Showing papers in "Progress in Neuro-psychopharmacology & Biological Psychiatry in 2015"

Decreased functional connectivity in an executive control network is related to impaired executive function in Internet gaming disorder

Abstract: Background Resting brain spontaneous neural activities across cortical regions have been correlated with specific functional properties in psychiatric groups. Individuals with Internet gaming disorder (IGD) demonstrate impaired executive control. Thus, it is important to examine executive control networks (ECNs) during resting states and their relationships to executive control during task performance. Methods Thirty-five IGD and 36 healthy control participants underwent a resting-state fMRI scan and performed a Stroop task inside and outside of the MRI scanner. Correlations between Stroop effect and functional connectivity among ECN regions of interest (ROIs) were calculated within and between groups. Results IGD subjects show lower functional connectivity in ECNs than do HC participants during resting state; functional-connectivity measures in ECNs were negatively correlated with Stroop effect and positively correlated with brain activations in executive-control regions across groups. Within groups, negative trends were found between Stroop effect and functional connectivity in ECNs in IGD and HC groups, separately; positive trends were found between functional connectivity in ECNs and brain activations in Stroop task in IGD and HC groups, separately. Conclusions Higher functional connectivity in ECNs may underlie better executive control and may provide resilience with respect to IGD. Lower functional connectivity in ECNs may represent an important feature in understanding and treating IGD.

Prenatal LPS-exposure - a neurodevelopmental rat model of schizophrenia - differentially affects cognitive functions, myelination and parvalbumin expression in male and female offspring

Abstract: Maternal infection during pregnancy increases the risk for the offspring to develop schizophrenia. Gender differences can be seen in various features of the illness and sex steroid hormones (e.g. estrogen) have strongly been implicated in the disease pathology. In the present study, we evaluated sex differences in the effects of prenatal exposure to a bacterial endotoxin (lipopolysaccharide, LPS) in rats. Pregnant dams received LPS-injections (100 μg/kg) at gestational day 15 and 16. The offspring was then tested for prepulse inhibition (PPI), locomotor activity, anxiety-like behavior and object recognition memory at various developmental time points. At postnatal day (PD) 33 and 60, prenatally LPS-exposed rats showed locomotor hyperactivity which was similar in male and female offspring. Moreover, prenatal LPS-treatment caused PPI deficits in pubertal (PD45) and adult (PD90) males while PPI impairments were found only at PD45 in prenatally LPS-treated females. Following prenatal LPS-administration, recognition memory for objects was impaired in both sexes with males being more severely affected. Additionally, we assessed prenatal infection-induced alterations of parvalbumin (Parv) expression and myelin fiber density. Male offspring born to LPS-challenged mothers showed decreased myelination in cortical and limbic brain regions as well as reduced numbers of Parv-expressing cells in the medial prefrontal cortex (mPFC), hippocampus and entorhinal cortex. In contrast, LPS-exposed female rats showed only a modest decrease in myelination and Parv immunoreactivity. Collectively, our data indicate that some of the prenatal immune activation effects are sex dependent and further strengthen the importance of taking into account gender differences in animal models of schizophrenia.

Altered gray matter density and disrupted functional connectivity of the amygdala in adults with Internet gaming disorder.

Abstract: Objectives The aim of this study was to evaluate the altered brain structure and functional connectivity (FC) among subjects with Internet gaming disorder (IGD). Methods We recruited 30 males with IGD and 30 controls and evaluated their gray matter density (GMD) and FC using resting fMRI. The severities of IGD, gaming urge, and impulsivity were also assessed. Results The results demonstrated that the subjects with IGD had a higher impulsivity and a greater severity of IGD. The subjects with IGD had a lower GMD over the bilateral amygdala than the controls. Further, the subjects with IGD had lower FC with the left amygdala over the left dorsolateral prefrontal lobe (DLPFC) and with the right amygdala over the left DLPFC and orbital frontal lobe (OFL). They also had higher FC with the bilateral amygdala over the contralateral insula than the controls. The FC between the left amygdala and DLPFC was negatively correlated with impulsivity. The FC of the right amygdala to the left DLPFC and orbital frontal lobe was also negatively correlated with impulsivity. Our results indicated that the altered GMD over the amygdala might represent vulnerability to IGD, such as impulsivity. Further analysis of the amygdala demonstrated impaired FC to the frontal lobe, which represents impulsivity. Conclusion The results of this study suggested that the amygdala plays a very influential role in the mechanism of IGD. Its detailed role should be further evaluated in future study and should be considered in the treatment of IGD.

Neuroendocrine regulation of the stress response in adult zebrafish, Danio rerio.

Abstract: The main objectives of this study were to investigate the dynamics of the cortisol stress response and the underlying molecular regulation in adult zebrafish exposed to acute and long-term stressors that differed in nature, duration and relative intensity. Fish showed a very rapid and prolonged increase in trunk cortisol concentrations, starting at around 15min and returning to basal levels at around 2h following exposure to acute stressors. In addition, acute stress affected significantly brain mRNA expression levels of several genes (corticotropin-releasing factor, crf; pro-opiomelanocortin, pomc; glucocorticoid receptor, gr; MR/GR ratio; prolactin, prl; hypocretin/orexin, hcrt; brain-derived neurotrophic factor, bdnf; c-fos). Exposure of fish to unpredictable relatively low-grade environmental and husbandry stressors (SP-1) did not affect the overall behaviour of fish, as well as trunk cortisol concentrations. Fish exposed to relatively higher-grade long-term stressors (SP-2) showed elevated cortisol levels as well as significant changes in most of gene transcripts. In particular, fish exposed to SP-2 showed statistically significant upregulation in brain gr, mr, prl and hcrt compared to SP-1 and control individuals. The highest mean values of bdnf transcripts were found in SP-2 exposed zebrafish and the lowest in control fish, while an approximately 5 to 6-fold upregulation was observed in c-fos mean relative mRNA levels of long-term stress-exposed fish, regardless of stressor intensity, compared to control zebrafish. In conclusion, we developed realistic acute and unpredictable long-term stress protocols, based on husbandry and environmental stressors and physical, chemical, mechanical and social stimuli that fish may experience either in nature or under intensive rearing conditions.

