Biological Psychiatry - Articles in Press

Hair Cortisol Level as a Biomarker for Altered Hypothalamic-Pituitary-Adrenal Activity in Female Adolescents with Posttraumatic Stress Disorder After the 2008 Wenchuan Earthquake - Corrected Proof

2012-02-03

Background: The present study evaluated the accumulated changes in hair cortisol levels of patients with posttraumatic stress disorder (PTSD) attributed to the 2008 Wenchuan earthquake in China. Methods: Sixty-four female adolescents from two townships who experienced the earthquake were recruited 7 months after the disaster, including 32 subjects with PTSD (PTSD group) and 32 subjects without PTSD (non-PTSD group). Twenty matched adolescents were recruited from an area that was not affected significantly by the earthquake as the control group. Hair cortisol concentrations were measured by the electrochemiluminescence immunoassay in each 3-cm segment of hair sample from the scalp. Results: There was no significant difference at the baseline hair cortisol level in the three groups before the traumatic event (p > .6). Hair cortisol levels changed over time and differed among groups (p = .0042). The hair cortisol levels among the PTSD and non-PTSD subjects were elevated, suggesting increasing levels in response to stress. However, these two groups differed in their response. The non-PTSD subjects showed a significantly higher cortisol level than the PTSD group between month 2 and month 4 (p = .0137) and also between month 5 and month 7 (p = .0438) after the traumatic event. Conclusions: This study revealed a blunted response curve to the disaster among PTSD subjects compared with subjects without PTSD. These findings suggest that hair cortisol level could be used to assess the integrated hypothalamic-pituitary-adrenal activity over a period of months after traumatic events and be used to serve as a biomarker in patients with PTSD.

Replication of Ketamine's Antidepressant Efficacy in Bipolar Depression: A Randomized Controlled Add-On Trial - Corrected Proof

2012-02-02

Background: Currently, no pharmacological treatments for bipolar depression exist that exert rapid (within hours) antidepressant or antisuicidal effects. We previously reported that intravenous administration of the N-methyl-D-aspartate antagonist ketamine produced rapid antidepressant effects in patients with treatment-resistant bipolar depression. The present study sought to replicate this finding in an independent sample. Methods: In this double-blind, randomized, crossover, placebo-controlled study, 15 subjects with DSM-IV bipolar I or II depression maintained on therapeutic levels of lithium or valproate received a single intravenous infusion of either ketamine hydrochloride (.5 mg/kg) or placebo on 2 test days 2 weeks apart. The primary outcome measure was the Montgomery-Asberg Depression Rating Scale, which was used to rate overall depressive symptoms at baseline; at 40, 80, 110, and 230 minutes postinfusion; and on days 1, 2, 3, 7, 10, and 14 postinfusion. Results: Within 40 minutes, depressive symptoms, as well as suicidal ideation, significantly improved in subjects receiving ketamine compared with placebo (d = .89, 95% confidence interval = .61–1.16, and .98, 95% confidence interval = .64–1.33, respectively); this improvement remained significant through day 3. Seventy-nine percent of subjects responded to ketamine and 0% responded to placebo at some point during the trial. The most common side effect was dissociative symptoms, which occurred only at the 40-minute time point. Conclusions: This study replicated our previous finding that patients with bipolar depression who received a single ketamine infusion experienced a rapid and robust antidepressant response. In addition, we found that ketamine rapidly improved suicidal ideation in these patients.

Association of COL25A1 with Comorbid Antisocial Personality Disorder and Substance Dependence - Corrected Proof

2012-02-02

Background: Antisocial personality disorder (ASPD) is a psychiatric disorder characterized by a long-term pattern of manipulating, exploiting, or violating the rights of others. Methods: Subjects ascertained for genetic studies of substance dependence (SD) and diagnosed with ASPD and comorbid SD were included in a two-stage genetic association study. In the discovery stage, 627 single nucleotide polymorphisms (SNPs) located in 179 candidate genes for addiction were analyzed in a case-control cohort and family-based cohort. The significant findings were replicated in an independent case-control cohort. Results: One SNP, rs13134663, in the collagen XXV alpha 1 gene (COL25A1) was significantly associated with ASPD in both African Americans and European Americans (smallest p values were .0002 and .0004, respectively). There was also evidence of association with the same SNP in independent samples of African American and European American cases and control subjects (p = .035 and .033, respectively). Analysis of the combined set of case-control subjects yielded an allelic p value of 9 × 10−6 with odds ratio (95% confidence interval) of 1.3 (1.16, 1.47) (smallest p = 1 × 10−7; Bonferroni threshold p = .00012). Conclusions: The COL25A1 gene, located at chromosome 4q25, encodes the collagen-like Alzheimer amyloid plaque component precursor, a type II transmembrane protein specifically expressed in neurons; it co-localizes with amyloid β in senile plaques in Alzheimer disease brains. This SNP maps to the transcription factor binding site and is conserved in 17 vertebrates, including mice and rats. Our findings suggest that COL25A1 may be associated with ASPD, especially in the context of SD.

Increasing Histone Acetylation in the Hippocampus-Infralimbic Network Enhances Fear Extinction - Corrected Proof

James M. Stafford, Jonathan D. Raybuck, Andrey E. Ryabinin, K. Matthew Lattal — 2012-01-30

Background: A key finding from recent studies of epigenetic mechanisms of memory is that increasing histone acetylation after a learning experience enhances memory consolidation. This has been demonstrated in several preparations, but little is known about whether excitatory and inhibitory memories are equally sensitive to drugs that promote histone acetylation and how transcriptional changes in the hippocampal-medial prefrontal cortex network contribute to these drug effects. Methods: We compare the long-term behavioral consequences of systemic, intrahippocampal and intra–medial prefrontal cortex administration of the histone deacetylase inhibitor sodium butyrate (NaB) after contextual fear conditioning and extinction 1 and/or 14 days later in male c57BL/6J mice (n = 302). Levels of histone acetylation and expression of the product of the immediate-early gene c-Fos were assessed by immunohistochemistry following infusion of NaB into the hippocampus (n = 26). Results: Across a variety of conditions, the effects of NaB on extinction were larger and more persistent compared to the effects on initial memory formation. NaB administered following weak extinction induced behavioral extinction, infralimbic histone acetylation and c-Fos expression consistent with strong extinction. No similar effect was seen in the prelimbic cortex. The involvement of the infralimbic cortex was confirmed as infusions of NaB into the infralimbic, but not prelimbic cortex, induced extinction enhancements. Conclusions: These studies show that the memory modulating ability of drugs that enhance acetylation is sensitive to a variety of behavioral and molecular conditions. We further identify transcriptional changes in the hippocampal-infralimbic circuit associated with extinction enhancements induced by the histone deacetylase inhibitor NaB.

Dopamine Release in Chronic Cannabis Users: A [11C]Raclopride Positron Emission Tomography Study - Corrected Proof

2012-01-30

Background: Low striatal dopamine 2/3 receptor (D2/3) availability and low ventrostriatal dopamine (DA) release have been observed in alcoholism and cocaine and heroin dependence. Less is known about the dopaminergic system in cannabis dependence. We assessed D2/3 availability and DA release in abstinent cannabis users compared with control subjects and explored relationships to cannabis use history using [11C]raclopride positron emission tomography and an amphetamine challenge paradigm. Methods: Sixteen recently abstinent, psychiatrically healthy cannabis-using participants (27.3 ± 6.1 years, 1 woman, 15 men) and 16 matched control subjects (28.1 ± 6.7 years, 2 women, 14 men) completed two positron emission tomography scans, before and after injection of intravenous d-amphetamine (.3 mg/kg). Percent change in [11C]raclopride binding after amphetamine (change in nondisplaceable binding potential, ΔBPND) in subregions of the striatum was compared between groups. Correlations with clinical parameters were examined. Results: Cannabis users had an average consumption of 517 ± 465 estimated puffs per month, indicating mild to moderate cannabis dependence. Neither baseline BPND nor ΔBPND differed from control subjects in any region of interest, including ventral striatum. In cannabis-dependent subjects, earlier age of onset of use correlated with lower [ΔBPND] in the associative striatum when controlling for current age. Conclusions: Unlike other addictions, cannabis dependence of mild to moderate severity is not associated with striatal DA alterations. However, earlier or longer duration of use is related to lower DA release in the associative striatum. These observations suggest a more harmful effect of use during adolescence; more research is needed to distinguish effects of chronicity versus onset.

Cortical Volume, Surface Area, and Thickness in Schizophrenia and Bipolar Disorder - Corrected Proof

2012-01-27

Background: Magnetic resonance imaging studies have shown that structural brain abnormalities are present in both schizophrenia and bipolar disorder. Most previous studies have focused on brain tissue volumes, but advances in neuroimaging data processing have made it possible to separate cortical area and cortical thickness. The purpose of the present study was to provide a more complete picture of cortical morphometric differences in schizophrenia and bipolar disorder, decomposing cortical volume into its constituent parts, cortical thickness and cortical area. Methods: We analyzed magnetic resonance imaging images from a sample of 173 patients with schizophrenia, 139 patients with bipolar disorder, and 207 healthy control subjects. Maps of cortical volume, area, and thickness across the continuous cortical surface were generated within groups and compared between the groups. Results: There were widespread reductions in cortical volume in schizophrenia relative to healthy control subjects and patients with bipolar disorder type I. These reductions were mainly driven by cortical thinning, but there were also cortical area reductions in more circumscribed regions, which contributed to the observed volume reductions. Conclusions: The current surface-based methodology allows for a distinction between cortical thinning and reduction in cortical area and reveals that cortical thinning is the most important factor in volume reduction in schizophrenia. Cortical area reduction was not observed in bipolar disorder type I and may be unique to schizophrenia.

