Role In Anxiety Disorders Research Articles

The impact of hypervigilance: Evidence for a forward feedback loop

A number of prominent theories suggest that hypervigilance and attentional bias play a central role in anxiety disorders and PTSD. It is argued that hypervigilance may focus attention on potential threats and precipitate or maintain a forward feedback loop in which anxiety is increased. While there is considerable data to suggest that attentional bias exists, there is little evidence to suggest that it plays this proposed but critical role. This study investigated how manipulating hypervigilance would impact the forward feedback loop via self-reported anxiety, visual scanning, and pupil size. Seventy-one participants were assigned to either a hypervigilant, pleasant, or control condition while looking at a series of neutral pictures. Those in the hypervigilant condition had significantly more fixations than those in the other two groups. These fixations were more spread out and covered a greater percentage of the ambiguous scene. Pupil size was also significantly larger in the hypervigilant condition relative to the control condition. Thus the study provided support for the role of hypervigilance in increasing visual scanning and arousal even to neutral stimuli and even when there is no change in self-reported anxiety. Implications for the role this may play in perpetuating a forward feedback loop are discussed.

Indicators of implicit and explicit social anxiety influence threat-related interpretive bias as a function of working memory capacity

Interpretive biases play a crucial role in anxiety disorders. The aim of the current study was to examine factors that determine the relative strength of threat-related interpretive biases that are characteristic of individuals high in social anxiety. Different (dual process) models argue that both implicit and explicit processes determine information processing biases and behavior, and that their impact is moderated by the availability of executive resources such as working memory capacity (WMC). Based on these models, we expected indicators of implicit social anxiety to predict threat-related interpretive bias in individuals low, but not high in WMC. Indicators of explicit social anxiety should predict threat-related interpretive bias in individuals high, but not low in WMC. As expected, WMC moderated the impact of implicit social anxiety on threat-related interpretive bias, although the simple slope for individuals low in WMC was not statistically significant. The hypotheses regarding explicit social anxiety (with fear of negative evaluation used as an indicator) were fully supported. The clinical implications of these findings are discussed.

The role of the serotonergic and GABA system in translational approaches in drug discovery for anxiety disorders

There is ample evidence that genetic factors play an important role in anxiety disorders. In support, human genome-wide association studies have implicated several novel candidate genes. However, illumination of such genetic factors involved in anxiety disorders has not resulted in novel drugs over the past decades. A complicating factor is the heterogeneous classification of anxiety disorders in the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) and diverging operationalization of anxiety used in preclinical and clinical studies. Currently, there is an increasing focus on the gene × environment (G × E) interaction in anxiety as genes do not operate in isolation and environmental factors have been found to significantly contribute to the development of anxiety disorders in at-risk individuals. Nevertheless, extensive research on G × E mechanisms in anxiety has not resulted in major breakthroughs in drug discovery. Modification of individual genes in rodent models has enabled the specific study of anxiety in preclinical studies. In this context, two extensively studied neurotransmitters involved in anxiety are the gamma-aminobutyric acid (GABA) and 5-HT (5-hydroxytryptamine) system. In this review, we illustrate the complex interplay between genes and environment in anxiety processes by reviewing preclinical and clinical studies on the serotonin transporter (5-HTT), 5-HT1A receptor, 5-HT2 receptor, and GABAA receptor. Even though targets from the serotonin and GABA system have yielded drugs with known anxiolytic efficacy, the relation between the genetic background of these targets and anxiety symptoms and development of anxiety disorders is largely unknown. The aim of this review is to show the vast complexity of genetic and environmental factors in anxiety disorders. In light of the difficulty with which common genetic variants are identified in anxiety disorders, animal models with translational validity may aid in elucidating the neurobiological background of these genes and their possible role in anxiety. We argue that, in addition to human genetic studies, translational models are essential to map anxiety-related genes and to enhance our understanding of anxiety disorders in order to develop potentially novel treatment strategies.

