium and the Expanding Brain.

  Authors: William T Regenold

  Biological psychiatry.

• Cholinergic aspects of aging and Alzheimer's disease.

  Authors: Marsel Mesulam

  Biological psychiatry. 71(9):760-1.

• Is the Idle Mind a Devil's Workshop?

  Authors: P Murali Doraiswamy

  Biological psychiatry. 71(9):765-6.

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

  Authors: Kevin G Bath, Jocelyn Chuang, Joanna L Spencer-Segal, Dima Amso, Margaret Altemus, Bruce S McEwen, Francis S Lee

  Biological psychiatry.

  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 acrossBACKGROUND: 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.

• Depressive symptoms and mild cognitive impairment in the elderly: an ominous combination.

  Authors: David C Steffens

  Biological psychiatry. 71(9):762-4.

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