Increased Cerebrospinal Fluid Levels of Double-Stranded RNA-Dependant Protein Kinase in Alzheimer's Disease - Corrected Proof

2012-01-27

Background: The pathological hallmarks of Alzheimer's disease (AD) include accumulation of amyloid-β (Aß) peptide forming extracellular senile plaques, neurofibrillary tangles made of hyperphosphorylated tau protein with neuronal loss. Aβ peptide (1–42), total tau (T-tau), and phosphorylated tau at threonine 181 (p181tau) levels in the cerebrospinal fluid (CSF) are now validated biomarkers. The proapoptotic kinase R (PKR), is activated by Aβ accumulates in degenerating neurons in AD brains and controls protein synthesis and indirectly tau phosphorylation. Methods: In a prospective cohort study, the CSF of 91 patients were studied (AD: 45; amnestic mild cognitive impairment: 11; neurological disease control subjects [NDC]: 35). The levels of total PKR (T-PKR), phosphorylated PKR (pPKR), Aß 1–42, T-tau, and p181tau were assessed by immunoblotting or enzyme-linked immunosorbent assay methods. Receivers operating characteristic curves were used to examine the discriminatory power of T-PKR, pPKR, and pPKR/T-PKR ratio between AD and NDC patients. Results: Total PKR and pPKR concentrations were elevated in AD and amnestic mild cognitive impairment subjects. We have determined a pPKR value (optical density units) that could discriminate AD patients from control subjects with a sensitivity of 91.1% and a specificity of 94.3%. Among AD patients, T-PKR and pPKR levels correlate with CSF p181tau levels. Some AD patients with normal CSF Aß, T-tau, or p181tau levels had abnormal T-PKR and pPKR levels. Conclusions: The evaluation of CSF T-PKR and pPKR can discriminate between AD patients and NDC and could help to improve the biochemical diagnosis of AD.

Effective Deep Brain Stimulation in Heroin Addiction: A Case Report with Complementary Intracranial Electroencephalogram - Corrected Proof

2012-01-27

Deep brain stimulation (DBS) treatment consists of permanently implanted electrodes that deliver electrical pulses to a target brain region. DBS of the nucleus accumbens shows encouraging results as treatment for certain therapy-resistant psychiatric disorders () and has been suggested for therapy-resistant addiction (). Heroin addiction is a chronic relapsing brain disorder seriously affecting both the individual and the public (), and DBS could provide a new intervention for those patients who do not respond to current treatments. One central issue in DBS treatment is adaptation of the stimulation parameters: to achieve effective DBS treatment, an extensive optimization period is required in which stimulation parameters— such as contact points, current, and pulse width—are adapted based on clinical observations.

Electrophysiological Assessment of Auditory Stimulus-Specific Plasticity in Schizophrenia - Corrected Proof

Ryan P. Mears, Kevin M. Spencer — 2012-01-27

Background: Disrupted neuroplasticity may be an important aspect of the neural basis of schizophrenia. We used event-related brain potentials (ERPs) to assay neuroplasticity after auditory conditioning in chronic schizophrenia patients (SZ) and matched healthy control subjects (HC). Methods: Subjects (15 HC, 14 SZ) performed an auditory oddball task during electroencephalogram recording before and after auditory tetanic stimulation (Pre/Post Blocks). Each oddball block consisted of 1000-Hz and 1500-Hz standards and 400-Hz targets. During tetanic conditioning, 1000-Hz tones were presented at 11 Hz for 2.4 min. We analyzed the standard trials, comparing the ERPs evoked by the tetanized stimuli (1000 Hz tones: TS+) and untetanized stimuli (1500 Hz tones: TS–) in the Post Blocks with ERPs from the Pre Blocks (averaged into Baseline ERPs). Results: In Post Block 1 in HC, TS+ tones evoked a negative shift (60–350 msec) at right temporal electrodes relative to Baseline. No pre-/post-tetanus effects were found in SZ. In Post Block 2 in HC, TS+ tones evoked a positive shift (200–300 msec) at bilateral frontal electrodes. In SZ, TS+ tones evoked a positive shift (100–400 msec) at right frontotemporal electrodes. No pre-/post-tetanus effects were found in either subject group for the TS– tones. The right temporal Post Block 1 and 2 effects were correlated in SZ, suggesting a trade-off in the expression of these effects. Conclusions: These results suggest that stimulus-specific auditory neuroplasticity is abnormal in schizophrenia. The electrophysiologic assessment of stimulus-specific plasticity may yield novel targets for drug treatment in schizophrenia.

Magnitude of Impact of Executive Functioning and IQ on Episodic Memory in Schizophrenia - Corrected Proof

2012-01-24

Background: Research has implicated IQ and executive function (EF) as contributors to episodic memory impairments in schizophrenia. However, it has been difficult to quantitatively apportion the respective contributions of these factors. We conducted a series of analyses to objectively parse the associated variance and to determine to what extent episodic memory impairment in schizophrenia is independent of IQ and EF. Methods: Participants included 323 schizophrenia patients and 327 healthy controls from the National Insitute of Mental Health Sibling Study. Neurocognitive tests assessing IQ, EF, and episodic memory were administered. We examined group differences while controlling for IQ or EF in analyses of covariance, we used linear regression to quantify the amount of variance not explained by IQ or EF, and we matched control and patient subgroups on IQ or EF to determine if memory measures remained different. Results: Analyses of covariance revealed significant group differences between schizophrenia individuals and healthy control subjects across multiple episodic memory measures after controlling for IQ or EF. Furthermore, regressions with IQ and/or EF factors entered left more than 50% of variance in memory unaccounted. Follow-up true score variance analyses indicated that the majority of this variance was directly related to memory function. Matched subgroups also yielded subgroup differences on all memory measures. Conclusions: Findings across the multiple statistical strategies suggested that the mechanisms underlying the memory impairment in schizophrenia are fully attributable neither to IQ nor EF. Rather, they most likely reflect compromises in episodic memory processing itself and, by inference, the medial temporal system.

β-Arrestin2 Regulates Cannabinoid CB1 Receptor Signaling and Adaptation in a Central Nervous System Region–Dependent Manner - Corrected Proof

2012-01-24

Background: Cannabinoid CB1 receptors (CB1Rs) mediate the effects of ▵9-tetrahydrocannabinol (THC), the psychoactive component in marijuana. Repeated THC administration produces tolerance and dependence, which limit therapeutic development. Moreover, THC produces motor and psychoactive side effects. β-arrestin2 mediates receptor desensitization, internalization, and signaling, but its role in these CB1R effects and receptor regulation is unclear. Methods: CB1R signaling and behaviors (antinociception, hypothermia, catalepsy) were assessed in β-arrestin2-knockout (βarr2-KO) and wild-type mice after THC administration. Cannabinoid-stimulated [35S]GTPγS and [3H]ligand autoradiography were assessed by statistical parametric mapping and region-of-interest analysis. Results: β-arrestin2 deletion increased CB1R-mediated G-protein activity in subregions of the cortex but did not affect CB1R binding, in vehicle-treated mice. βarr2-KO mice exhibited enhanced acute THC-mediated antinociception and hypothermia, with no difference in catalepsy. After repeated THC administration, βarr2-KO mice showed reduced CB1R desensitization and/or downregulation in cerebellum, caudal periaqueductal gray, and spinal cord and attenuated tolerance to THC-mediated antinociception. In contrast, greater desensitization was found in hypothalamus, cortex, globus pallidus, and substantia nigra of βarr2-KO compared with wild-type mice. Enhanced tolerance to THC-induced catalepsy was observed in βarr2-KO mice. Conclusions: β-arrestin2 regulation of CB1R signaling following acute and repeated THC administration was region-specific, and results suggest that multiple, overlapping mechanisms regulate CB1Rs. The observations that βarr2-KO mice display enhanced antinociceptive responses to acute THC and decreased tolerance to the antinociceptive effects of the drug, yet enhanced tolerance to catalepsy, suggest that development of cannabinoid drugs that minimize CB1R interactions with β-arrestin2 might produce improved cannabinoid analgesics with reduced motor suppression.

Extracellular Signal-Regulated Kinase 2 Signaling in the Hippocampal Dentate Gyrus Mediates the Antidepressant Effects of Testosterone - Corrected Proof

Nicole Carrier, Mohamed Kabbaj — 2012-01-24

Background: Human and animal studies suggest that testosterone may have antidepressant effects. In this study, we sought to investigate the molecular mechanisms underlying the antidepressant effects of testosterone within the hippocampus, an area that is fundamental in the etiology of depression. Methods: The effects of testosterone replacements in gonadectomized adult male rats were investigated using the sucrose preference and forced swim tests. We explored possible effects of testosterone on hippocampal neurogenesis and gene expression of stress-related molecules. Through the use of viral vectors, we pursued the antidepressant molecular mechanism(s) of testosterone in mediating anhedonia and manipulated extracellular signal-regulated kinase 2 (ERK2) expression in the dentate gyrus in gonadectomized rats with testosterone replacements. Results: Testosterone had antidepressant effects, likely mediated by aromatization to estrogen metabolites, in the sucrose preference and forced swim tests despite having no effects on hippocampal cell proliferation or survival. We found a testosterone-dependent regulation of hippocampal ERK2 expression. Functionally, reducing ERK2 activity within the dentate gyrus induced anhedonia in gonadectomized rats receiving testosterone supplementation, whereas the overexpression of ERK2 rescued this behavior in gonadectomized rats. Conclusions: These results implicate a role for ERK2 signaling within the dentate gyrus area of the hippocampus as a key mediator of the antidepressant effects of testosterone.