Schizophrenia and the gut-brain axis.

Abstract: Several risk factors for the development of schizophrenia can be linked through a common pathway in the intestinal tract. It is now increasingly recognized that bidirectional communication exists between the brain and the gut that uses neural, hormonal, and immunological routes. An increased incidence of gastrointestinal (GI) barrier dysfunction, food antigen sensitivity, inflammation, and the metabolic syndrome is seen in schizophrenia. These findings may be influenced by the composition of the gut microbiota. A significant subgroup of patients may benefit from the initiation of a gluten and casein-free diet. Antimicrobials and probiotics have therapeutic potential for reducing the metabolic dysfunction and immune dysregulation seen in patients with schizophrenia.

Impaired risk evaluation in people with Internet gaming disorder: fMRI evidence from a probability discounting task.

Abstract: This study examined how Internet gaming disorder (IGD) subjects modulating reward and risk at a neural level under a probability-discounting task with functional magnetic resonance imaging (fMRI). Behavioral and imaging data were collected from 19 IGD subjects (22.2 ± 3.08 years) and 21 healthy controls (HC, 22.8 ± 3.5 years). Behavior results showed that IGD subjects prefer the probabilistic options to fixed ones and were associated with shorter reaction time, when comparing to HC. The fMRI results revealed that IGD subjects show decreased activation in the inferior frontal gyrus and the precentral gyrus when choosing the probabilistic options than HC. Correlations were also calculated between behavioral performances and brain activities in relevant brain regions. Both of the behavioral performance and fMRI results indicate that people with IGD show impaired risk evaluation, which might be the reason why IGD subjects continue playing online games despite the risks of widely known negative consequence.

Kappa opioid receptor signaling in the brain: Circuitry and implications for treatment.

Abstract: Kappa opioid receptors (KORs) in the central nervous system have been known to be important regulators of a variety of psychiatry illnesses, including anxiety and addiction, but their precise involvement in these disorders is complex and has yet to be fully elucidated. Here, we briefly review the pharmacology of KORs in the brain, including KOR's involvement in anxiety, depression, and drug addiction. We also review the known neuronal circuitry impacted by KOR signaling, and interactions with corticotrophin-releasing factor (CRF), another key peptide in anxiety-related illnesses, as well as the role of glucocorticoids. We suggest that KORs are a promising therapeutic target for a host of neuropsychiatric conditions.

Purinergic system dysfunction in mood disorders: a key target for developing improved therapeutics.

Abstract: Uric acid and purines (such as adenosine) regulate mood, sleep, activity, appetite, cognition, memory, convulsive threshold, social interaction, drive, and impulsivity. A link between purinergic dysfunction and mood disorders was first proposed a century ago. Interestingly, a recent nationwide population-based study showed elevated risk of gout in subjects with bipolar disorder (BD), and a recent meta-analysis and systematic review of placebo-controlled trials of adjuvant purinergic modulators confirmed their benefits in bipolar mania. Uric acid may modulate energy and activity levels, with higher levels associated with higher energy and BD spectrum. Several recent genetic studies suggest that the purinergic system - particularly the modulation of P1 and P2 receptor subtypes - plays a role in mood disorders, lending credence to this model. Nucleotide concentrations can be measured using brain spectroscopy, and ligands for in vivo positron emission tomography (PET) imaging of adenosine (P1) receptors have been developed, thus allowing potential target engagement studies. This review discusses the key role of the purinergic system in the pathophysiology of mood disorders. Focusing on this promising therapeutic target may lead to the development of therapies with antidepressant, mood stabilization, and cognitive effects.

A critical review of the efficacy of non-steroidal anti-inflammatory drugs in depression

Abstract: Non-steroidal anti-inflammatory drugs (NSAIDs) require further investigation given mixed results regarding efficacy. We critically and systematically reviewed the literature to determine whether selective COX-2 and non-selective COX inhibitor NSAIDs as adjuncts or monotherapy affect depressive symptoms. Electronic databases including Embase, PsycINFO, Ovid Medline, ScienceDirect, Google Scholar and the Cochrane Central Register of Controlled Trials database were searched up to September 2013. We utilised randomised controlled trials (RCTs), cohort studies and an open label study examining the efficacy of NSAIDs as adjuncts or monotherapy on depressive symptoms in subjects without major comorbidities. There were a total of 6 studies exploring the efficacy of selective COX-2 inhibitor NSAIDs on depressive symptoms with a total of 2706 subjects from 6 RCTs. 4 of the RCTs showed a significant effect of NSAIDs; 2 demonstrated no effect. There were a total of 5 studies exploring the efficacy of non-selective COX inhibitor NSAIDs on depressive symptoms with a total of 7978 subjects. There was 1 RCT, 3 cohort studies and 1 open label pilot study. The RCT failed to show a significant result. 1 of the retrospective cohort studies showed a positive result, with the other 2 showing no effect. The pilot study showed a positive result for NSAIDs. These studies demonstrated significant methodological heterogeneity (i.e. age range, sex, presence of antidepressant use, method of depression measure, severity of depressive symptoms, duration and study design (RCT vs. cohort)). The efficacy of NSAIDs on depressive symptoms appears negligible, however firm conclusions are difficult given the inconsistent findings and substantial methodological heterogeneity. Further high quality research is needed to explore NSAID efficacy in clinical and biological subtypes of depression, as monotherapy and adjunct with various antidepressants, and across various ages.

