Pathogenesis Of Anxiety Disorders Research Articles

Gene discovery and biological insights into anxiety disorders from a large-scale multi-ancestry genome-wide association study.

We leveraged information from more than 1.2 million participants, including 97,383 cases, to investigate the genetics of anxiety disorders across five continental groups. Through ancestry-specific and cross-ancestry genome-wide association studies, we identified 51 anxiety-associated loci, 39 of which were novel. In addition, polygenic risk scores derived from individuals of European descent were associated with anxiety in African, admixed American and East Asian groups. The heritability of anxiety was enriched for genes expressed in the limbic system, cerebral cortex, cerebellum, metencephalon, entorhinal cortex and brain stem. Transcriptome-wide and proteome-wide analyses highlighted 115 genes associated with anxiety through brain-specific and cross-tissue regulation. Anxiety also showed global and local genetic correlations with depression, schizophrenia and bipolar disorder and widespread pleiotropy with several physical health domains. Overall, this study expands our knowledge regarding the genetic risk and pathogenesis of anxiety disorders, highlighting the importance of investigating diverse populations and integrating multi-omics information.

Adenosine A2a Receptor Polymorphisms and Susceptibility to Anxiety Disorders.

Anxiety disorders (ADs) are a group of mental disorders characterized by feelings of tension, fear, and excessive worrying in the face of life experiences. Aberrant signaling of adenosine A2a receptor (ADORA2A) is believed to be involved in the pathogenesis of ADs. Polymorphisms in the ADORA2A gene were shown to be associated with some of the patterns presented by ADs. The results of these studies have been inconsistent, making it hard to draw definitive conclusions. Therefore, this study performed a systematic review to clarify the associations between ADORA2A gene polymorphisms and ADs susceptibility. PubMed/Medline, Web of Science, and Scopus database using appropriate keywords, then screened for separation of suitable studies based on inclusion/exclusion criteria. Collectively, rs5751876 (1976T>C or previously 1083C>T) and rs35060421 (2592C>Tins) polymorphisms of ADORA2A were associated with an increased susceptibility to ADs. Moreover, rs2298383 TT genotype may be the causal regulatory factor, and ADORA2A T/C (rs2298383/rs3761422) haplotypes have significant susceptibility to ADs development. Additional research is needed to further define the role of ADORA2A gene polymorphisms in the pathogenesis of ADs.

Recent advances in anxiety disorders: Focus on animal models and pathological mechanisms.

Anxiety disorders have become one of the most severe psychiatric disorders, and the incidence is increasing every year. They impose an extraordinary personal and socioeconomic burden. Anxiety disorders are influenced by multiple complex and interacting genetic, psychological, social, and environmental factors, which contribute to disruption or imbalance in homeostasis and eventually cause pathologic anxiety. The selection of a suitable animal model is important for the exploration of disease etiology and pathophysiology, and the development of new drugs. Therefore, a more comprehensive understanding of the advantages and limitations of existing animal models of anxiety disorders is helpful to further study the underlying pathological mechanisms of the disease. This review summarizes animal models and the pathogenesis of anxiety disorders, and discusses the current research status to provide insights for further study of anxiety disorders.

Effect of cross-cultural education combined with music therapy on anxiety disorders

BackgroundAnxiety disorder usually refers to anxiety disorder. Common anxiety disorders include social phobia and separation anxiety disorder. Different anxiety disorders have different incidence rates. At present, the pathogenesis of anxiety disorder is not yet clear, but its common causes include genetic and psychological factors. Music therapy treats diseases from both physiological and psychological perspectives.Subjects and MethodsIn order to analyze the relief effect of cross-cultural education combined with music therapy on academic anxiety disorder in university students, the study selected 80 students with anxiety disorder. They were randomly divided into two groups, the observation group and the control group, with 40 students in each group. Among them, the control group only received cross-cultural education, while the observation group received music therapy based on cross-cultural education. Both groups were treated three times a week for a total of 8 weeks. After the treatment, the study evaluated the treatment results using the Self Rating Anxiety Scale, Self Rating Depression Scale, and SPSS23.0.ResultsThe results showed that there was a significant decrease in anxiety and depression scores between the observation group and the control group students after treatment, and there was a significant difference compared to before treatment (P<0.05). In addition, after treatment, the anxiety and depression scores of the observation group students decreased more than those of the control group, and the difference between the two was significant (P<0.05).ConclusionsIn summary, the combination of cross-cultural education and music therapy in universities has a certain alleviating effect on students’ academic anxiety disorder.