Adenylate Cyclase 7 Is Implicated in the Biology of Depression and Modulation of Affective Neural Circuitry - Corrected Proof

2012-01-24

Background: Evolutionarily conserved genes and their associated molecular pathways can serve as a translational bridge between human and mouse research, extending our understanding of biological pathways mediating individual differences in behavior and risk for psychopathology. Methods: Comparative gene array analysis in the amygdala and cingulate cortex between the serotonin transporter knockout mouse, a genetic animal model replicating features of human depression, and existing brain transcriptome data from postmortem tissue derived from clinically depressed humans was conducted to identify genes with similar changes across species (i.e., conserved) that may help explain risk of depressive-like phenotypes. Human neuroimaging analysis was then used to investigate the impact of a common single-nucleotide polymorphism (rs1064448) in a gene with identified conserved human-mouse changes, adenylate cyclase 7 (ADCY7), on threat-associated amygdala reactivity in two large independent samples. Results: Comparative analysis identified genes with conserved transcript changes in amygdala (n = 29) and cingulate cortex (n = 19), both critically involved in the generation and regulation of emotion. Selected results were confirmed by real-time quantitative polymerase chain reaction, including upregulation in the amygdala of transcripts for ADCY7, a gene previously implicated in human depression and associated with altered emotional responsiveness in mouse models. Translating these results back to living healthy human subjects, we show that genetic variation (rs1064448) in ADCY7 biases threat-related amygdala reactivity. Conclusions: This converging cross-species evidence implicates ADCY7 in the modulation of mood regulatory neural mechanisms and, possibly, risk for and pathophysiology of depression, together supporting a continuous dimensional approach to major depressive disorder and other affective disorders.

A Polymorphism Associated with Depressive Disorders Differentially Regulates Brain Derived Neurotrophic Factor Promoter IV Activity - Corrected Proof

2012-01-20

Background: Changes in brain derived neurotrophic factor (BDNF) expression have been associated with mood disorders and cognitive dysfunction. Transgenic models that overexpress or underexpress BDNF demonstrate similar deficits in cognition and mood. We explored the hypothesis that BDNF expression is controlled by balancing the activity of BDNF promoter IV (BP4) with a negative regulatory region containing a polymorphism associated with cognitive dysfunction and mood disorders. Methods: We used comparative genomics, transgenic mouse production, and magnetofection of primary neurons with luciferase reporters and signal transduction agonist treatments to identify novel polymorphic cis-regulatory regions that control BP4 activity. Results: We show that BP4 is active in the hippocampus, the cortex, and the amygdala and responds strongly to stimuli such as potassium chloride, lithium chloride, and protein kinase C agonists. We also identified a highly conserved sequence 21 kilobase 5' of BP4 that we called BE5.2, which contains rs12273363, a polymorphism associated with decreased BDNF expression, mood disorders, and cognitive decline. BE5.2 modulated the ability of BP4 to respond to different stimuli. Intriguingly, the rarer disease associated allele, BE5.2(C), acted as a significantly stronger repressor of BP4 activity than the more common BE5.2(T) allele. Conclusions: This study shows that the C allele of rs12273363, which is associated with mood disorder, modulates BP4 activity in an allele-specific manner following cell depolarization or the combined activity of protein kinase A and protein kinase C pathways. The relevance of these findings to the role of BDNF misexpression in mood disorders and cognitive decline is discussed.

Contrasting Effects of Haloperidol and Lithium on Rodent Brain Structure: A Magnetic Resonance Imaging Study with Postmortem Confirmation - Corrected Proof

2012-01-16

Background: Magnetic resonance imaging (MRI) studies suggest that antipsychotic -treated patients with schizophrenia show a decrease in gray-matter volumes, whereas lithium-treated patients with bipolar disorder show marginal increases in gray-matter volumes. Although these clinical data are confounded by illness, chronicity, and other medications, they do suggest that typical antipsychotic drugs and lithium have contrasting effects on brain volume. Methods: Rodent models offer a tractable system to test this hypothesis, and we therefore examined the effect of chronic treatment (8 weeks) and subsequent withdrawal (8 weeks) with clinically relevant dosing of an antipsychotic (haloperidol, HAL) or lithium (Li) on brain volume using longitudinal in vivo structural MRI and confirmed the findings postmortem using unbiased stereology. Results: Chronic HAL treatment induced decreases in whole brain volume (−4%) and cortical gray matter (−6%), accompanied by hypertrophy of the corpus striatum (+14%). In contrast, chronic Li treatment induced increases in whole-brain volume (+5%) and cortical gray matter (+3%) without a significant effect on striatal volume. Following 8 weeks of drug withdrawal, HAL-induced changes in brain volumes normalized, whereas Li-treated animals retained significantly greater total brain volumes, as confirmed postmortem. However, the distribution of these contrasting changes was topographically distinct: with the haloperidol decreases more prominent rostral, the lithium increases were more prominent caudal. Conclusions: The implications of these findings for the clinic, potential mitigation strategies, and further drug development are discussed.

Does Stress Contribute to the Incubation of Craving? - Corrected Proof

Hollis C. Karoly, Kent E. Hutchison — 2012-01-13

The concept of incubation of craving in humans was first noted over 25 years ago in cocaine addicts who experienced increased drug craving and drug seeking in response to drug cues that persisted even after long periods of abstinence (). This phenomenon has since been observed using the extinction/reinstatement paradigm in rodents. Animals have shown time-dependent increases in drug seeking after withdrawal from cocaine (), alcohol (), heroin (), and methamphetamine (). Dovetailing this work, Bedi et al. () found that cue-induced craving in abstinent human smokers increases with time, even as baseline levels of craving and withdrawal decrease. Taken together, this evidence has clear implications for treatment and relapse prevention. However, mechanisms underlying incubation of craving are not well understood, and it is unclear whether drug cues alone precipitate incubation of craving and relapse or whether another confounding factor, such as stress, may be the causal agent. Stress is known to be a significant risk factor that predisposes individuals to develop substance use disorders and puts recovering addicts at risk for relapse (). By looking at the role of stress using parallel animal and human models, we can perhaps gain a new perspective on the issue of incubation of craving.

Presynaptic Inhibition of Gamma-Aminobutyric Acid Release in the Bed Nucleus of the Stria Terminalis by Kappa Opioid Receptor Signaling - Corrected Proof

2012-01-09

Background: The kappa opioid receptor (KOR) and its endogenous agonist, the neuropeptide dynorphin, are a critical component of the central stress system. Both dynorphin and KOR are expressed in the bed nucleus of the stria terminalis (BNST), a brain region associated with anxiety and stress. This suggests that KOR activation in this region may play a role in the regulation of emotional behaviors. To date, however, there has been no investigation of the ability of KOR to modulate synaptic transmission in the BNST. Methods: We used whole-cell patch-clamp recordings from acutely prepared mouse brain slices to examine the actions of KOR on inhibitory transmission in the BNST. Additionally, we used neurochemical and pathway-specific optogenetic manipulations to selectively stimulate gamma-aminobutyric acid (GABA)ergic fibers from the central nucleus of the amygdala (CeA) to the BNST. Results: We found that activation of KOR reduced GABAergic transmission through a presynaptic mechanism. Furthermore, we examined the signal transduction pathways that mediate this inhibition and provide the first functional information implicating extracellular signal-regulated kinase in KOR-mediated presynaptic modulation. Moreover, we found that at KOR signaling robustly reduced inhibitory synaptic transmission in the CeA to BNST pathway. Conclusions: Together, these results demonstrate that KOR provides important inhibitory control over presynaptic GABAergic signaling within the BNST and provides the first direct functional demonstration of KOR-sensitive long-range GABAergic connections between the CeA and the BNST.

Comparison of the Effects of Estradiol and Progesterone on Serotonergic Function - Corrected Proof

2012-01-09

Background: Ovarian hormones may contribute to the vulnerability to depression, as well as to the response to antidepressants (ADs). Previously, we reported that acute systemic treatment with estradiol or progesterone blocked the ability of the selective serotonin reuptake inhibitor, fluvoxamine, to inhibit serotonin transporter function in ovariectomized rats. In this study, behavioral consequences, as well as receptor mechanisms underlying these hormonal effects, were investigated. Methods: Using the forced swimming test, the acute effect of estradiol and/or progesterone on fluvoxamine's AD-like effects was investigated. Using in vivo chronoamperometry, the effect of local application of estradiol or progesterone into the hippocampus of ovariectomized rats on serotonin (5-HT) clearance, as well as on the ability of fluvoxamine to slow 5-HT clearance, were investigated. Results: The decreased immobility and increased swimming caused by fluvoxamine in the forced swimming test was blocked in rats treated with estradiol and/or progesterone. Local application of estradiol, but not progesterone, slowed 5-HT clearance and both hormones blocked the ability of fluvoxamine to slow 5-HT clearance. Use of hormone receptor agonists and antagonists, revealed that the effects of estradiol are mediated by activation of membrane, as well as nuclear estrogen receptors (ER). The AD-like effect of estradiol involved ER beta and G-protein coupled receptor 30, whereas its blockade of fluvoxamine's effects was ER alpha-mediated. The effects of progesterone occurred solely by activation of intracellular progesterone receptors. Conclusions: Targeting of ER beta or G-protein coupled receptor 30 might reveal a strategy to permit beneficial effects of estrogen without its deleterious effect on selective serotonin reuptake inhibitor efficacy.