Maternal thyroid autoantibody and elevated risk of autism in a national birth cohort

Abstract: Objective Autoimmune disruption may contribute to risk for autism; however, since previous studies relied upon clinical diagnoses, exposure misclassification and recall bias are limitations. Thyroid peroxidase antibody (TPO-Ab) is an autoantibody involved in autoimmune thyroiditis. We aimed to test the a priori hypothesis that positivity to maternal serum TPO-Ab (TPO-Ab +) (defined as > 156 IU/ml) during pregnancy is related to childhood autism. Method The study was based on a nested case-control design of the Finnish Prenatal Study of Autism (FiPS-A), a national birth cohort that includes prospectively drawn archived maternal serum specimens from virtually the entire pregnant population of Finland beginning in 1983. Cases of childhood autism (ICD-10F84.0) born from 1987 to 2005 were ascertained by performing linkages between national birth and inpatient/outpatient registries. All diagnosed cases in Finland over the birth years, and comparison subjects without ASD or severe/profound intellectual disability were matched 1:1 on date of birth, sex, birthplace, and residence in Finland. Maternal serum specimens were assayed in 967 matched case–control pairs for TPO-Ab by a chemiluminescent microparticle immunoassay blind to case/control status. Data were analyzed by conditional logistic regression for matched sets. Results The prevalence of maternal TPO-Ab + was significantly increased in pregnancies giving rise to autism cases (6.15%) compared to controls (3.54%). The odds of autism were increased by nearly 80% among offspring of mothers who were TPO-Ab + during pregnancy (OR = 1.78, 95% CI = 1.16–2.75, p = 0.009), compared to mothers negative for this autoantibody. There was also a significant relationship between maternal TPO-Ab defined as a continuous variable and odds of autism (OR = 1.09, 95% CI = 1.01, 1.17, p = 0.02). Measures of maternal thyroid hormones did not differ between groups. Conclusions These findings provide the first biomarker-based evidence that a class of known maternal autoimmune disorders is related to autism in offspring.

Transcranial electric stimulation and neurocognitive training in clinically depressed patients: A pilot study of the effects on rumination

Abstract: Rumination is a cognitive-affective thinking style that plays a key role in the onset and maintenance of depression. Recently, it was shown that clinically depressed patients who received a neurocognitive training - involving two weeks of repetitive cognitive control exercises that necessitate prefrontal engagement - are more able to control over ruminative negative thoughts than patients who only received treatment as usual. Transcranial Direct Current Stimulation (tDCS) is a biological technique that can directly modulate prefrontal excitability via the manipulation of neural membrane potentials. In this randomized double-blind trial, we investigated whether bifrontal tDCS (anode over the left/cathode over the right dorsolateral prefrontal cortex (DLPFC)) would enhance the influence of a neurocognitive training on depressive brooding, the maladaptive form of rumination. Major depressed patients were trained using a procedure based on the Paced Auditory Serial Addition Task (PASAT), a task that relies heavily on working memory and is found to engage the DLPFC. One group (n=19) completed the PASAT training together with active tDCS and another group (n=14) completed the same training together with sham (placebo) tDCS. In both groups, depressive brooding was reduced following the PASAT training. Moreover, we observed that improvement in working memory over the course of the training was associated with a greater reduction in depressive brooding post- versus pre-intervention. However, tDCS did not moderate this association between changes in working memory and changes in depressive brooding. Possible explanations for this absent moderation of tDCS, as well as avenues for future research to influence ruminative thinking in depression, are discussed.

Deviant white matter structure in adults with attention-deficit/hyperactivity disorder points to aberrant myelination and affects neuropsychological performance

Abstract: Attention-deficit/hyperactivity disorder (ADHD) in childhood is characterized by gray and white matter abnormalities in several brain areas. Considerably less is known about white matter microstructure in adults with ADHD and its relation with clinical symptoms and cognitive performance. In 107 adult ADHD patients and 109 gender-, age- and IQ-matched controls, we used diffusion tensor imaging (DTI) with tract-based spatial statistics (TBSS) to investigate whole-skeleton changes of fractional anisotropy (FA) and mean, axial, and radial diffusivity (MD, AD, RD). Additionally, we studied the relation of FA and MD values with symptom severity and cognitive performance on tasks measuring working memory, attention, inhibition, and delay discounting. In comparison to controls, participants with ADHD showed reduced FA in corpus callosum, bilateral corona radiata, and thalamic radiation. Higher MD and RD were found in overlapping and even more widespread areas in both hemispheres, also encompassing internal and external capsule, sagittal stratum, fornix, and superior lateral fasciculus. Values of FA and MD were not associated with symptom severity. However, within some white matter clusters that distinguished patients from controls, worse inhibition performance was associated with reduced FA and more impulsive decision making was associated with increased MD. This study shows widespread differences in white matter integrity between adults with persistent ADHD and healthy individuals. Changes in RD suggest aberrant myelination as a pathophysiological factor in persistent ADHD. The microstructural differences in adult ADHD may contribute to poor inhibition and greater impulsivity but appear to be independent of disease severity.