Attentional threat avoidance and familial risk are independently associated with childhood anxiety disorders

Twin studies in children reveal that familial aggregation of anxiety disorders is due to both genetic and environmental factors. Cognitive biases for threat information are considered a robust characteristic of childhood anxiety. However, little is known regarding the underlying aetiology of such biases and their role in anxiety disorders. A face version of the dot-probe task measuring attentional biases for negative (anger, fear, sad, disgust) and positive (happy) facial expressions was completed by 600, 8-year-old twins; the largest study of its kind. Twin correlations for attentional bias scores were compared to estimate genetic and environmental effects. Parent-report diagnostic interviews identified children with an anxiety disorder. Indices of inferred genetic and familial risk for anxiety disorders were created for each child. Data were analysed using a series of logistic regressions. Anxious children showed greater attentional avoidance of negative faces than nonanxious children; t (548) = 2.55, p < .05. Attentional avoidance was not under genetic or shared environmental influence. Risk for anxiety disorders was predicted by familial factors. Both attentional avoidance and inferred familial risk were significant but independent predictors of anxiety disorders (ORs = .65 and 3.64, respectively). Anxiety-related attentional biases and familial risk play important but independent roles in childhood anxiety disorders. If replicated, these findings indicate that links between genetic risk and anxiety disorders lie outside the domain of attentional processes.

Big effects of small RNAs: a review of microRNAs in anxiety.

Epigenetic and regulatory elements provide an additional layer of complexity to the heterogeneity of anxiety disorders. MicroRNAs (miRNAs) are a class of small, noncoding RNAs that have recently drawn interest as epigenetic modulators of gene expression in psychiatric disorders. miRNAs elicit their effects by binding to target messenger RNAs (mRNAs) and hindering translation or accelerating degradation. Considering their role in neuronal differentiation and synaptic plasticity, miRNAs have opened up new investigative avenues in the aetiology and treatment of anxiety disorders. In this review, we provide a thorough analysis of miRNAs, their targets and their functions in the central nervous system (CNS), focusing on their role in anxiety disorders. The involvement of miRNAs in CNS functions (such as neurogenesis, neurite outgrowth, synaptogenesis and synaptic and neural plasticity) and their intricate regulatory role under stressful conditions strongly support their importance in the aetiology of anxiety disorders. Furthermore, miRNAs could provide new avenues for the development of therapeutic targets in anxiety disorders.

Serotonergic Modulation of Conditioned Fear

Conditioned fear plays a key role in anxiety disorders as well as depression and other neuropsychiatric conditions. Understanding how neuromodulators drive the associated learning and memory processes, including memory consolidation, retrieval/expression, and extinction (recall), is essential in the understanding of (individual differences in vulnerability to) these disorders and their treatment. The human and rodent studies I review here together reveal, amongst others, that acute selective serotonin reuptake inhibitor (SSRI) treatment facilitates fear conditioning, reduces contextual fear, and increases cued fear, chronic SSRI treatment reduces both contextual and cued fear, 5-HT1A receptors inhibit the acquisition and expression of contextual fear, 5-HT2A receptors facilitates the consolidation of cued and contextual fear, inactivation of 5-HT2C receptors facilitate the retrieval of cued fear memory, the 5-HT3 receptor mediates contextual fear, genetically induced increases in serotonin levels are associated with increased fear conditioning, impaired cued fear extinction, or impaired extinction recall, and that genetically induced 5-HT depletion increases fear conditioning and contextual fear. Several explanations are presented to reconcile seemingly paradoxical relationships between serotonin levels and conditioned fear.

FMRI fingerprint of unconditioned fear-like behavior in rats exposed to trimethylthiazoline