Cumulative Adversity and Smaller Gray Matter Volume in Medial Prefrontal, Anterior Cingulate, and Insula Regions - Corrected Proof

Emily B. Ansell, Kenneth Rando, Keri Tuit, Joseph Guarnaccia, Rajita Sinha — 2012-01-05

Background: Cumulative adversity and stress are associated with risk of psychiatric disorders. While basic science studies show repeated and chronic stress effects on prefrontal and limbic neurons, human studies examining cumulative stress and effects on brain morphology are rare. Thus, we assessed whether cumulative adversity is associated with differences in gray matter volume, particularly in regions regulating emotion, self-control, and top-down processing in a community sample. Methods: One hundred three healthy community participants, aged 18 to 48 and 68% male, completed interview assessment of cumulative adversity and a structural magnetic resonance imaging protocol. Whole-brain voxel-based-morphometry analysis was performed adjusting for age, gender, and total intracranial volume. Results: Cumulative adversity was associated with smaller volume in medial prefrontal cortex (PFC), insular cortex, and subgenual anterior cingulate regions (familywise error corrected, p < .001). Recent stressful life events were associated with smaller volume in two clusters: the medial PFC and the right insula. Life trauma was associated with smaller volume in the medial PFC, anterior cingulate, and subgenual regions. The interaction of greater subjective chronic stress and greater cumulative life events was associated with smaller volume in the orbitofrontal cortex, insula, and anterior and subgenual cingulate regions. Conclusions: Current results demonstrate that increasing cumulative exposure to adverse life events is associated with smaller gray matter volume in key prefrontal and limbic regions involved in stress, emotion and reward regulation, and impulse control. These differences found in community participants may serve to mediate vulnerability to depression, addiction, and other stress-related psychopathology.

Fear Processing and Social Networking in the Absence of a Functional Amygdala - Corrected Proof

2012-01-05

Background: The human amygdala plays a crucial role in processing social signals, such as face expressions, particularly fearful ones, and facilitates responses to them in face-sensitive cortical regions. This contributes to social competence and individual amygdala size correlates with that of social networks. While rare patients with focal bilateral amygdala lesion typically show impaired recognition of fearful faces, this deficit is variable, and an intriguing possibility is that other brain regions can compensate to support fear and social signal processing. Methods: To investigate the brain's functional compensation of selective bilateral amygdala damage, we performed a series of behavioral, psychophysiological, and functional magnetic resonance imaging experiments in two adult female monozygotic twins (patient 1 and patient 2) with equivalent, extensive bilateral amygdala pathology as a sequela of lipoid proteinosis due to Urbach-Wiethe disease. Results: Patient 1, but not patient 2, showed preserved recognition of fearful faces, intact modulation of acoustic startle responses by fear-eliciting scenes, and a normal-sized social network. Functional magnetic resonance imaging revealed that patient 1 showed potentiated responses to fearful faces in her left premotor cortex face area and bilaterally in the inferior parietal lobule. Conclusions: The premotor cortex face area and inferior parietal lobule are both implicated in the cortical mirror-neuron system, which mediates learning of observed actions and may thereby promote both imitation and empathy. Taken together, our findings suggest that despite the pre-eminent role of the amygdala in processing social information, the cortical mirror-neuron system may sometimes adaptively compensate for its pathology.

The Effects of Stimulant Medication on Working Memory Functional Connectivity in Attention-Deficit/Hyperactivity Disorder - Corrected Proof

Christina G. Wong, Michael C. Stevens — 2012-01-03

Background: Working memory impairments are commonly found in attention-deficit/hyperactivity disorder (ADHD) and often improve with psychostimulant treatment. Little is known about how these medications affect the function of frontoparietal brain regions engaged for working memory. This study used functional magnetic resonance imaging (fMRI) to examine medication-related changes in brain activation and functional connectivity in ADHD. Methods: Eighteen ADHD-combined subtype youths (ages 11–17) twice completed a Sternberg working memory fMRI task in a randomized, double-blind, placebo-controlled design. Medications were individualized as patients' standard, clinically effective psychostimulant (e.g., methylphenidate or dextroamphetamine/amphetamine combination) dose. Brain activity and functional connectivity were characterized using group independent component analysis. SPM5 repeated-measures t tests compared ADHD patients' network engagement and regional functional connectivity on and off medication. Results: Independent component analysis identified six frontoparietal networks/components with hemodynamic responses to encoding/maintenance or retrieval phases of the Sternberg fMRI task. On medication, three of these networks significantly increased activation. Functional connectivity analyses found medication led to recruitment of additional brain regions that were not engaged into the networks when participants were on placebo. Also, medication strengthened connectivity of some frontoparietal regions. Many connectivity changes were directly related to improved working memory reaction time. Overall, there was strong evidence for regional functional connectivity changes following medication in structures previously implicated as abnormal in ADHD, such as anterior cingulate, ventrolateral prefrontal cortex, and precuneus. Conclusions: Stimulant medication has widespread effects on the functional connectivity of frontoparietal brain networks, which might be a mechanism that underlies their beneficial effects on working memory performance.

Optogenetics, Sex, and Violence in the Brain: Implications for Psychiatry - Corrected Proof

David J. Anderson — 2012-01-03

Pathological aggression and the inability to control aggressive impulses takes a tremendous toll on society. Yet aggression is a normal component of the innate behavior repertoire of most vertebrate animal species as well as of many invertebrates. Progress in understanding the etiology of disorders of aggressive behavior, whether genetic or environmental in nature, therefore requires an understanding of the brain circuitry that controls normal aggression. Efforts to understand this circuitry at the level of specific neuronal populations have been constrained by the limited resolution of classical methodologies, such as electrical stimulation and electrolytic lesion. The availability of new, genetically based tools for mapping and manipulating neural circuits at the level of specific, genetically defined neuronal subtypes provides an opportunity to investigate the functional organization of aggression circuitry with cellular resolution. However, these technologies are optimally applied in the mouse, where there has been surprisingly little traditional work on the functional neuroanatomy of aggression. Here we discuss recent, initial efforts to apply optogenetics and other state-of-the-art methods to the dissection of aggression circuitry in the mouse. We find, surprisingly, that neurons necessary and sufficient for inter-male aggression are located within the ventrolateral subdivision of the ventromedial hypothalamic nucleus, a structure traditionally associated with reproductive behavior. These neurons are intermingled with neurons activated during male–female mating, with approximately 20% overlap between the populations. We discuss the significance of these findings with respect to neuroethological and neuroanatomical perspectives on the functional organization of innate behaviors and their potential implications for psychiatry.

Cocaine Hydrolase Encoded in Viral Vector Blocks the Reinstatement of Cocaine Seeking in Rats for 6 Months - Corrected Proof

2012-01-03

Background: Cocaine dependence is a pervasive disorder with high rates of relapse. In a previous study, direct administration of a quadruple mutant albumin-fused butyrylcholinesterase that efficiently catalyzes hydrolysis of cocaine to benzoic acid and ecgonine methyl ester acutely blocked cocaine seeking in an animal model of relapse. In the present experiments, these results were extended to achieve a long-duration blockade of cocaine seeking with a gene transfer paradigm using a related butyrylcholinesterase-based cocaine hydrolase (CocH). Methods: Male and female rats were allowed to self-administer cocaine under a fixed-ratio 1 schedule of reinforcement for approximately 14 days. Following the final self-administration session, rats were injected with CocH vector or a control injection (empty vector or saline), and their cocaine solutions were replaced with saline for 14 days to allow for extinction of lever pressing. Subsequently, they were tested for drug-primed reinstatement by administering intraperitoneal injections of saline (S), cocaine (C) (5, 10, and 15 mg/kg), and d-amphetamine according to the following sequence: S, C, S, C, S, C, S, d-amphetamine. Rats then received cocaine-priming injections once weekly for 4 weeks and, subsequently, once monthly for up to 6 months. Results: Administration of CocH vector produced substantial and sustained CocH activity in plasma that corresponded with diminished cocaine-induced (but not amphetamine-induced) reinstatement responding for up to 6 months following treatment (compared with high-responding control animals). Conclusions: These results demonstrate that viral transfer of CocH may be useful in promoting long-term resistance to relapse to cocaine addiction.