Acute anticonvulsant effects of capric acid in seizure tests in mice

Abstract: Capric acid (CA10) is a 10-carbon medium-chain fatty acid abundant in the medium-chain triglyceride ketogenic diet (MCT KD). The purpose of this study was to characterize acute anticonvulsant effects of CA10 across several seizure tests in mice. Anticonvulsant effects of orally (p.o.) administered CA10 were assessed in the maximal electroshock seizure threshold (MEST), 6-Hz seizure threshold, and intravenous pentylenetetrazole (i.v. PTZ) seizure tests in mice. Acute effects of CA10 on motor coordination were assessed in the grip and chimney tests. Plasma and brain concentrations of CA10 were measured. Co-administration studies with CA10 and another abundant medium-chain fatty acid, caprylic acid (CA8) were performed. CA10 showed significant and dose-dependent anticonvulsant properties by increasing seizure thresholds in the 6-Hz and MEST seizure tests; it was ineffective in the i.v. PTZ seizure test. At higher doses than those effective in the 6-Hz and MEST seizure tests, CA10 impaired motor performance in the grip and chimney tests. An enhanced anticonvulsant response in the 6-Hz seizure test was produced when CA8 and CA10 were co-administered. An acute p.o. administration of CA10 resulted in dose-proportional increases in its plasma and brain concentrations. CA10 exerted acute anticonvulsant effects at doses that produce plasma exposures comparable to those reported in epileptic patients on the MCT KD. An enhanced anticonvulsant effect is observed when CA10 and the other main constituent of the MCT KD, CA8, were co-administered. Thus, acute anticonvulsant properties of CA10 and CA8 may influence the overall clinical efficacy of the MCT KD.

Resting-state regional homogeneity as a biological marker for patients with Internet gaming disorder: A comparison with patients with alcohol use disorder and healthy controls

Abstract: Objective Internet gaming disorder (IGD) shares core clinical features with other addictive disorders, such as gambling disorder and substance use disorder. Designation of IGD as a formal disorder requires elucidation of its neurobiological features and comparison of these with those of other addictive disorders. The aims of the present study were to identify the neurobiological features of the resting-state brain of patients with IGD, alcohol use disorder (AUD), and healthy controls, and to examine brain regions related to the clinical characteristics of IGD. Method Functional magnetic resonance imaging was performed on 16 subjects with IGD, 14 subjects with AUD, and 15 healthy controls during the resting-state. We computed regional homogeneity (ReHo) measures to identify intrinsic local connectivity and to explore associations with clinical status and impulsivity. Results We found significantly increased ReHo in the posterior cingulate cortex (PCC) of the IGD and AUD groups, and decreased ReHo in the right superior temporal gyrus (STG) of those with IGD, compared with the AUD and HC groups. We also found decreased ReHo in the anterior cingulate cortex of patients with AUD. Scores on Internet addiction severity were positively correlated with ReHo in the medial frontal cortex, precuneus/PCC, and left inferior temporal cortex (ITC) among those with IGD. Furthermore, impulsivity scores were negatively correlated with that in the left ITC in individuals with IGD. Conclusion Our results provide evidence of distinctive functional changes in the resting-state of patients with IGD and demonstrate that increased ReHo in the PCC may be a common neurobiological feature of IGD and AUD and that reduced ReHo in the STG may be a candidate neurobiological marker for IGD, differentiating individuals with this disorder from those with AUD and healthy controls.

Neural correlates during working memory processing in major depressive disorder

Abstract: Background Functional magnetic resonance imaging (fMRI) studies in major depressive disorder (MDD) have revealed cortical-limbic-subcortical dysfunctions during working memory (WM) processing, but the results are inconsistent and it is unclear to what extent these findings are influenced by demographic, clinical characteristics and task performance of patients. The present study conducted a quantitative coordinate-based meta-analysis of fMRI data to investigate the hypothesized dysfunction in the neural correlates during WM processing in MDD. Methods A systematic research was conducted for fMRI studies during WM processing comparing MDD patients with healthy controls (HC). Meta-analysis was performed using effect size signed differential mapping (ES-SDM). Meta-regression analyses with age, sex and medication as factors were performed in MDD group. Results Functional MRI data of 160 MDD patients and 203 HC from 13 WM experiments across 11 studies were included in this meta-analysis. In the pooled meta-analysis of all included studies, significant increased activation during WM in the left lateral prefrontal cortex, left precentral gyrus, left insula, right superior temporal and right supramarginal areas, and significant decreased activity in the right precentral gyrus, right precuneus and right insula were observed in MDD compared with controls. In the subgroup analysis of the studies with matched task performance, MDD subgroup showed hyperactivation only in the left prefrontal cortex and hypoactivation in the regions similar to the pooled analysis. The meta-regression with age, sex and medication showed no significance in MDD group. Conclusions Regardless of differences in task performance between groups, patients with MDD showed consistent functional abnormalities in the cortical-limbic-subcortical circuitry during WM processing. Distinct patterns of neural engagement may reflect compensatory neural strategies to potential dysfunction in MDD.

Imipramine protects against the deleterious effects of chronic corticosterone on depression-like behavior, hippocampal reelin expression, and neuronal maturation.