Anxiety disorders in general medical practice – clinical picture, diagnosis, optimized approaches to therapy

Anxiety disorders are widespread in the population and in general medical practice and have a pronounced negative impact on the quality of life and functioning of patients. Currently, the prerequisites for the diagnosis and treatment of anxiety disorders outside the psychiatric network are accumulating by therapists, general practitioners and other non-psychiatric doctors. A review of the most significant factors contributing to a wider diagnosis and treatment of anxiety disorders in general medical practice is given. This review presents modern ideas about the pathogenesis of anxiety disorders, substantiates the modern idea of their multifactorial nature, the contribution of genetic and epigenetic, psychological and social factors, outlines the concepts of the neurobiological basis of pathological anxiety based on neuroimaging studies. In the future, information is provided on the general manifestations of anxiety disorders, the main clusters of anxiety, the systematics of anxiety disorders according to ICD-10. Modern ideas about the diagnosis of anxiety disorders using both scales and a clinical approach are given, a detailed review of currently available diagnostic scales validated for clinical practice is presented. The main approaches to conducting a clinical conversation are also presented, recommendations are given for the most successful collection of information about the clinical condition of patients. At the end of the review, information is given on existing approaches to psychopharmacotherapy and psychotherapy of anxiety disorders. Taking into account pharmacological and clinical studies, the place of drugs tofisopam (an atypical allosteric modulator of GABA receptors) and buspirone (a partial agonist of serotonin 1A receptors) in the treatment of anxiety disorders in general medical practice has been argued.

Febrile Seizures Cause Depression and Anxiogenic Behaviors in Rats.

Febrile seizure (FS) is a common type of seizure occurring in human during infancy and childhood. Although an epileptic seizure is associated with psychiatric disorders and comorbid diseases such as depression, anxiety, autism spectrum disorders, sleep disorders, attention deficits, cognitive impairment, and migraine, the causal relationship between FS and psychiatric disorders is poorly understood. The objective of the current study was to investigate the relationship of FS occurrence in childhood with the pathogenesis of anxiety disorder and depression using an FS rat model. We induced febrile seizures in infantile rats (11 days postnatal) using a mercury vapor lamp. At 3 weeks and 12 weeks after FS induction, we examined behaviors and recorded local field potentials (LFPs) to assess anxiety and depression disorder. Interestingly, after FS induction in infantile rats, anxiogenic behaviors and depression-like phenotypes were found in both adult and juvenile FS rats. The analysis of LFPs revealed that 4–7 Hz hippocampal theta rhythm, a neural oscillatory marker for anxiety disorder, was significantly increased in FS rats compared with their wild-type littermates. Taken together, our findings suggest that FS occurrence in infants is causally related to increased levels of anxiety-related behaviors and depression-like symptoms in juvenile and adult rodents.

Impaired fear learning and extinction, but not generalization, in anxious and non-anxious depression

Fear conditioning and generalization are well-known mechanisms in the pathogenesis of anxiety disorders. Extinction of conditioned fear responses is crucial for the psychotherapeutic treatment of these diseases. Anxious depression as a subtype of major depression shares characteristics with anxiety disorders. We therefore aimed to compare fear learning mechanisms in patients with anxious versus non-anxious depression. Fear learning mechanisms in patients with major depression (n = 79; for subgroup analyses n = 41 patients with anxious depression and n = 38 patients with non-anxious depression) were compared to 48 healthy participants. We used a well-established differential fear conditioning paradigm investigating acquisition, generalization, and extinction. Ratings of valence, arousal and probability of expected threat were assessed as well as skin conductance response as an objective psychophysiological measure. Patients with major depression showed impaired acquisition of conditioned fear. In addition, depressed patients showed impaired extinction of conditioned fear responses after successful fear conditioning. Generalization was not affected. However, there was no difference between patients with anxious and non-anxious depression. Results differed between objective and subjective measures. Our findings show altered fear acquisition and extinction in major depression as compared to healthy controls, but they do not favor differential fear learning and extinction mechanisms in the pathogenesis of anxious versus non-anxious depression. The results of impaired extinction warrant future studies addressing extinction learning elements in the treatment of depression.