Unconditioned fear plays an important yet poorly understood role in anxiety disorders, and only few neuroimaging studies have focused on evaluating the underlying neuronal mechanisms. In rodents the predator odor trimethylthiazoline (TMT), a synthetic component of fox feces, is commonly used to induce states of unconditioned fear. In this study, arterial spin labeling-based functional magnetic resonance imaging (fMRI) was applied to detect TMT-induced regional modulations of neuronal activity in Wistar rats. During TMT exposure the rats displayed increased freezing behavior and reduced exploration in the odor-associated area. Neuronal activity was selectively increased in the dorsal periaqueductal gray, superior colliculus and medial thalamus and reduced in the median raphe, locus coeruleus, nucleus accumbens shell, ventral tegmental area, ventral pallidum and entorhinal piriform cortex. This fMRI fingerprint involving distinct neuronal pathways was used to describe a schematic model of fear processing. Key brain areas known to underlie fear and anxiety-related autonomic and behavioral responses as well as centers of motivational processing were identified as being part of this functional circuitry of innate fear. Thus, preclinical fMRI studies based on unconditioned fear methods may provide a valuable translational approach to better characterize etiological and pathological processes underlying anxiety disorders.

But what about the Empress of Racnoss? The allocation of attention to spiders and Doctor Who in a visual search task is predicted by fear and expertise.

If there is a spider in the room, then the spider phobic in your group is most likely to point it out to you. This phenomenon is believed to arise because our attentional systems are hardwired to attend to threat in our environment, and, to a spider phobic, spiders are threatening. However, an alternative explanation is simply that attention is quickly drawn to the stimulus of most personal relevance in the environment. Our research examined whether positive stimuli with no biological or evolutionary relevance could be allocated preferential attention. We compared attention to pictures of spiders with pictures from the TV program Doctor Who, for people who varied in both their love of Doctor Who and their fear of spiders. We found a double dissociation: interference from spider and Doctor-Who-related images in a visual search task was predicted by spider fear and Doctor Who expertise, respectively. As such, allocation of attention reflected the personal relevance of the images rather than their threat content. The attentional system believed to have a causal role in anxiety disorders is therefore likely to be a general system that responds not to threat but to stimulus relevance; hence, nonevolutionary images, such as those from Doctor Who, captured attention as quickly as fear-relevant spider images. Where this leaves the Empress of Racnoss, we are unsure.

Panic disorder as a risk factor for post-partum depression: Results from the Perinatal Depression-Research & Screening Unit (PND-ReScU) study

Background Although the role of anxiety disorders on the development of Post-partum Depression (PPD) have already been studied in literature, that of individual anxiety disorders has not received specific attention. The aim of this study is to investigate the role of Panic Disorder (PD) and family history for PD as risk factors for PPD. Methods Six hundred women were recruited in a prospective, observational study at the 3rd month of pregnancy and followed up until the 6th month after delivery. At baseline, risk factors for PPD, Axis-I disorders and family history for psychiatric disorders were assessed. We investigated minor and major depression (mMD) occurred at 1st, 3rd and 6th months post-partum. Logistic regression models were used to estimate the association between PD, family history for PD and PPD. Results Forty women had mMD in the post-partum. PD during pregnancy (RR = 4.25; 95%CI:1.48–12.19), a history of PD (RR 2.47; 95%CI:1.11–5.49) and family history for PD (RR = 2.1; 95%CI:1.06–4.4) predicted PPD after adjusting for lifetime depression and risk factors for PPD. Limitations The response rate is moderately low, but it is similar to other studies. The drop out rate is slightly high, however the 600 women who completed the 6th month follow-up did not differ from the presence of PD at baseline. Conclusions PD is an independent risk factor for PPD, underscoring need to assess PD symptoms during pregnancy. Furthermore, PD represents an important risk factor for the development of PPD and should be routinely screened in order to develop specific preventive interventions.

γ1- and γ2-melanocyte stimulating hormones induce central anxiogenic effects and potentiate ethanol withdrawal responses in the elevated plus-maze test in mice