Abstract: We have hypothesized that a downregulation of reelin and deficient maturation of adult-born hippocampal neurons are important factors in the pathogenesis of depression. This hypothesis is based on previous work showing that depression-like behavior in rats treated with protracted corticosterone develops in concert with decreased dendritic complexity in newborn hippocampal granule neurons and decreased reelin expression in the proliferative subgranular zone of the dentate gyrus. In addition, heterozygous reeler mice with approximately 50% of normal brain levels of reelin are more vulnerable to the depressogenic effects of corticosterone than wild-type mice. The purpose of this experiment was to provide pharmacological validation for the link between reelin, neuronal maturation, and depression by examining whether the deleterious effects of corticosterone on these measures could be prevented by co-administration of the antidepressant imipramine. Rats received corticosterone injections, corticosterone injections plus either 10 or 15mg/kg imipramine injections, or vehicle injections for 21 consecutive days. They were then subjected to the forced swim test to assess depression-like behavior and sacrificed for immunohistochemical examination of immature neuron number and dendritic complexity and the presence of reelin+cells. We found that corticosterone increases depression-like behavior, decreases the number of reelin+cells in the subgranular zone, and decreases the number and complexity of immature neurons in the granule cell layer. All of these behavioral and cellular phenotypes were prevented by imipramine, providing further support for the idea that reelin is involved in the pathogenesis of depression.

Dissociation of decision making under ambiguity and decision making under risk: a neurocognitive endophenotype candidate for obsessive-compulsive disorder.

Abstract: Evidence in the literature suggests that executive dysfunction is regarded as an endophenotype candidate for obsessive-compulsive disorder (OCD). Decision making is an important domain of executive function. However, few studies that have investigated whether decision making is a potential endophenotype for OCD have produced inconsistent results. Differences in the findings across these studies may be attributed to several factors: different study materials, comorbidity, medication, etc. There are at least two types of decision making that differ mainly in the degree of uncertainty and how much useful information about consequences and their probabilities are provided to the decision maker: decision making under ambiguity and decision making under risk. The aim of the present study was to simultaneously examine decision making under ambiguity as assessed by the Iowa Gambling Task (IGT) and decision making under risk as measured by the Game of Dice Task (GDT) in OCD patients and their unaffected first-degree relative (UFDR) for the first time. The study analyzed 55 medication-naive, non-depressed OCD patient probands, 55 UFDRs of the OCD patients and 55 healthy matched comparison subjects (CS) without a family history of OCD with the IGT, the GDT and a neuropsychological test battery. While the OCD patients and the UFDRs performed worse than the CS on the IGT, they were unimpaired on the GDT. Our study supports the claim that decision making under ambiguity differs from decision making under risk and suggests that dissociation of decision making under ambiguity and decision making under risk may qualify to be a neurocognitive endophenotypes for OCD.

Disrupted structural connectivity network in treatment-naive depression.

Abstract: Background Neuroimaging studies suggest that treatment-naive depression (TD) is characterized by abnormal functional connectivity between specific brain regions. However, the question surrounding the structural basis of functional aberrations in TD patients still remains. Methods In the present study, diffusion tensor imaging tractography was employed to construct structural connectivity networks in 22 early adult-onset, first-episode TD patients and 19 healthy controls (HC). Graph theory and network-based statistic (NBS) were then employed to investigate systematically the alteration of whole brain structural topological organization and structural connectivity in TD patients. Results Graph theoretical analysis revealed that, compared with HC, TD patients exhibited altered structural topological measures, including decreased shortest path length, normalized clustering coefficient, normalized shortest path length, and small-worldness, as well as increased global and local efficiency. NBS results further revealed that TD patients showed two altered structural sub-networks. One sub-network mainly involved connections between the right orbitofrontal cortex (OFC) and the right insula, putamen, caudate, hippocampus, fusiform gyrus, inferior temporal gyrus and lingual gyrus. The other sub-network mainly included connections between the left OFC and the left gyrus rectus, insula, putamen, caudate, thalamus, pallidum and middle occipital gyrus. Conclusions The findings suggest that TD patients exhibit a disruption in the topological organization of structural brain networks. The altered orbitofrontal connectivity may particularly contribute to the manifestation of symptoms in TD patients. The abnormalities may facilitate understanding of the functional disturbances of mood and cognition in the disease.

Behavioral alterations in rat offspring following maternal immune activation and ELR-CXC chemokine receptor antagonism during pregnancy: implications for neurodevelopmental psychiatric disorders.

Abstract: Research suggests that maternal immune activation (MIA) during pregnancy increases the risk of neurodevelopmental disorders including schizophrenia and autism in the offspring. Current theories suggest that inflammatory mediators including cytokines and chemokines may underlie the increased risk of these disorders in humans. For example, elevated maternal interleukin-8 (IL-8) during pregnancy is associated with increased risk of schizophrenia in the offspring. Given this association, the present experiments examined ELR-CXC chemokines CXCL1 and CXCL2, rodent homologues of human IL-8, and activation of their receptors (CXCR1 and CXCR2) in an established rodent model of MIA. Pregnant Long Evans rats were treated with the viral mimetic polyinosinic-polycytidylic acid (polyI:C; 4 mg/kg, i.v.) on gestational day 15. Protein analysis using multiplex assays and ELISA showed that polyI:C significantly increased maternal serum concentrations of interleukin-1β, tumor necrosis factor, and CXCL1 3h after administration. Subsequent experiments tested the role of elevated maternal CXCL1 on behavior of the offspring by administering a CXCR1/CXCR2 antagonist (G31P; 500 μg/kg, i.p.; 1h before, 48 and 96 h after polyI:C treatment). The male offspring of dams treated with polyI:C demonstrated subtle impairments in prepulse inhibition (PPI), impaired associative and crossmodal recognition memory, and altered behavioral flexibility in an operant test battery. While G31P did not completely reverse the behavioral impairments caused by polyI:C, it enhanced PPI during adolescence and strategy set-shifting and reversal learning during young adulthood. These results suggest that while polyI:C treatment significantly increases maternal CXCL1, elevations of this chemokine are not solely responsible for the effects of polyI:C on the behavior of the offspring.