Cortical Thickness and Folding Deficits in Conduct-Disordered Adolescents - Corrected Proof

Christopher J. Hyatt, Emily Haney-Caron, Michael C. Stevens — 2012-01-03

Background: Studies of pediatric conduct disorder (CD) have described frontal and temporal lobe structural abnormalities that parallel findings in antisocial adults. The purpose of this study was to examine previously unexplored cortical thickness and folding as markers for brain abnormalities in “pure CD”–diagnosed adolescents. On the basis of current frontotemporal theories, we hypothesized that CD youth would have thinner cortex or less cortical folding in temporal and frontal lobes than control subjects. Methods: We obtained T1-weighted brain structure images from 24 control and 19 CD participants aged 12 to 18 years, matched by gender and age. We measured group differences in cortical thickness and local gyrification index (regional cortical folding measure) using surface-based morphometry with clusterwise correction for multiple comparisons. Results: The CD participants, compared with control subjects, showed both reduced cortical thickness and folding. Thinner cortex was located primarily in posterior brain regions, including left superior temporal and parietal lobes, temporoparietal junction and paracentral lobule, right superior temporal and parietal lobes, temporoparietal junction, and precuneus. Folding deficits were located mainly in anterior brain regions and included left insula, ventro- and dorsomedial prefrontal, anterior cingulate and orbitofrontal cortices, temporal lobe, right superior frontal and parietal lobes, and paracentral lobule. Conclusions: Our findings generally agree with previous CD volumetric studies but here show the unique contributions of cortical thickness and folding to gray matter reductions in pure CD in different brain regions.

Psychostimulants Act Within the Prefrontal Cortex to Improve Cognitive Function - Corrected Proof

Robert C. Spencer, Raymond M. Klein, Craig W. Berridge — 2012-01-03

Background: At low and clinically relevant doses, psychostimulants enhance cognitive and behavioral function dependent on the prefrontal cortex (PFC) and extended frontostriatal circuitry. These actions are observed in individuals with attention-deficit/hyperactivity disorder, as well as in normal human and animal subjects. Despite the widespread use of these drugs, the sites of action involved in their cognition-enhancing and therapeutic effects are poorly understood. Indirect and/or correlative evidence suggests the cognition-enhancing/therapeutic effects of psychostimulants may involve actions directly within the PFC or extended frontostriatal circuitry. The current studies examined the degree to which methylphenidate (MPH) (Ritalin) acts within distinct frontostriatal subfields to improve PFC-dependent cognition as measured in a delayed-response test of spatial working memory. Methods: Working memory performance was assessed following microinfusion of vehicle or varying doses of MPH (.03–8.0 μg/500 nL) directly into the dorsomedial PFC (dorsal prelimbic and dorsal anterior cingulate cortex), the ventromedial PFC (infralimbic), and the dorsomedial striatum of rats (n = 69). Results: Methylphenidate infusion into the dorsomedial PFC, but not ventromedial PFC, elicited an inverted U-shaped facilitation of PFC-dependent cognition as measured in this task. The magnitude of this improvement was comparable with that seen with systemic administration. Additional studies demonstrated that although the dorsomedial striatum is necessary for accurate performance in this task, MPH infusion into this region did not affect working memory performance. Conclusions: These observations provide the first definitive evidence that the PFC is a site of action in the cognition-enhancing and presumably therapeutic actions of low-dose psychostimulants.

Neural Activation During Facial Emotion Processing in Unmedicated Bipolar Depression, Euthymia, and Mania - Corrected Proof

2011-12-30

Background: Studies incorporating direct comparisons across all phases of bipolar (BP) disorder are needed to elucidate the pathophysiology of bipolar disorder. However, functional neuroimaging studies that differentiate bipolar mood states from each other and from healthy subjects are few and have yielded inconsistent findings. Methods: One hundred five unmedicated adults were recruited: 30 with current bipolar depression (BPD), 30 with current bipolar hypomania or mania (BPM), 15 bipolar euthymic (BPE), and 30 healthy control subjects (HC). All subjects were diagnosed with DSM-IV BP (type I or II) using a structured clinical interview. Groups were age- and gender-ratio matched. In 3T functional magnetic resonance imaging experiments, subjects completed a negative facial emotion matching task. Results: Bipolar euthymic and BPD groups exhibited increased amygdala activation compared with HCs in response to the negative faces; however, in the BPM group, this increase was not seen. Conversely, both BPE and BPM groups had increased activation in the insula relative to HCs, but in the BPD group, this effect was not seen. All three BP groups exhibited increased activation of the putamen compared with HCs. In the cortical areas, the BPM group exhibited decreased left lateral orbitofrontal cortex activation compared with both BPEs and HCs, increased dorsal anterior cingulate cortex activation compared with the BPD group, and increased dorsolateral prefrontal cortical activation compared with all other groups. Conclusions: Both state- and trait-related abnormalities in corticolimbic activation were seen in response to the negative facial emotion processing in a large sample of unmedicated adults across BP mood states.

Functional Magnetic Resonance Imaging Correlates of Emotional Word Encoding and Recognition in Depression and Anxiety Disorders - Corrected Proof

2011-12-30

Background: Major depressive disorder (MDD), panic disorder, and social anxiety disorder are among the most prevalent and frequently co-occurring psychiatric disorders in adults and may be characterized by a common deficiency in processing of emotional information. Methods: We used functional magnetic resonance imaging during the performance of an emotional word encoding and recognition paradigm in patients with MDD (n = 51), comorbid MDD and anxiety (n = 59), panic disorder and/or social anxiety disorder without comorbid MDD (n = 56), and control subjects (n = 49). In addition, we studied effects of illness severity, regional brain volume, and antidepressant use. Results: Patients with MDD, prevalent anxiety disorders, or both showed a common hyporesponse in the right hippocampus during positive (>neutral) word encoding compared with control subjects. During negative encoding, increased insular activation was observed in both depressed groups (MDD and MDD + anxiety), whereas increased amygdala and anterior cingulate cortex activation during positive word encoding were observed as depressive state-dependent effects in MDD only. During recognition, anxiety patients showed increased inferior frontal gyrus activation. Overall, effects were unaffected by medication use and regional brain volume. Conclusions: Hippocampal blunting during positive word encoding is a generic effect in depression and anxiety disorders, which may constitute a common vulnerability factor. Increased insular and amygdalar involvement during negative word encoding may underlie heightened experience of, and an inability to disengage from, negative emotions in depressive disorders. Our results emphasize a common neurobiological deficiency in both MDD and anxiety disorders, which may mark a general insensitiveness to positive information.

Multiple Clinical Traits Predict Clinical Diagnosis of Depersonalization Disorder: Implications for DSM-V - Corrected Proof

2011-12-30

There is currently no final conclusion to which nosological group depersonalization disorder (DPD) can be assigned. DPD is characterized by three features—namely, a distorted body image, estrangement from reality in the absence of any psychotic perceptual interference, and estrangement from emotional and bodily feelings (). In the ICD-10, DPD constitutes a separate nosological category, whereas in the DSM-IV, it is subsumed under dissociative disorders. Some clinical experts claim that DPD rather shares features with either anxiety disorders or with depression (). To elucidate this problem further, we investigated cerebral emotion processing in DPD patients sampled nationwide across England, where we correlated relevant personality traits with brain response to happy and sad facial stimuli. Differential regression analyses were computed in which the regions discriminating DPD and normal control subjects (NC) groups were indicated by significant differences in regression slopes for these two groups.

Reply to: Neurobiology of Emotional Dysfunction in Schizophrenia: New Directions Revealed Through Meta-Analyses - Corrected Proof

2011-12-30

We appreciate the comments of Anticevic and colleagues () about our recent meta-analysis and neuroimaging of emotional processing in schizophrenia (). We also appreciate that they recognized our results represent an interim report from the field, as we stated in the article. Considering meta-analyses of neuroimaging data in general, one is struck both by the power to address specific questions about a single structure, as well as the ability to direct exploratory questions at the complex, interacting networks of the brain. Meta-analytic studies will undoubtedly play a greater role in neuroimaging research to condense and extract sense from the field of disparate findings, and there are many considerations to keep in mind as these studies come out. Our intention in this analysis was to explore networks throughout the brain, using several organizing constructs, such as implicit–explicit processing, perception–experience of emotion. We are pleased to see that the results appear useful, and gratified to know that the results are also appreciated as a “work in progress.” Questions about positive valence, interactions with cognition, modality effects, effects of medication, correlations with symptoms, and more remain for future iterations of meta-analytic work on emotional dysfunction in schizophrenia.

Neurobiology of Emotional Dysfunction in Schizophrenia: New Directions Revealed Through Meta-Analyses - Corrected Proof

Alan Anticevic, Jared X. Van Snellenberg, Deanna M. Barch — 2011-12-30

Affective dysfunction is a prominent feature of schizophrenia psychopathology. Behavioral studies converge on several distinct aspects of emotional dysfunction, namely, 1) emotion expression (); 2) recognition of facial expressions and emotional classification (); and 3) anticipation of hedonic experience (). However, precise neural deficits across these domains remain obscure. For a decade, neuroimaging studies have probed affective dysfunction in schizophrenia under a variety of conditions, but no clear consensus emerged. These equivocal findings revealed a clear need for meta-analytic summaries of reported effects: over the past year, three groups have independently conducted meta-analyses of the functional neuroimaging literature of emotional processing in schizophrenia (), with somewhat different, but complementary goals: 1) Li et al. examined evidence for differences in activation peaks across studies of facial emotion; 2) Anticevic and colleagues quantified the magnitude of activation differences in the amygdala; and 3) Taylor and colleagues expanded the search across all cortical and subcortical regions.