Little is known about the endogenous functions of γ1- and γ2-melanocyte stimulating hormones (γ1- and γ2-MSH). Although γ-MSHs bind to melanocortin receptor subtypes 3 and 4, we have previously shown that these peptides also influence non-melanocortinergic processes, such as dopaminergic and GABAergic. The aim of this study was to determine the effects of γ1- and γ2-MSH (at doses 0.3, 1 and 2 nmol/mouse/5 μl) on the anxiety levels in mice in elevated plus maze. Three experimental paradigms were performed to assess the effects of peptides on: a) ethanol withdrawal; b) acute ethanol-induced anxiolytic action; c) peptides per se. We used ethanol as the model substance, since its action involves either dopaminergic/GABAergic or melanocortinergic processes. γ-MSHs were administered intracisternally in mice and behavioural responses were assessed in the elevated plus maze test. This study provides the first demonstration of an anxiogenic effect of γ1- and γ2-MSH, their synergistic/additive effect on ethanol withdrawal-induced anxiety behaviour, and an antagonism of peptides involved in the anxiolytic action of ethanol. Furthermore, results suggest that γ-MSHs belong to an anxiogenic peptide family that may play an important role in anxiety disorders as well as in the development of alcohol dependence and/or alcohol withdrawal-induced behaviours.

Predictors of response to pharmacotherapy in mood and anxiety disorders: Commonalities, differences and indications

The pharmacological treatment of mood and anxiety disorders reduced their morbidity and improved mental health for millions of people. Unfortunately, not all subjects benefit from treatments.The aim of the present review is to summarize available knowledge about antidepressants and anxiolytics’ genetic, demographic, psychosocial and clinical predictors of response, identifying common and specific predictors.A literature search was conducted using MEDLINE and references of selected articles. The search strategy sought only studies published in English.Many predictors have been identified. The main genetic finding regards the serotonin transporter gene promoter (SERTPR) polymorphisms which long variant seems to be related to a positive response to therapy in mood disorders and could have a role in anxiety disorders as well. Other genetic predictors as the catechol-O-methyltransferase, the dopamine receptor and the serotonin receptor polymorphisms have been analyzed. Anyway the role of genetic predictors seems nowadays very limited in common clinical practice.Among other predictors, the main factors common to most disorders are: a comorbid axis II disorder, early onset and a longer duration of illness, which seem related to a worse response to therapy and the presence of a good social support, a good social adjustment and spirituality related to a better outcome. A number of other specific predictors have also been consistently reported.Possible limitations and suggestions for future researches and clinical practice based on a more integrated vision of human complexity, network of interactions and dynamicity are explained and discussed.

A single administration of cortisol acutely reduces preconscious attention for fear in anxious young men

Chronically elevated HPA activity has often been associated with fear and anxiety, but there is evidence that single administrations of glucocorticoids may acutely reduce fear. Moreover, peri-traumatic cortisol elevation may protect against development of post-traumatic stress disorder. Hypervigilant processing of threat information plays a role in anxiety disorders and although relations with HPA functioning have been established, causality of these relations remains unclear. Presently, self-reported anxiety and response time patterns on a masked emotional Stroop task with fearful faces were measured in 20 healthy young men after double-blind, placebo-controlled oral administration of 40 mg cortisol. The masked fearful Stroop task measures vocal colornaming response latencies for pictures of neutral and fearful faces presented below the threshold for conscious perception. Results showed increased response times on trials for fearful compared to neutral faces after placebo, but this emotional Stroop effect was acutely abolished by cortisol administration. This effect was most pronounced in subjects with heightened anxiety levels. This is the first evidence showing that exogenous cortisol acutely reduces anxiety-driven selective attention to threat. These results extend earlier findings of acute fear reduction after glucocorticoid administration. This suggests interactions of HPA functioning and vigilant attention in the pathogenesis of anxiety disorders. Possible neuroendocrine mechanisms of action are discussed.

Association of a Met88Val diazepam binding inhibitor (DBI) gene polymorphism and anxiety disorders with panic attacks

Several lines of evidence suggest that anxiety disorders have a strong genetic component, but so far only few susceptibility genes have been identified. There is preclinical and clinical evidence for a dysregulation of the central γ-aminobutyric acid (GABA)-ergic tone in the pathophysiology of anxiety disorders. Diazepam binding inhibitor (DBI) has been suggested to play a pivotal role in anxiety disorders through direct and indirect, i.e. via synthesis of neuroactive steroids, modulation of GABA A receptor function. These findings suggest that the DBI gene can be postulated as a candidate for a genetic association study in this disorder. Thus, single nucleotide polymorphisms (SNPs) of the DBI gene were investigated for putative disease associations in a German sample of anxiety disorder patients suffering from panic attacks and matched controls. We were able to detect a significant association between a non-synonymous coding variant of DBI with anxiety disorders with panic attacks. The rare allele of this polymorphism was more frequent in controls than in patients (OR = 0.43; 95% CI: 0.19–0.95). In conclusion, these results suggest a central role of DBI genetic variants in the susceptibility for the development of anxiety disorders that are characterized by the occurrence of panic attacks.