Perspectives on the mGluR2/3 agonists as a therapeutic target for schizophrenia: Still promising or a dead end?

Abstract: Group II metabotropic glutamate receptor (mGluR2/3) agonists once showed promise as non-dopaminergic antipsychotic drugs because of their efficacy in alleviating symptoms of schizophrenia (SZ) in both animal models and human patients. However, the recent failure of Phase III clinical trials dealt a huge blow to the scientific community and the aftershock of the setback in mGluR2/3 research can be felt everywhere from grant support and laboratory studies to paper publication. An immediate question raised is whether mGluR2/3 is still a promising therapeutic target for schizophrenia. Answering this question is not easy, but apparently a new strategy is needed. This article provides a focused review of literature on the study of mGluR2/3 agonists, especially on mGluR2/3 agonists' mechanism of action and efficacy in both normal conditions and animal models of SZ, as well as clinical studies in human patients with the disease. We argue that the cellular and molecular actions of mGluR2/3 agonists, the distinct roles between mGluR2 and mGluR3, as well as their effects on different stages of the disease and different subpopulations of patients, remain incompletely studied. Until the mechanisms associated with mGluR2/3 are clearly elucidated and all treatment options are tested, it would be a great mistake to terminate the study of mGluR2/3 as a therapeutic target for schizophrenia. This review will thus shed light on the comprehensive features of the translational potential mGluR2/3 agonists as well as the need for further research into the more selective activation of mGluR2.

Widespread white matter but focal gray matter alterations in depressed individuals with thoughts of death.

Abstract: Background Past work demonstrates that depressed individuals with suicidal thoughts or behaviors exhibit specific neuroanatomical alterations. This may represent a distinct phenotype characterized by specific findings on neuroimaging, but it is unclear if these findings extend to individuals with milder thoughts of death. We examined this question in outpatients with recurrent Major Depressive Disorder not receiving antidepressant treatment. Methods We examined 165 subjects: 53 depressed without thoughts of death, 21 depressed with thoughts of death, and 91 healthy comparison subjects. Participants completed 3 T cranial MRI, including anatomical and diffusion tensor imaging acquisitions. Automated methods measured regional gray matter volumes in addition to cortical thickness. White matter analyses examined diffusion measures within specific fiber tracts and included voxelwise comparisons. Results After adjustment for multiple comparisons, the depressed group with thoughts of death did not exhibit differences in regional gray matter volume, but did exhibit reduced cortical thickness in frontoparietal regions and the insula. This depressed group with thoughts of death also exhibited widespread white matter differences in fractional anisotropy and radial diffusivity. These differences were observed primarily in posterior parietal white matter regions and central white matter tracts adjacent to the basal ganglia and thalamus. Conclusions Mild thoughts of death are associated with structural alterations in regions of the salience network, default mode network, and thalamocortical circuits. Further work is needed to understand the pathological basis of these findings.

Bardoxolone methyl prevents high-fat diet-induced alterations in prefrontal cortex signalling molecules involved in recognition memory

Abstract: High fat (HF) diets are known to induce changes in synaptic plasticity in the forebrain leading to learning and memory impairments. Previous studies of oleanolic acid derivatives have found that these compounds can cross the blood–brain barrier to prevent neuronal cell death. We examined the hypothesis that the oleanolic acid derivative, bardoxolone methyl (BM) would prevent diet-induced cognitive deficits in mice fed a HF diet. C57BL/6J male mice were fed a lab chow (LC) (5% of energy as fat), a HF (40% of energy as fat), or a HF diet supplemented with 10 mg/kg/day BM orally for 21 weeks. Recognition memory was assessed by performing a novel object recognition test on the treated mice. Downstream brain-derived neurotrophic factor (BDNF) signalling molecules were examined in the prefrontal cortex (PFC) and hippocampus of mice via Western blotting and N-methyl-d-aspartate (NMDA) receptor binding. BM treatment prevented HF diet-induced impairment in recognition memory (p 0.05). In the PFC and hippocampus of the HF diet fed mice, BM administration improved downstream BDNF signalling as indicated by increased protein levels of BDNF, phosphorylated tropomyosin related kinase B (pTrkB) and phosphorylated protein kinase B (pAkt), and increased phosphorylated AMP-activated protein kinase (pAMPK) (p < 0.05). BM administration also prevented the HF diet-induced increase in the protein levels of inflammatory molecules, phosphorylated c-Jun N-terminal kinase (pJNK) in the PFC, and protein tyrosine phosphatase 1B (PTP1B) in both the PFC and hippocampus. In summary, these findings suggest that BM prevents HF diet-induced impairments in recognition memory by improving downstream BDNF signal transduction, increasing pAMPK, and reducing inflammation in the PFC and hippocampus.

Intramuscular long-acting paliperidone palmitate in acute patients with schizophrenia unsuccessfully treated with oral antipsychotics.