Characterizing human safety learning via Pavlovian conditioned inhibition

Deficient safety learning has been implicated in the pathogenesis of anxiety disorders. Despite increased translational interest, there has been limited research on the basis of safety learning in humans. Here, we examined safety learning in seventy-three healthy participants via a modified Pavlovian conditioned inhibition paradigm, featuring a conditioned threat stimulus that was reinforced alone (A+), but not when combined with a second stimulus (the conditioned inhibitor, AX-). During a test phase, X and a control safety cue (C) were combined with a second threat stimulus to assess their inhibition of threat responses, measured via skin conductance (SCRs) and US-expectancy ratings. Both stimuli exhibited conditioned inhibition, but X suppressed ratings by a greater magnitude than C. Trait anxiety also predicted increased US-expectancy ratings of X. These findings suggest that a Pavlovian inhibitor accrues greater safety value than a merely unreinforced safety signal. Conditioned inhibition paradigms may have utility in the ongoing study of safety learning and its relevance to anxious psychopathology.

Peripheral Biomarkers in DSM-5 Anxiety Disorders: An Updated Overview.

Anxiety disorders are prevalent and highly disabling mental disorders. In recent years, intensive efforts focused on the search for potential neuroimaging, genetic, and peripheral biomarkers in order to better understand the pathophysiology of these disorders, support their diagnosis, and characterize the treatment response. Of note, peripheral blood biomarkers, as surrogates for the central nervous system, represent a promising instrument to characterize psychiatric disorders, although their role has not been extensively applied to clinical practice. In this report, the state of the art on peripheral biomarkers of DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, 5th edition) Anxiety Disorders is presented, in order to examine their role in the pathogenesis of these conditions and their potential application for diagnosis and treatment. Available data on the cerebrospinal fluid and blood-based biomarkers related to neurotransmitters, neuropeptides, the hypothalamic–pituitary–adrenal axis, neurotrophic factors, and the inflammation and immune system are reviewed. Despite the wide scientific literature and the promising results in the field, only a few of the proposed peripheral biomarkers have been defined as a specific diagnostic instrument or have been identified as a guide in the treatment response to DSM-5 Anxiety Disorders. Therefore, further investigations are needed to provide new biological insights into the pathogenesis of anxiety disorders, to help in their diagnosis, and to tailor a treatment.

Dissociable neural signatures of passive extinction and instrumental control over threatening events.

Aberrant fear learning processes are assumed to be a key factor in the pathogenesis of anxiety disorders. Thus, effective behavioral interventions to reduce dysfunctional fear responding are needed. Beyond passive extinction learning, instrumental control over threatening events is thought to diminish fear. However, the neural mechanisms underlying instrumental control—and to what extent these differ from extinction—are not well understood. We therefore contrasted the neural signatures of instrumental control and passive extinction using an aversive learning task, relative to a control condition. Participants (n = 64) could either learn to exert instrumental control over electric shocks, received a yoked number and sequence of shocks without instrumental control or did not receive any shocks. While both passive extinction and instrumental control reduced threat-related skin conductance responses (SCRs) relative to pre-extinction/control, instrumental control resulted in a significantly more pronounced decrease of SCRs. Instrumental control was further linked to decreased striatal activation and increased cross talk of the ventromedial prefrontal cortex (vmPFC) with the amygdala, whereas passive extinction was associated with increased vmPFC activation. Our findings demonstrate that instrumental learning processes may shape Pavlovian fear responses and that the neural underpinnings of instrumental control are critically distinct from those of passive extinction learning.

An investigation of genetic variability of DNA methyltransferases DNMT3A and 3B does not provide evidence for a major role in the pathogenesis of panic disorder and dimensional anxiety phenotypes.