Optogenetic Modulation of Neural Circuits that Underlie Reward Seeking - Corrected Proof

Garret D. Stuber, Jonathan P. Britt, Antonello Bonci — 2011-12-26

The manifestation of complex neuropsychiatric disorders, such as drug and alcohol addiction, is thought to result from progressive maladaptive alterations in neural circuit function. Clearly, repeated drug exposure alters a distributed network of neural circuit elements. However, a more precise understanding of addiction has been hampered by an inability to control and, consequently, identify specific circuit components that underlie addictive behaviors. The development of optogenetic strategies for selectively modulating the activity of genetically defined neuronal populations has provided a means for determining the relationship between circuit function and behavior with a level of precision that has been previously unobtainable. Here, we briefly review the main optogenetic studies that have contributed to elucidate neural circuit connectivity within the ventral tegmental area and the nucleus accumbens, two brain nuclei that are essential for the manifestation of addiction-related behaviors. Additional targeted manipulation of genetically defined neural populations in these brain regions, as well as afferent and efferent structures, promises to delineate the cellular mechanisms and circuit components required for the transition from natural goal-directed behavior to compulsive reward seeking despite negative consequences.

Pre- and Perinatal Risk Factors in Adults with Attention-Deficit/Hyperactivity Disorder - Corrected Proof

Anne Halmøy, Kari Klungsøyr, Rolv Skjærven, Jan Haavik — 2011-12-26

Background: Attention-deficit/hyperactivity disorder (ADHD) is a prevalent and disabling lifespan disorder, but little is yet known about risk factors for ADHD persisting beyond adolescence. The present study investigates the association between pregnancy and birth complications and ADHD in adulthood. Methods: We used data from the Medical Birth Registry of Norway to compare pre-and perinatal risk factors among 2323 adults approved for medical treatment for ADHD, with the remaining population born during the same years, 1967–1987, and surviving into adulthood (n = 1,170,073). Relative risks (RR) adjusted for potential confounders were calculated. Results: Preterm (< 37 weeks of gestation) and extremely preterm birth (< 28 weeks of gestation) were associated with 1.3- and 5-fold increased risks of ADHD, respectively. Birth weights <2500 g and <1500 g also increased the risk of ADHD (RR: 1.5, 95% confidence interval [CI]: 1.2–1.8, and RR: 2.1, 95% CI: 1.3–3.6, respectively). Five-minute Apgar scores <4 and <7 were associated with 2.8- and 1.5-fold increased risks of persisting ADHD, respectively. Maternal epilepsy (RR: 1.7, 95% CI: 1.1–2.7) and offspring oral cleft (RR: 2.8, 95% CI: 1.6–4.9) occurred more frequently among adult ADHD patients. Conclusions: This is the first population-based study of pre-and perinatal risk factors in adults with ADHD. We show that low birth weight, preterm birth, and low Apgar scores increase the risk of ADHD, persisting up to 40 years after birth. The increased risk of ADHD related to oral cleft and to maternal epilepsy warrants further investigation to explore possible causal mechanisms.

The Stress-Induced Cytokine Interleukin-6 Decreases the Inhibition/Excitation Ratio in the Rat Temporal Cortex via Trans-Signaling - Corrected Proof

2011-12-26

Background: Although it is known that stress elevates the levels of pro-inflammatory cytokines and promotes hyper-excitable central conditions, a causal relationship between these two factors has not yet been identified. Recent studies suggest that increases in interleukin 6 (IL-6) levels are specifically associated with stress. We hypothesized that IL-6 acutely and directly induces cortical hyper-excitability by altering the balance between synaptic excitation and inhibition. Methods: We used patch-clamp to determine the effects of exogenous or endogenous IL-6 on electrically evoked postsynaptic currents on a cortical rat slice preparation. We used control subjects or animals systemically injected with lipopolysaccharide or subjected to electrical foot-shock as rat models of stress. Results: In control animals, IL-6 did not affect excitatory postsynaptic currents but selectively and reversibly reduced the amplitude of inhibitory postsynaptic currents with a postsynaptic effect. The IL-6-induced inhibitory postsynaptic currents decrease was inhibited by drugs interfering with receptor trafficking and/or internalization, including wortmannin, Brefeldin A, 2-Br-hexadecanoic acid, or dynamin peptide inhibitor. In both animal models, stress-induced decrease in synaptic inhibition/excitation ratio was prevented by prior intra-ventricular injection of an analog of the endogenous IL-6 trans-signaling blocker gp130. Conclusions: Our results suggest that stress-induced IL-6 shifts the balance between synaptic inhibition and excitation in favor of the latter, possibly by decreasing the density of functional γ-aminobutyric acid A receptors, accelerating their removal and/or decreasing their insertion rate from/to the plasma membrane. We speculate that this mechanism could contribute to stress-induced detrimental long-term increases in central excitability present in a variety of neurological and psychiatric conditions.

Differential Relationships of Mismatch Negativity and Visual P1 Deficits to Premorbid Characteristics and Functional Outcome in Schizophrenia - Corrected Proof

Tamara Friedman, Pejman Sehatpour, Elisa Dias, Megan Perrin, Daniel C. Javitt — 2011-12-23

Background: Mismatch negativity (MMN) and visual P1 are established event-related potential (ERP) markers of impaired auditory and visual sensory function in schizophrenia. Differential relationships of these measures with premorbid and present function and with clinical course have been noted previously in independent cohorts, but measures have not yet been compared within the same patient group. Methods: Twenty-six schizophrenia patients and 19 control subjects participated in a simultaneous visual and auditory ERPs experiment. Attended visual ERPs were obtained to low- and high-spatial frequency stimuli. Simultaneously, MMN was obtained to unattended pitch, duration, and intensity deviant stimuli. Premorbid function, symptom, and global outcome measures were obtained as correlational measures. Results: Patients showed substantial P1 reductions to low- but not high-spatial frequency stimuli, unrelated to visual acuity. Patients also exhibited reduced MMN to all deviant types. No significant correlations were observed between visual ERPs and premorbid or global outcome measures or illness duration. In contrast, MMN amplitude correlated significantly and independently with premorbid educational achievement, cognitive symptoms, global function, and illness duration. The MMN to duration versus other deviants was differentially reduced in individuals with poor premorbid function. Conclusions: Visual and auditory ERP measures are differentially related to the pathophysiology of schizophrenia. Visual deficits correlate poorly with functional measures and illness duration and serve primarily as trait vulnerability markers. The MMN deficits are independently related to premorbid function and illness duration, suggesting independent neurodevelopmental and neurodegenerative contributions. The lack of correlation between auditory and visual ERPs in schizophrenia suggests contributions from divergent underlying neurophysiological processes.

Evidence of a Dissociation Pattern in Resting-State Default Mode Network Connectivity in First-Episode, Treatment-Naive Major Depression Patients - Corrected Proof

2011-12-19

Background: Imaging studies have shown that major depressive disorder (MDD) is associated with altered activity patterns of the default mode network (DMN). However, the neural correlates of the resting-state DMN and MDD-related pathopsychological characteristics, such as depressive rumination and overgeneral autobiographical memory (OGM) phenomena, still remain unclear. Methods: Using independent component analysis, we analyzed resting-state functional magnetic resonance imaging data obtained from 35 first-episode, treatment-naive young adults with MDD and from 35 matched healthy control subjects. Results: Patients with MDD exhibited higher levels of rumination and OGM than did the control subjects. We observed increased functional connectivity in the anterior medial cortex regions (especially the medial prefrontal cortex and anterior cingulate cortex) and decreased functional connectivity in the posterior medial cortex regions (especially the posterior cingulate cortex/precuneus) in MDD patients compared with control subjects. In the depressed group, the increased functional connectivity in the anterior medial cortex correlated positively with rumination score, while the decreased functional connectivity in the posterior medial cortex correlated negatively with OGM score. Conclusions: We report dissociation between anterior and posterior functional connectivity in resting-state DMNs of first-episode, treatment-naive young adults with MDD. Increased functional connectivity in anterior medial regions of the resting-state DMN was associated with rumination, whereas decreased functional connectivity in posterior medial regions was associated with OGM. These results provide new evidence for the importance of the DMN in the pathophysiology of MDD and suggest that abnormal DMN activity may be an MDD trait.

Rare Copy Number Variants in Tourette Syndrome Disrupt Genes in Histaminergic Pathways and Overlap with Autism - Corrected Proof

2011-12-15

Background: Studies of copy number variation (CNV) have characterized loci and molecular pathways in a range of neuropsychiatric conditions. We analyzed rare CNVs in Tourette syndrome (TS) to identify novel risk regions and relevant pathways, to evaluate burden of structural variation in cases versus controls, and to assess overlap of identified variations with those in other neuropsychiatric syndromes. Methods: We conducted a case-control study of 460 individuals with TS, including 148 parent-child trios and 1131 controls. CNV analysis was undertaken using 370 K to 1 M probe arrays, and genotyping data were used to match cases and controls for ancestry. CNVs present in < 1% of the population were evaluated. Results: While there was no significant increase in the number of de novo or transmitted rare CNVs in cases versus controls, pathway analysis using multiple algorithms showed enrichment of genes within histamine receptor (subtypes 1 and 2) signaling pathways (p = 5.8 × 10−4 − 1.6 × 10−2), as well as axon guidance, cell adhesion, nervous system development, and synaptic structure and function processes. Genes mapping within rare CNVs in TS showed significant overlap with those previously identified in autism spectrum disorders but not intellectual disability or schizophrenia. Three large, likely pathogenic, de novo events were identified, including one disrupting multiple gamma-aminobutyric acid receptor genes. Conclusions: We identify further evidence supporting recent findings regarding the involvement of histaminergic and gamma-aminobutyric acidergic mechanisms in the etiology of TS and show an overlap of rare CNVs in TS and autism spectrum disorders.