Abstract: In this prospective multicentre, open-label, 6-month study (Paliperidone Palmitate Flexible Dosing in Schizophrenia [PALMFlexS]), tolerability, safety and treatment response with paliperidone palmitate (PP) were explored in patients with acute symptoms of schizophrenia following switching from previously unsuccessful treatment with oral antipsychotics. This pragmatic study was conducted in a large, more representative sample of the general schizophrenia population compared to randomized controlled pivotal trials, to specifically mimic real-world clinical situations. After initiation on Day 1 and Day 8, patients received PP once monthly at flexible doses (50-150mgeq.) intramuscularly. The primary efficacy outcome was defined as the percentage of patients achieving ≥30% improvement in PANSS total score from baseline (BL) to last-observation-carried-forward (LOCF) endpoint (EP). Safety and tolerability assessments included Extrapyramidal Symptom Rating Scale (ESRS) total score and treatment-emergent adverse events (TEAEs). Overall, 212 patients received PP at least once after switching from oral antipsychotics, primarily due to lack of efficacy (45.8%). Significant improvements from BL in mean (SD) PANSS total score were observed from Day 8 onwards (BL to LOCF EP: -31.0 [29.0]; p<0.0001). At endpoint, two-thirds (66.7%) and 43.5% of patients achieved a ≥30% and ≥50% improvement in mean PANSS total score, respectively. PP was associated with significant improvements across secondary measures of symptom severity, subjective well-being, medication satisfaction, illness-related disorders of activity and participation, and patient functioning (p<0.0001; BL to LOCF EP). PP was generally well tolerated, with significant reductions in ESRS total score (p<0.0001) and mainly mild-to-moderate TEAEs. TEAEs reported in ≥5% of patients were injection-site pain (13.7%), insomnia (10.8%), psychotic disorder (10.4%), headache and anxiety (both 6.1%). The PALMFlexS study findings provide valuable pragmatic clinical data on PP treatment in patients with acute schizophrenia previously unsuccessfully treated with oral antipsychotics.

Changes in brain activation following psychotherapy for youth with mood dysregulation at familial risk for bipolar disorder

Abstract: Background Psychotherapy for youth with mood dysregulation can help stabilize mood and improve functioning, but the neural mechanisms of this improvement are not known. In this study we investigated the changes in brain activation underlying improvement in mood symptoms. Methods Twenty-four subjects (ages 13–17) participated: 12 patients with clinically significant symptoms of depression and/or mania, and 12 healthy comparison subjects (HC) matched for age and sex. All subjects completed functional magnetic resonance imaging while viewing facial expressions. The patients then received up to 4 months of psychotherapy and were rescanned at end of treatment. Whole brain differences between patient and control groups were assessed with a voxel-wise analysis. Changes in activation from pre- to post-treatment within the patient group were tested for correlation with changes in mood symptoms. Results At baseline the patient group had hypoactivation in the dorsolateral prefrontal cortex (DLPFC) and hyperactivation in the posterior cingulate cortex compared to the HC group. Between pre- and post-treatment activation increased in the DLPFC and decreased in the amygdala. Increases in DLPFC activation were significantly correlated with improvement in mania symptoms. Discussion Enhancement of frontal executive control brain regions may underlie improvement in mood dysregulation in pediatric patients at familial risk for bipolar disorder.

Neural systems mediating decision-making and response inhibition for social and nonsocial stimuli in autism.

Abstract: Autism is marked by impairments in social reciprocity and communication, along with restricted, repetitive and stereotyped behaviors. Prior studies have separately investigated social processing and executive function in autism, but little is known about the brain mechanisms of cognitive control for both emotional and nonemotional stimuli. We used functional magnetic resonance imaging to identify differences in neurocircuitry between individuals with high functioning autism (HFA) and neurotypical controls during two versions of a go/no-go task: emotional (fear and happy faces) and nonemotional (English letters). During the letter task, HFA participants showed hypoactivation in the ventral prefrontal cortex. During the emotion task, happy faces elicited activation in the ventral striatum, nucleus accumbens and anterior amygdala in neurotypical, but not HFA, participants. Response inhibition for fear faces compared with happy faces recruited occipitotemporal regions in HFA, but not neurotypical, participants. In a direct contrast of emotional no-go and letter no-go blocks, HFA participants showed hyperactivation in extrastriate cortex and fusiform gyrus. Accuracy for emotional no-go trials was negatively correlated with activation in fusiform gyrus in the HFA group. These results indicate that autism is associated with abnormal processing in socioemotional brain networks, and support the theory that autism is marked by a social motivational deficit.

Selective activation of the trace amine-associated receptor 1 decreases cocaine's reinforcing efficacy and prevents cocaine-induced changes in brain reward thresholds.

Abstract: The newly discovered trace amine-associated receptor 1 (TAAR1) has emerged as a promising target for medication development in stimulant addiction due to its ability to regulate dopamine (DA) function and modulate stimulants' effects. Recent findings indicate that TAAR1 activation blocks some of the abuse-related physiological and behavioral effects of cocaine. However, findings from existing self-administration studies are inconclusive due to the very limited range of cocaine unit doses tested. Here, in order to shed light on the influence of TAAR1 on cocaine's reward and reinforcement, we studied the effects of partial and full activation of TAAR1on (1) the dose-response curve for cocaine self-administration and (2) cocaine-induced changes in intracranial self-stimulation (ICSS). In the first experiment, we examined the effects of the selective full and partial TAAR1 agonists, RO5256390 and RO5203648, on self-administration of five unit-injection doses of cocaine (0.03, 0.1, 0.2, 0.45, and 1mg/kg/infusion). Both agonists induced dose-dependent downward shifts in the cocaine dose-response curve, indicating that both partial and full TAAR1 activation decrease cocaine, reinforcing efficacy. In the second experiment, RO5256390 and the partial agonist, RO5263397, dose-dependently prevented cocaine-induced lowering of ICSS thresholds. Taken together, these data demonstrated that TAAR1 stimulation effectively suppresses the rewarding and reinforcing effects of cocaine in self-administration and ICSS models, supporting the candidacy of TAAR1 as a drug discovery target for cocaine addiction.