While DNA methylation patterns have been studied for a role in the pathogenesis of anxiety disorders, the role of the enzymes establishing DNA methylation-DNA methyltransferases (DNMTs)-has yet to be investigated. In an effort to investigate DNMT genotype-specific effects on dimensional anxiety traits in addition to the categorical phenotype of panic disorder, 506 panic disorder patients and 3112 healthy participants were assessed for anxiety related cognition [Agoraphobic Cognitions Questionnaire (ACQ)], anxiety sensitivity [Anxiety Sensitivity Index (ASI)] as well as pathological worry [Penn State Worry Questionnaire (PSWQ)] and genotyped for five single nucleotide polymorphisms (SNPs) in the DNMT3A (rs11683424, rs1465764, rs1465825) and DNMT3B (rs2424932, rs4911259) genes, which have previously been found associated with clinical and trait-related phenotypes. There was no association with the categorical phenotype panic disorder. However, a significant association was discerned between DNMT3A rs1465764 and PSWQ scores in healthy participants, with the minor allele conveying a protective effect. In addition, a marginally significant association between questionnaire scores (PSWQ, ASI) in healthy participants and DNMT3B rs2424932 was detected, again with the minor allele conveying a protective effect. The present results suggest a possible minor role of DNMT3A and DNMT3B gene variation in conveying resilience towards anxiety disorders. As the observed associations indicated a protective effect of two SNPs particularly with pathological worry, future studies are proposed to explore these variants in generalized anxiety disorder rather than panic disorder.

(-)-Syringaresinol-4-O-β-D-glucopyranoside from Cortex Albizziae inhibits corticosterone-induced PC12 cell apoptosis and relieves the associated dysfunction

The neuroprotective effects and potential mechanisms of (-)-Syringaresinol-4-O-β-D-glucopyranoside (SRG), a natural lignan glycoside extracted from Cortex Albizziae, were investigated using corticosterone (CORT)-induced PC12 cells as an in vitro anxiety model. PC12 cells were treated with 100 μM CORT and 5, 10, or 20 μM SRG for 48 h. Cell viability and lactate dehydrogenase (LDH) leakage were measured. Apoptosis were detected using FITC-coupled Annexin V (AV) and propidium iodide (PI) staining flow cytometric analyses and TUNEL assays. Rhodamine 123 and Fluo-3-AM staining flow cytometric analyses were used to detect mitochondrial membrane potential (ΔΨm) and intracellular calcium concentration ([Ca2+]i), respectively. Western blot was used to detect brain-derived neurotrophic factor (BDNF), Bax, Bcl-2, cAMP-response element binding protein (CREB), cytosolic cytochrome c (Cyt c), caspase-3, and cleaved caspase-3. Experimental data showed that SRG promoted cell proliferation, reduced LDH release, inhibited apoptosis, improved ΔΨm values, decreased [Ca2+]i, up-regulated CREB, BDNF, and Bcl-2, down-regulated Bax and Cyt c protein expression levels, and reduced caspase-3 activity. This suggests that SRG has neuroprotective and antiapoptotic effects in the pathogenesis of anxiety disorders, and its mechanisms are partly connecte to inhibition of the mitochondrial apoptotic pathway and activation of pathways involving CREB and BDNF.

The Potential Role of Epigenetic Drugs in the Treatment of Anxiety Disorders.

There is increasing evidence that abnormalities in epigenetic mechanisms of gene expression contribute to the pathogenesis of anxiety disorders (ADs). This article discusses the role of epigenetic mechanisms of gene expression in the pathogenesis of ADs. It also discusses the data so far obtained from preclinical and clinical trials on the use of epigenetic drugs for treating ADs. Most drug trials investigating the use of epigenetic drugs for treating ADs have used histone deacetylase inhibitors (HDACi). HDACi are showing favorable results in both preclinical and clinical drug trials for treating ADs. However, at present the mode of action of HDACi in ADs is not clear. More work needs to be done to elucidate how epigenetic dysregulation contributes to the pathogenesis of ADs. More work also needs to be done on the mode of action of HDACi in alleviating the signs and symptoms of ADs.