Controlling the Elements: An Optogenetic Approach to Understanding the Neural Circuits of Fear - Corrected Proof

Joshua P. Johansen, Steffen B.E. Wolff, Andreas Lüthi, Joseph E. LeDoux — 2011-12-15

Neural circuits underlie our ability to interact in the world and to learn adaptively from experience. Understanding neural circuits and how circuit structure gives rise to neural firing patterns or computations is fundamental to our understanding of human experience and behavior. Fear conditioning is a powerful model system in which to study neural circuits and information processing and relate them to learning and behavior. Until recently, technological limitations have made it difficult to study the causal role of specific circuit elements during fear conditioning. However, newly developed optogenetic tools allow researchers to manipulate individual circuit components such as anatomically or molecularly defined cell populations, with high temporal precision. Applying these tools to the study of fear conditioning to control specific neural subpopulations in the fear circuit will facilitate a causal analysis of the role of these circuit elements in fear learning and memory. By combining this approach with in vivo electrophysiological recordings in awake, behaving animals, it will also be possible to determine the functional contribution of specific cell populations to neural processing in the fear circuit. As a result, the application of optogenetics to fear conditioning could shed light on how specific circuit elements contribute to neural coding and to fear learning and memory. Furthermore, this approach may reveal general rules for how circuit structure and neural coding within circuits gives rise to sensory experience and behavior.

Protein Kinase Mζ Is Necessary for Cocaine-Induced Synaptic Potentiation in the Ventral Tegmental Area - Corrected Proof

Shih-Yin Ho, Chih-Hao Chen, Tsung-Han Liu, Hsiao-Fu Chang, Jau-Cheng Liou — 2011-12-12

Background: Much progress has been made in our understanding of brain regions and specific receptors that are involved in the action of cocaine addiction. Although long-term modifications of mesolimbic reward circuit following cocaine exposure are responsible for cocaine-addicted behaviors, the underlying molecular mechanism at the cellular level is still obscure. Here, we investigated the possible participation of protein kinase Mζ (PKMζ) in synaptic potentiation following cocaine exposure. Methods: Spontaneous and evoked synaptic activity of glutamate synapse in saline- and cocaine-treated rats were examined by preparing acute brain slices and performing whole-cell voltage-clamp recordings from individual dopamine neurons in the ventral tegmental area (VTA). We also assessed the role of PKMζ on the behavioral responses by cocaine conditioned place preference. Results: Chelerythrine, an inhibitor of PKMζ, reversed the cocaine-induced facilitation of spontaneous synaptic transmission in the VTA. PKMζ inhibition by chelerythrine or myristoylated ζ inhibitory peptide significantly attenuated the cocaine exposure-induced enhancement of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor/N-methyl-D-aspartate receptor ratio. Myristoylated ζ inhibitory peptide had no effect on spike timing-dependent long-term potentiation in rats previously injected with saline but remarkably restored spike timing-dependent long-term potentiation in VTA dopamine neurons in slices prepared from rats that received single or multiple cocaine exposure. Western blot analyses showed that both single and five consecutive cocaine injections induced a significant increase in PKMζ level. Furthermore, intracranial infusion of myristoylated ζ inhibitory peptide in the VTA disrupted cocaine conditioned place preference. Conclusions: Our results suggest that persistent activity of PKMζ is a requisite for cocaine-induced enhancement of synaptic plasticity in the VTA and cocaine conditioned place preference.

1H-[13C]-Nuclear Magnetic Resonance Spectroscopy Measures of Ketamine's Effect on Amino Acid Neurotransmitter Metabolism - Corrected Proof

2011-12-12

Ketamine has recently gained significant attention owing to its psychotomimetic and more recently discovered rapid antidepressant-like properties. 1H-[13C]-nuclear magnetic resonance studies were employed to explore potential physiological processes underlying these unique effects. [1-13C]glucose and [2-13C]acetate-nuclear magnetic resonance ex vivo studies were performed on the medial prefrontal cortex (mPFC) and hippocampus of rats acutely treated with 30 mg/kg or 80 mg/kg ketamine and compared with saline-treated animals to determine the effects of ketamine on amino acid neurotransmitter cycling and glial metabolism. A subanesthetic, but not anesthetic, dose of ketamine significantly increased the percentage of 13C-enrichments of glutamate, γ-aminobutyric acid, and glutamine in the mPFC of rats. Subanesthetic doses of ketamine increased mPFC amino acid neurotransmitter cycling, as well as neuronal and glial energy metabolism. These data add to previous reports suggesting increased mPFC levels of glutamate release, following the administration of subanesthetic doses of ketamine, are related to the drug's acute effects on cognition, perception, and mood.

Punishing Food: What Brain Activity Can Tell Us About the Representation of Food in Recovered Anorexia Nervosa - Corrected Proof

Carmelo M. Vicario, Cristiano Crescentini — 2011-12-12

Reinforcement, the neural processing of, and behavioral response to, reward and punishment drives behavior including learning, skill acquisition, and socialization. It shapes behaviors from the most primitive (fight–flight, ingest–regurgitate, approach–avoid) to the most complex (buy–sell). An understanding of abnormal processing and responding to reinforcing stimuli is critical in a range of issues and topics across the fields of psychology and psychiatry including psychiatric and neurological illness, addictive behaviors, and eating disorders.

Reply to: Punishing Food: What Brain Activity Can Tell Us About the Representation of Food in Recovered Anorexia Nervosa - Corrected Proof

Felicity A. Cowdrey, Rebecca J. Park, Catherine J. Harmer, Ciara McCabe — 2011-12-12

Eating disorders are characterized by aberrant cognitions and behaviors around food. We used a novel functional magnetic resonance imaging task in a sample of recovered anorexia nervosa subjects to study the neural response to both pleasant and aversive food tastes and pictures compared with a group of matched female subjects who had never had the disorder. We report that individuals recovered from anorexia nervosa have an increased neural response to rewarding and aversive food stimuli, in the form of chocolate (e.g., in the ventral striatum) and moldy strawberries (e.g., in the caudate). These increased neural responses were found despite no significant differences in subjective ratings of the stimuli compared with control subjects. We agree with Vicario and colleague that these findings are consistent with reports of altered interoceptive awareness in those with a history of anorexia nervosa.

Nociceptin/Orphanin FQ Blockade of Corticotropin-Releasing Factor-Induced Gamma-Aminobutyric Acid Release in Central Amygdala Is Enhanced After Chronic Ethanol Exposure - Corrected Proof

Maureen T. Cruz, Melissa A. Herman, Marsida Kallupi, Marisa Roberto — 2011-12-08

Background: The central nucleus of the amygdala (CeA) mediates stress- and addiction-related processes. Corticotropin-releasing factor (CRF) and nociceptin/orphanin FQ (nociceptin) regulate ethanol intake and anxiety-like behavior. In the rat, CRF and ethanol significantly augment CeA gamma-aminobutyric acid (GABA) release, whereas nociceptin diminishes it. Methods: Using electrophysiologic techniques in an in vitro slice preparation, we investigated the interaction of nociceptin and CRF on evoked and spontaneous GABAergic transmission in CeA slices of naive and ethanol-dependent rats and the mechanistic role of protein kinase A. Results: In neurons from naive animals, nociceptin dose-dependently diminished basal-evoked GABAA receptor-mediated inhibitory postsynaptic potentials (IPSPs) by decreasing GABA release and prevented, as well as reversed, CRF-induced augmentation of IPSPs, actions that required PKA signaling. In neurons from ethanol-dependent animals, nociceptin decreased basal GABAergic transmission and blocked the CRF-induced increase in GABA release to a greater extent than in naive controls. Conclusions: These data provide new evidence for an interaction between the nociceptin and CRF systems in the CeA. Nociceptin opposes CRF effects on CeA GABAergic transmission with sensitization of this effect in dependent animals. These properties of nociceptin may underlie its anti-alcohol and anxiolytic properties and identify the nociceptin receptor as a useful therapeutic target for alcoholism.

Abnormal Functional Connectivity in Children with Attention-Deficit/Hyperactivity Disorder - Corrected Proof

Dardo Tomasi, Nora D. Volkow — 2011-12-08

Background: Attention-deficit/hyperactivity disorder (ADHD) is typically characterized by symptoms of inattention and hyperactivity/impulsivity, but there is increased recognition of a motivation deficit too. This neuropathology may reflect dysfunction of both attention and reward-motivation networks. Methods: To test this hypothesis, we compared the functional connectivity density between 247 ADHD and 304 typically developing control children from a public magnetic resonance imaging database. We quantified short- and long-range functional connectivity density in the brain using an ultrafast data-driven approach. Results: Children with ADHD had lower connectivity (short- and long-range) in regions of the dorsal attention (superior parietal cortex) and default-mode (precuneus) networks and in cerebellum and higher connectivity (short-range) in reward-motivation regions (ventral striatum and orbitofrontal cortex) than control subjects. In ADHD children, the orbitofrontal cortex (region involved in salience attribution) had higher connectivity with reward-motivation regions (striatum and anterior cingulate) and lower connectivity with superior parietal cortex (region involved in attention processing). Conclusions: The enhanced connectivity within reward-motivation regions and their decreased connectivity with regions from the default-mode and dorsal attention networks suggest impaired interactions between control and reward pathways in ADHD that might underlie attention and motivation deficits in ADHD.