Les troubles anxieux comme facteurs de risque pour la dépression et les troubles liés à l'utilisation d'alcool

The object of this paper is to specify the role of anxiety disorders taken as a group or separately (including panic disorder, social phobia, specific phobia, obsessive-compulsive disorder, generalized anxiety disorder and post-traumatic stress disorder) as potential causal risk factors for depression and alcohol use disorders. Several studies have consistently suggested that some anxiety disorders are primary to other mental disorders in a majority of co-morbid cases and could increase the risk of their onset. We performed a computerized search (Pubmed) on recent published studies on this subject. We focused on recent prospective studies. Several findings have confirmed that the number and severity of some primary anxiety disorders may significantly increase the risk of subsequent mental disorders (such as depression and alcohol use disorders). However, the authors are not unanimous on this subject. A precise determination of whether various anxiety disorders could constitute causal risk factors for subsequent mental disorders would permit a better understanding of disease aetiology, improve the efficiency of diagnosis and would allow development of effective interventions.

Fluoxetine and norfluoxetine stereospecifically and selectively increase brain neurosteroid content at doses that are inactive on 5-HT reuptake

It has recently become more clearly understood that in human brain pathophysiology, neurosteroids play a role in anxiety disorders, premenstrual syndrome, postpartum depression, posttraumatic stress disorder, and depression. In the treatment of major depression, recent clinical studies indicate that the pharmacological profiles of fluoxetine and fluvoxamine are correlated with the ability of these drugs to increase the brain and cerebrospinal fluid content of allopregnanolone (Allo), a potent positive allosteric modulator of gamma-aminobutyric acid (GABA) action at GABAA receptors. Thus, the neurosteroid-induced positive allosteric modulation of GABA action at GABAA receptors is facilitated by fluoxetine or its congeners (i.e., paroxetine, fluvoxamine, sertraline), which may not block 5-HT reuptake at the doses currently prescribed in the clinic. However, these doses are effective in the treatment of premenstrual dysphoria, anxiety, and depression. In socially isolated mice, we tested the hypothesis that fluoxetine, norfluoxetine, and other specific serotonin reuptake inhibitor (SSRI) congeners stereoselectively upregulate neurosteroid content at doses insufficient to inhibit 5-HT reuptake; although they potentiate pentobarbital-induced sedation and exert antiaggressive action. Very importantly, the inhibition of 5-HT reuptake lacks stereospecificity and requires fluoxetine and norfluoxetine doses that are 50-fold greater than those required to increase brain Allo content, potentiate the action of pentobarbital, or antagonize isolation-induced aggression. Based on these findings, it could be inferred that the increase of brain Allo content elicited by fluoxetine and norfluoxetine, rather than the inhibition selective of 5-HT reuptake, may be operative in the fluoxetine-induced remission of the behavioral abnormalities associated with mood disorders. Therefore, the term "SSRI" may be misleading in defining the pharmacological profile of fluoxetine and its congeners. To this extent, the term "selective brain steroidogenic stimulants" (SBSSs) could be proposed.

Interpretation and Judgmental Biases in Socially Anxious and Nonanxious Individuals

Interpretation and judgmental biases for threat-relevant stimuli are thought to play a role in anxiety disorders. To investigate whether social anxiety is associated with interpretation and judgmental biases for unambiguous external social events, individuals high and low in social anxiety (N = 36 per group) were presented with unambiguous scenarios depicting positive and mildly negative social events. Interpretations were assessed by participants' answers to open-ended questions and by their ratings for experimenter-provided, alternative explanations. In addition, for each event, participants indicated the probability that the event would happen to them and estimated their own emotional reaction to it. Compared to low socially anxious group, individuals high in social anxiety were more likely to interpret positive social events in a negative way and to catastrophize in response to unambiguous, mildly negative social events. Also, they estimated the emotional cost of negative social events as higher and the probabilities of positive social events as lower.