Erbin in Amygdala Parvalbumin-Positive Neurons Modulates Anxiety-like Behaviors

BackgroundAnxiety disorders are the most common psychiatric diseases, affecting 28% of people worldwide within their lifetime. The excitation-inhibition imbalance in the amygdala is thought to be an underlying pathological mechanism; however, the cellular and molecular control of amygdala excitation-inhibition balance is largely unknown. MethodsBy using mice expressing chemogenetic activator or inhibitor channel in amygdala parvalbumin (PV) neurons, Erbin mutant mice, and mice with Erbin specifically knocked down in amygdala PV neurons, we systematically investigated the role of amygdala PV neurons and Erbin expressed therein in the pathogenesis of anxiety disorders using the combined approaches of immunohistochemistry, electrophysiology, and behavior. ResultsIn naïve mice, chemogenetic inhibition of PV neurons produced anxiogenic effects, suggesting an essential role in the regulation of anxiety. In stressed mice with anxiety, excitatory postsynaptic responses on amygdala PV neurons were selectively diminished, accompanied by a decreased expression of Erbin specifically in amygdala PV neurons. Remarkably, both Erbin mutant mice and amygdala PV–specific Erbin knockdown mice exhibited impaired excitatory postsynaptic responses on amygdala PV neurons and increased anxiety-like behaviors. Furthermore, chemogenetic activation of amygdala PV neurons normalized anxiety behaviors in amygdala PV–specific Erbin knockdown mice and stressed mice. ConclusionsTogether, these results demonstrate that Erbin in PV neurons is critical for maintaining the excitation-inhibition balance in the amygdala and reveal a novel pathophysiological mechanism for anxiety disorders.

<p>Disorder-specific dysfunction in dorsal anterior cingulate cortex and parietal cortex during cognitive reappraisal in anxiety disorder [Letter]</p>

Dear editor Following our recently published article1 in Neuropsychiatric Disease and Treatment, many readers have commented that the effects of comorbid depression cannot be ruled out as a factor in our results, since anxiety disorders and major depression are heterogeneous disorders. We would like to respond to the points made. Impaired cognitive emotion regulation is commonly seen in many psychiatric disorders.2 A recent review concluded that individuals with depressive disorders consistently show decreased activation of the ventrolateral prefrontal cortex (vlPFC) and dorsolateral prefrontal cortex (dlPFC) during cognitive reappraisal.3 Moreover, enhanced activity of the amygdala, which is associated with hyperactive bottom-up emotion responses during downregulation of negative emotion, is a disorder-specific deficit in the recruitment of brain regions during cognitive reappraisal in depression disorder.3 Our meta-analysis was intended to provide a comprehensive description of the brain mechanisms underlying cognitive reappraisal deficits in anxiety disorder. We concluded that patients with anxiety disorder could not recruit the frontoparietal network, including dorsal anterior cingulate cortex (dACC), parietal cortex, dorsomedial prefrontal cortex and supplementary motor area, to down-regulate their emotion responses. Notably, we did not find that abnormalities of vlPFC, dlPFC or amygdala activity were involved in anxiety disorder, which suggests that the cognitive-appraisal-related impairments in emotion regulation that occur in anxiety disorders and major depression have different neural correlates. There are several explanations for our negative findings. First, although we included some patients with anxiety disorder accompanied by depression, they were eligible for inclusion in the meta-analysis as anxiety disorder was the primary diagnosis. Second, although some studies reported that patients with anxiety disorder showed diminished vlPFC and dlPFC activity during downregulation of negative emotion,1 the results are mixed. Our comprehensive meta-analysis was performed to provide a robust description of the neurobiological underpinnings of anxiety. Third, although patients with major depression consistently show enhanced amygdala activity during cognitive reappraisal,3 none of the eight studies included in the meta-analysis reported enhanced amygdala during cognitive reappraisal in anxiety disorders.1 Using a more stringent significance criterion (p<0.001), we found that during cognitive reappraisal patients with anxiety disorder showed decreased activity relative to healthy controls in the dACC (peak MNI: 4, 12, 42; p=~0; Z =−2.838; voxels =2129) and parietal cortex (peak MNI: −48, −28, 46; p=0.000002563; Z =−2.329; voxels =544); thus, the main findings remained largely unchanged. The dACC is involved in allocating control and attentional resources during cognitive reappraisal,4 whilst parietal cortex is mainly associated with selective attention and may be involved in holding reappraisals in mind.5 Our results indicate that, in anxiety disorder, diminished dACC and parietal cortex activity may impair the allocation of attention and control during cognitive reappraisal. It should be noted that none of the nine major depressive disorder studies we reviewed reported reduced dACC and parietal cortex during cognitive reappraisal.3 Importantly, patients with anxiety disorder, unlike those with major depression, did not show enhanced amygdala activity or reduced vlPFC and dlPFC activity during cognitive reappraisal. Conversely, patient with major depression did not show decreased activation of the dACC and parietal cortex, unlike those with anxiety disorder. We believe, therefore, that the effects of comorbid depression in anxiety disorder on cognitive reappraisal in our meta-analysis are negligible or non-existent. These findings offer insight into the neurobiology of emotion dysregulation in anxiety disorder. They provide robust evidence that frontoparietal network impairments play a key role in the pathogenesis of anxiety disorder. More specifically, it appears that dysfunctions of dACC and parietal cortex, which are involved in allocation of attention and control, are relatively specific to anxiety disorder, rather than depression.