PER2 rs2304672 Polymorphism Moderates Circadian-Relevant Reward Circuitry Activity in Adolescents - Corrected Proof

2011-12-05

Background: Reward behavior in animals is influenced by circadian genes, including clock-pathway genes such as Period2 (PER2). Several forms of psychiatric illness are associated with both altered reward function and disturbances in circadian function. The PER2 single nucleotide polymorphism (SNP) rs2304672 has been associated with psychiatric illnesses involving reward dysfunction. Associations among circadian genes, function in neural reward circuits, and circadian-influenced behavior have not yet been studied in humans, however.Methods: 90 healthy adolescents underwent functional magnetic resonance imaging during a guessing task with monetary reward, genotyping for two PER2 SNPs (rs2304672, rs2304674), and actigraphy to measure sleep in their home environments. Weekend sleep midpoint, a behavioral index of circadian function, was derived from actigraphy. Puberty was measured by physical exam.Results: The rs2304672 SNP predicted blood oxygenation level-dependent response to monetary reward as constrained by sleep midpoint. Later sleep midpoint was associated with reduced activity in a key component of reward circuitry, medial prefrontal cortex (mPFC; Brodmann area 9/10/32), to reward outcome (pcorrected < .05). G allele carriers showed reduced activity in mPFC relative to CC homozygotes.Conclusions: Our findings are the first to indicate that circadian genes have a significant impact upon circadian-relevant reward circuitry in humans. These findings have the potential to elucidate gene-brain-behavior relationships underlying reward processing and psychopathology.

The Effect of N-Acetylcysteine in the Nucleus Accumbens on Neurotransmission and Relapse to Cocaine - Corrected Proof

2011-12-05

Background: Relapse to cocaine seeking has been linked with low glutamate in the nucleus accumbens core (NAcore) causing potentiation of synaptic glutamate transmission from prefrontal cortex (PFC) afferents. Systemic N-acetylcysteine (NAC) has been shown to restore glutamate homeostasis, reduce relapse to cocaine seeking, and depotentiate PFC-NAcore synapses. Here, we examine the effects of NAC applied directly to the NAcore on relapse and neurotransmission in PFC-NAcore synapses, as well as the involvement of the metabotropic glutamate receptors 2/3 (mGluR2/3) and 5 (mGluR5).Methods: Rats were trained to self-administer cocaine for 2 weeks and following extinction received either intra-accumbens NAC or systemic NAC 30 or 120 minutes, respectively, before inducing reinstatement with a conditioned cue or a combined cue and cocaine injection. We also recorded postsynaptic currents using in vitro whole cell recordings in acute slices and measured cystine and glutamate uptake in primary glial cultures.Results: NAC microinjection into the NAcore inhibited the reinstatement of cocaine seeking. In slices, a low concentration of NAC reduced the amplitude of evoked glutamatergic synaptic currents in the NAcore in an mGluR2/3-dependent manner, while high doses of NAC increased amplitude in an mGluR5-dependent manner. Both effects depended on NAC uptake through cysteine transporters and activity of the cysteine/glutamate exchanger. Finally, we showed that by blocking mGluR5 the inhibition of cocaine seeking by NAC was potentiated.Conclusions: The effect of NAC on relapse to cocaine seeking depends on the balance between stimulating mGluR2/3 and mGluR5 in the NAcore, and the efficacy of NAC can be improved by simultaneously inhibiting mGluR5.

Reply to: Are Antidepressants Good for the Soul but Bad for the Matter? Using Noninvasive Brain Stimulation to Detangle Depression/Antidepressants Effects on Heart Rate Variability and Cardiovascular Risk - Corrected Proof

Andrew H. Kemp — 2011-12-05

We thank Brunoni et al. () for their interesting and thoughtful commentary on our review and meta-analysis on heart rate variability (HRV) (). Heart rate variability has generated significant interest in the research and clinical communities, because it predicts future mortality () and might underlie the poor social functioning observed in a variety of psychiatric disorders (), including major depressive disorder (MDD).

Are Antidepressants Good for the Soul but Bad for the Matter? Using Noninvasive Brain Stimulation to Detangle Depression/Antidepressants Effects on Heart Rate Variability and Cardiovascular Risk - Corrected Proof

Andre Russowsky Brunoni, Paulo Andrade Lotufo, Isabela M. Benseñor — 2011-12-05

Heart rate variability (HRV) is an electrocardiograph-based technique that assesses sympathovagal activity over the heartbeat. Lower HRV (i.e., low power in the low frequency of the power spectral analysis) has been associated with an increased risk for myocardial infarction () and other cardiovascular conditions and thus is a biomarker for cardiac illness. Two articles recently published in Biological Psychiatry showed that lower HRV is observed in major depressive disorder (MDD). However, whereas the meta-analysis of Kemp et al. () showed that this was associated more robustly with MDD severity, the longitudinal study of Licht et al. () observed that antidepressants were associated with lower HRV and their withdrawal with HRV increasing, therefore suggesting that they could play a key role for diminished vagal control over the heart of MDD treated patients. Because such patients present increased cardiovascular burden (), it is mandatory to investigate whether antidepressants might decrease HRV and whether this contributes to such elevated cardiovascular risk.

Increased Stress-Induced Dopamine Release in Psychosis - Corrected Proof

2011-12-02

Background: A pathologic response to common life stressors, in which a hyperresponsive dopaminergic system is thought to play a key role, is a potential etiologic factor in the triggering and relapse of psychosis. However, there is no direct evidence that brain dopaminergic response to stress is exaggerated in psychosis.Methods: Using the ability of endogenous dopamine (DA) to compete with [11C]-(+)-PHNO binding, as measured with positron emission tomography, we examined stress-induced DA release in response to a validated psychosocial stress task. We studied 12 clinical high-risk (CHR), 10 antipsychotic-naive subjects with schizophrenia (SCZ), and 12 matched healthy volunteers (HV). Stress-induced DA release was estimated as the percent change in binding potential between conditions (stress and control scan) in the striatal subdivisions: limbic striatum (LST), associative striatum (AST), and sensorimotor striatum (SMST).Results: We found a significant difference between groups in the AST (F = 8.13, df = 2,31, p = .001), and at the SMST (F = 3,64, df = 2,31, p = .03) but not in the LST (F = .43, df = 2,31, p = .40) with CHR and SCZ having larger [11C]-(+)-PHNO displacement in response to the stress. Bonferroni-corrected comparisons confirmed that HV displacement (–2.86%) in the AST was significantly different in CHR (6.97%) and SCZ (11.44%) (with no significant difference between CHR and SCZ).Conclusions: This study reveals a sensitized dopaminergic response to stress in a psychiatric condition and may have important theoretical and clinical implications regarding efforts to abort or delay relapse and/or conversion to psychosis.

In Vivo Evidence of Deep Brain Stimulation-Induced Dopaminergic Modulation in Tourette's Syndrome - Corrected Proof

2011-12-02

Due to its large effect size, deep brain stimulation (DBS) is progressively considered in the treatment of medication-resistant Tourette's syndrome (TS) (). Nevertheless, the underlying beneficial mechanisms of DBS in TS are still a matter of debate (). Treatment strategies (D2-receptor antagonists) as well as previous research results point to a dysfunction of basal ganglia-related circuits and hyperactive dopaminergic innervations (). It might thus be hypothesized that DBS acts via modulation of dopamine transmission; however, corresponding in vivo evidence is lacking, except for one positive single-patient [18F]fallypride-positron emission tomography (FP) investigation (). In fact, FP allows for quantification of D2/3-receptor availability in striatal and extrastriatal regions within a single positron emission tomography (PET) scan but requires more than 3 hours of acquisition time. Because TS patients suffer from heavy motor tics, a long-term anesthesia was necessary during the PET scan. Encouraged by the observation of relevant FP-binding changes within the pilot-investigation, we proceeded to enlarge the number of such investigations.

Orbitofrontal Volumes in Early Adolescence Predict Initiation of Cannabis Use: A 4-Year Longitudinal and Prospective Study - Corrected Proof

2011-12-02

Background: There is growing evidence that long-term, heavy cannabis use is associated with alterations in regional brain volumes. Although these changes are frequently attributed to the neurotoxic effects of cannabis, it is possible that some abnormalities might predate use and represent markers of vulnerability. To date, no studies have examined whether structural brain abnormalities are present before the onset of cannabis use. This study aims to determine whether adolescents who have initiated cannabis use early (i.e., before age 17 years) show premorbid structural abnormalities in the amygdala, hippocampus, orbitofrontal cortex, and anterior cingulate cortex.Methods: Participants (n = 121) were recruited from primary schools in Melbourne, Australia, as part of a larger study examining adolescent emotional development. Participants underwent structural magnetic resonance imaging at age 12 years and were assessed for cannabis use 4 years later, at age 16 years. At the follow-up assessment, 28 participants had commenced using cannabis (16 female subjects [57%]), and 93 had not (43 female subjects [46%]).Results: Smaller orbitofrontal cortex volumes at age 12 years predicted initiation of cannabis use by age 16 years. The volumes of other regions (amygdala, hippocampus, and anterior cingulate cortex) did not predict later cannabis use.Conclusions: These findings suggest that structural abnormalities in the orbitofrontal cortex might contribute to risk for cannabis exposure. Although the results have important implications for understanding neurobiological predictors of cannabis use, further research is needed to understand their relationship with heavier patterns of use in adulthood as well as later abuse of other substances.