The role of neurotrophins in bipolar disorder.

Abstract: Bipolar disorder (BD) is a chronic psychiatric illness of which the pathophysiology remains partially unknown. Abnormalities of neurotrophins and other trophic factors orchestrate important alterations which could be implicated in the etiology of BD. Therefore, the main objective of this review is to examine the recent findings and critically evaluate the potential role of neurotrophins that may allow us to substantially improve the development of novel treatments. The most recently published findings highlight that brain-derived neurotrophic factor (BDNF), insulin-like growth factor (IGF-1) and vascular endothelial growth factor (VEGF) present distinct patterns in the different stages of BD, suggesting their potential in the identification of the BD subgroups and may ultimately advance treatment strategies.

Acute and chronic ethanol exposure differentially alters alcohol dehydrogenase and aldehyde dehydrogenase activity in the zebrafish liver.

Abstract: Chronic ethanol exposure paradigms have been successfully used in the past to induce behavioral and central nervous system related changes in zebrafish. However, it is currently unknown whether chronic ethanol exposure alters ethanol metabolism in adult zebrafish. In the current study we examine the effect of acute ethanol exposure on adult zebrafish behavioral responses, as well as alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) activity in the liver. We then examine how two different chronic ethanol exposure paradigms (continuous and repeated ethanol exposure) alter behavioral responses and liver enzyme activity during a subsequent acute ethanol challenge. Acute ethanol exposure increased locomotor activity in a dose-dependent manner. ADH activity was shown to exhibit an inverted U-shaped curve and ALDH activity was decreased by ethanol exposure at all doses. During the acute ethanol challenge, animals that were continuously housed in ethanol exhibited a significantly reduced locomotor response and increased ADH activity, however, ALDH activity did not change. Zebrafish that were repeatedly exposed to ethanol demonstrated a small but significant attenuation of the locomotor response during the acute ethanol challenge but ADH and ALDH activity was similar to controls. Overall, we identified two different chronic ethanol exposure paradigms that differentially alter behavioral and physiological responses in zebrafish. We speculate that these two paradigms may allow dissociation of central nervous system-related and liver enzyme-dependent ethanol induced changes in zebrafish.

The medial forebrain bundle as a deep brain stimulation target for treatment resistant depression: A review of published data.

Abstract: Introduction Despite a wide variety of therapeutic interventions for major depressive disorder (MDD), treatment resistant depression (TRD) remains to be prevalent and troublesome in clinical practice. In recent years, deep brain stimulation (DBS) has emerged as an alternative for individuals suffering from TRD not responding to combining antidepressants, multiple adjunctive strategies and electroconvulsive therapy (ECT). Although the best site for TRD-DBS is still unclear, pilot data suggests that the medial forebrain bundle (MFB) might be a key target to accomplish therapeutic efficacy in TRD patients. Objective To explore the anatomic, electrophysiologic, neurocognitive and treatment data supporting the MFB as a target for TRD-DBS. Results The MFB connects multiple targets involved in motivated behavior, mood regulation and antidepressant response. Specific phenomenology associated with TRD can be linked specifically to the superolateral branch (sl) of the MFB (slMFB). TRD patients who received DBS-slMFB reported high response/remission rates with an improvement in functioning and no significant adverse outcomes in their physical health or neurocognitive performance. Discussion The slMFB is an essential component of a network of structural and functional pathways connecting different areas possibly involved in the pathogenesis of mood disorders. Therefore, the slMFB should be considered as an exciting therapeutic target for DBS therapy to achieve a sustained relief in TRD patients. Conclusion There is an urgent need for clinical trials exploring DBS-slMFB in TRD. Further efforts should pursue measuring baseline pro-inflammatory cytokines, oxidative stress, and cognition as possible biomarkers of DBS-slMFB response in order to aid clinicians in better patient selection.

NMDA receptor activation regulates sociability by its effect on mTOR signaling activity.

Abstract: Tuberous Sclerosis Complex is one example of a syndromic form of autism spectrum disorder associated with disinhibited activity of mTORC1 in neurons (e.g., cerebellar Purkinje cells). mTORC1 is a complex protein possessing serine/threonine kinase activity and a key downstream molecule in a signaling cascade beginning at the cell surface with the transduction of neurotransmitters (e.g., glutamate and acetylcholine) and nerve growth factors (e.g., Brain-Derived Neurotrophic Factor). Interestingly, the severity of the intellectual disability in Tuberous Sclerosis Complex may relate more to this metabolic disturbance (i.e., overactivity of mTOR signaling) than the density of cortical tubers. Several recent reports showed that rapamycin, an inhibitor of mTORC1, improved sociability and other symptoms in mouse models of Tuberous Sclerosis Complex and autism spectrum disorder, consistent with mTORC1 overactivity playing an important pathogenic role. NMDA receptor activation may also dampen mTORC1 activity by at least two possible mechanisms: regulating intraneuronal accumulation of arginine and the phosphorylation status of a specific extracellular signal regulating kinase (i.e., ERK1/2), both of which are "drivers" of mTORC1 activity. Conceivably, the prosocial effects of targeting the NMDA receptor with agonists in mouse models of autism spectrum disorders result from their ability to dampen mTORC1 activity in neurons. Strategies for dampening mTORC1 overactivity by NMDA receptor activation may be preferred to its direct inhibition in chronic neurodevelopmental disorders, such as autism spectrum disorders.