Functional coupling of Tmem74 and HCN1 channels regulates anxiety-like behavior in BLA neurons.

Anxiety disorders are the most prevalent psychiatric disorders, but their pathogenic mechanism remains poorly understood. Here, we report that transmembrane protein 74 (TMEM74), which contains two putative transmembrane domains and exhibits high levels of mRNA in the brain, is closely associated with the pathogenesis of anxiety disorders. TMEM74 was decreased in the serum of patients with anxiety and the basolateral amygdaloid nucleus (BLA) in chronic stress mice. Furthermore, genetic deletion of Tmem74 or selective knockdown of Tmem74 in BLA pyramidal neurons resulted in anxiety-like behaviors in mice. Whole-cell recordings in BLA pyramidal neurons revealed lower hyperpolarization-activated cation current (Ih) and greater input resistance and excitability in Tmem74-/- neurons than in wild-type neurons. Accordingly, surface expression of hyperpolarization-activated cyclic nucleotide-gated 1 (HCN1) channels was also lower in the BLA of Tmem74-/- mice. The Ih current blocker ZD7288 mimicked these effects in BLA pyramidal neurons in wild-type mice but not in Tmem74-/- mice. Consistent with the improvement in anxiety-like behaviors, Tmem74 overexpression restored HCN1 channel trafficking and pyramidal neuron excitability in the BLA of Tmem74-/- and chronic stress mice. Mechanistically, we demonstrate that interactions between Tmem74 and HCN1 are physiologically relevant and that transmembrane domain 1 (TM1) is essential for the cellular membrane localization of Tmem74 to enhance Ih. Together, our findings suggest that Tmem74 coupling with HCN1 acts as a critical component in the pathophysiology of anxiety and is a potential target for new treatments of anxiety disorders.

Association of NPSR1 rs324981 polymorphism and treatment response to antidepressants in Chinese Han population with generalized anxiety disorder

In previous studies, neuropeptide S (NPS) and its cognate receptor (NPSR) have been involved in the pathogenesis of anxiety disorders in previous studies. Here, we aimed to investigate the association of NPSR1 polymorphism with generalized anxiety disorder (GAD) and its treatment response in Chinese Han population. Three hundred and thirty seven patients and one hundred and seventy seven healthy controls were involved in our study for 8 weeks. Further, Hamilton Anxiety Scale (HAMA) was used to assess anxiety symptom at baseline and the 1st, 2nd, 4th, 8th week. And all participants were genotyped for NPSR1 (rs324981) variants by polymerase chain reaction. Using Repeated-measures analysis, it showed significant reduction on HAMA scores in patients treated with escitalopram (F = 1.03, P = 0.362) and venlafaxine (F = 0.27, P = 0.763) respectively through 8 weeks treatment. Additionally, patients with AA and TT homozygous genotypes treated with venlafaxine XR had a higher reduction of HAMA scores compared to AT heterozygotic carriers (F = 4.18, P = 0.004), while no significant differences were found in patients treated with escitalopram (F = 1.05, P = 0.383). Thus, our study provides preliminary evidence that NPSR1 AA and TT homozygous genotypes have better treatment responses to venlafaxine XR in Chinese GAD patients, but not to escitalopram. Further studies are needed to verify the observation.