Association analysis of the functional Ala111Glu polymorphism of the glyoxalase I gene in panic disorder

The zinc metalloenzyme glyoxalase I (GLO1) is thought to play a role in anxiety disorders because a reduced brain expression of GLO1 has been associated with increased anxiety-behaviours in mice. Recently, a functional Ala111Glu polymorphism in GLO1 has been shown to result in a reduced enzyme activity. The present study tested the hypothesis that this common genetic variant could confer susceptibility to panic disorder using an Italian population sample of 162 panic disorder patients and 288 matched controls. Statistical analysis failed to show association with the overall diagnosis of the disease. However, a weak but significant association was demonstrated between this polymorphism and panic disorder without agoraphobia. While our data suggest that this polymorphism is unlikely to have a major function in the pathogenesis of panic disorder, it could play a role in the subgroup of patients without agoraphobic avoidance.

Evidence for disturbed cortical signal processing and altered serotonergic neurotransmission in generalized anxiety disorder

Background Current pathophysiological concepts of generalized anxiety disorder (GAD) assume a disturbed exteroceptive sensory system. Furthermore, central serotonergic neurotransmission has been shown to play an important role in anxiety disorder. Cortical signal processing as measured by auditory evoked potentials (AEPs) may reflect the integrity of the exteroceptive sensory system. Because a special aspect of AEP, the loudness dependence of the N1/P2-component (LD), has been related to central serotonergic activity, the LD may be useful for investigating serotonergic dysfunctions in GAD. Methods The LD was recorded in 31 medication-free patients with GAD without any psychiatric co-morbidity and in 31 matched control subjects. Dipole source analysis was performed to separate the LD of regions including the primary (LD-tangential dipole) and regions including the secondary auditory cortex (LD-radial dipole). Results A shallower LD-tangential was observed in patients with GAD as compared to healthy control subjects [ F(1,60) = 6.727, p = .012; one-way analysis of variance]. The LD-radial showed no differences between groups. Severity of the anxiety symptoms was not related to the LDs. Conclusions The results indicate an altered exteroceptive sensory system in GAD occurring at the level of the primary but not secondary auditory cortex. Because a shallow LD of the primary auditory cortex was related to a high firing rate of neurons in the dorsal raphe nucleus, the results may support evidence for an enhanced serotonergic activity in GAD.

Effects of lesioning noradrenergic neurones in the locus coeruleus on conditioned and unconditioned aversive behaviour in the rat

1. The brain noradrenergic system may have a role in anxiety disorder. This study has examined the effect of bilateral 6-hydroxydopamine lesions of the noradrenergic neurones in the locus coeruleus (LC) of male Lister hooded rats on behaviour produced by unconditioned and conditioned aversive stimuli. 2. The 6-hydroxydopamine (4μg) lesions markedly reduced the noradrenaline content of the locus coeruleus hypothalamus, frontal cortex and the periaqueductal grey area without altering the levels of either dopamine or 5-hydroxytryptamine measured 14 days after administration. 3. Exposure to ultrasound (20 kHz at 98 dB for 60 sec), an unconditioned aversive stimulus, induced a defence response in the rats characterised by an increase in activity (running and jumping) followed by a period of inactivity (freezing). 4. Lesioning of the LC significantly attenuated the duration of freezing but was without effect on the active phase of the response. A similar reduction in freezing behaviour was seen with LC lesions when rats were exposed (3 hours after the acquisition) to the contextual cue of the conditioned emotion response paradigm. 5. These findings confirm that the locus coeruleus is involved in the regulation of fear-related behaviour in the rat both in an unconditioned and a conditioned model. Furthermore the results indicate that noradrenaline modifies defence behaviour rather than being the principle activating mechanism.

Researchers Offer Theories On Chronic Fatigue Causes

Researchers Offer Theories On Chronic Fatigue Causes