Prefrontoparietal dysfunction during emotion regulation in anxiety disorder: a meta-analysis of functional magnetic resonance imaging studies.

ObjectiveImpairments in emotion regulation, and more specifically in cognitive reappraisal, are thought to play a key role in the pathogenesis of anxiety disorders. However, the available evidence on such deficits is inconsistent. To further illustrate the neurobiological underpinnings of anxiety disorder, the present meta-analysis summarizes functional magnetic resonance imaging (fMRI) findings for cognitive reappraisal tasks and investigates related brain areas.MethodsWe performed a comprehensive series of meta-analyses of cognitive reappraisal fMRI studies contrasting patients with anxiety disorder with healthy control (HC) subjects, employing an anisotropic effect-size signed differential mapping approach. We also conducted a subgroup analysis of medication status, anxiety disorder subtype, data-processing software, and MRI field strengths. Meta-regression was used to explore the effects of demographics and clinical characteristics. Eight studies, with 11 datasets including 219 patients with anxiety disorder and 227 HC, were identified.ResultsCompared with HC, patients with anxiety disorder showed relatively decreased activation of the bilateral dorsomedial prefrontal cortex (dmPFC), bilateral dorsal anterior cingulate cortex (dACC), bilateral supplementary motor area (SMA), left ventromedial prefrontal cortex (vmPFC), bilateral parietal cortex, and left fusiform gyrus during cognitive reappraisal. The subgroup analysis, jackknife sensitivity analysis, heterogeneity analysis, and Egger’s tests further confirmed these findings.ConclusionsImpaired cognitive reappraisal in anxiety disorder may be the consequence of hypo-activation of the prefrontoparietal network, consistent with insufficient top-down control. Our findings provide robust evidence that functional impairment in prefrontoparietal neuronal circuits may have a significant role in the pathogenesis of anxiety disorder.

Absence of fear renewal and functional connections between prefrontal cortex and hippocampus in infant mice.

Impairment in fear extinction is widely viewed as a major contributor to, or even an underlying mechanism of, the pathogenesis of anxiety disorders and PTSD. Children with traumatic experience have a higher risk for developing anxiety disorders and PTSD in the adult. Little is known about the nature of fear memory extinction and its underlying mechanism during this period. Here we showed that while renewal of fear memory is context-specific in adult mice, it is absent in infant mice (P17). Using local injection of GABAa receptor antagonist picrotoxin, we found that there is no functional connectivity between infralimbic prefrontal cortex and hippocampus in P17 mice, while prefrontal cortex projection to amygdala is functioning. Hence, the lack of fear renewal is likely caused by the lack of connections between hippocampus and prefrontal cortex which are known to be involved in the regulation of extinction memory.

Anxiety disorders and CRP in a population cohort study with 54,326 participants: The LifeLines study

Objectives: Growing evidence indicates that inflammatory processes may play a role in the pathogenesis of anxiety disorders. Nevertheless, much remains to be learned about the involvement of inflammation, including C-reactive protein (CRP), in specific anxiety disorders. This study examines the relation between anxiety disorders and CRP.Methods: Associations of serum CRP with anxiety disorders were determined in a large population study (n = 54,326 participants, mean age = 47 years; 59% female), the LifeLines cohort. Depressive and anxiety disorders (generalized anxiety disorder, social anxiety phobia, panic disorder with or without agoraphobia and agoraphobia without panic disorder) were assessed using the Mini-International Neuropsychiatric Interview.Results: Anxiety disorders, with the exception of social anxiety disorder, were significantly associated with increased CRP. After adjusting for demographics, life style factors, health factors, medication use, depression, and psychological stressors, CRP remained significantly associated with panic disorder with agoraphobia (β = 0.01, P = .013). Moreover, CRP levels were significantly higher in people with panic disorder with agoraphobia compared to other anxiety disorders, independent of all covariates (F = 3.00, df = 4, P = .021).Conclusions: Panic disorder with agoraphobia is associated with increased CRP, although the effect size of this association is small. This indicates that neuroinflammatory mechanisms may play a potential role in its pathophysiology.