免疫、神经和内分泌系统是动物和人体内三大调节系统.这三大系统 之间不仅存在大的回路,而且彼此之间还进行着直接的双向交流,维持着机体正常的生命活动.这种功能上的相互联系是通过三大系统共同存在的细胞因子、神经递 质和内分泌激素及受体实现的.本文综述了这三个系统间关系的研究进展.

基于神经学方法的运用,情绪、情绪调节研究发现,事件相关电位的晚正成分(LPP)与情绪刺激的自动化加工、有意控制加工之间有着紧密的联系。LPP源于枕叶和后顶叶皮层,由蓝斑——去甲肾上腺素系统对情绪刺激进行反应时产生,反映了注意对情绪刺激的持续偏向和加工。由于个体生活经历、年龄发展及基因的不同,LPP存在个体差异性。情绪调节的ERP研究发现,LPP的时程可作为情绪调节的替代指标。在此基础上,提出ERP在较完整理解情绪加工和调节这一应用领域中的未来发展方向。

抑郁症的病因学研究已久,但目前仍无法确切阐述其病理生理学机制。目前抑郁症相关的发病机制主要有炎症反应学说、单胺类神经递质及其受体学说、HPA轴功能失调等学说。近年来随着DNA甲基化的深入研究,发现DNA甲基化与抑郁症的发生、发展之间存在一定的相关性,一些相关基因的甲基化水平在抑郁症的发病中可能发挥着重要的作用,对抑郁症的诊治具有重要意义。本文就一些抑郁症相关基因DNA甲基化的研究进展进行了综述。

目的 探讨惊恐障碍患者神经内分泌轴与临床特征的关系。方法 90例惊恐障碍患者接受基线惊恐障碍严重程度量表（PDSS）、汉密尔顿焦虑量表（HAMA）评估及外周血下丘脑-垂体-肾上腺（HPA）和下丘脑-垂体-甲状腺（HPT）轴激素检测。结果 促肾上腺皮质激素（ACTH）与年龄及HAMA12因子分正相关（P〈0.05）;总甲状腺激素（TT4）与HAMA1及PDSS4因子分负相关（P〈0.05）;促甲状腺激素（TSH）与HAMA7因子分负相关（P〈0.05）;HPA轴正常者HAMA12及PDSS3因子分均显著低于HPA轴异常者（P〈0.05）。结论 HPA及HPT轴功能异常与惊恐障碍患者某些临床症状相关,为基于神经内分泌的疾病临床分型及个体化优化治疗提供了一定线索。

目的了解男女神经心理学和神经内分泌功能之间的相关性,为认知功能的性别差异生物学基础提供依据。方法对年龄在16～75岁的健康成人156例(男64例、女92例)进行神经心理测验,包括部分WAIS智力测验项目、WMS逻辑记忆和视觉记忆测验、STROOP字色干扰测验、词汇流畅性测验、连线测验、汉诺塔木块移动测验(TOH)、威斯康星卡片分类测验改良版(M-WCST)。同时对下丘脑-垂体-性腺轴激素包括雌二醇(E2)、孕酮(P)、睾丸酮(T)、黄体生成素(LH)、促卵泡素(FSH)、泌乳素(PRL)和下丘脑-垂体-肾上腺轴激素包括促肾上腺皮质激素(ACTH)、皮质醇(PTC)进行测定。结果男女在认知功能、神经内分泌水平方面存在明显差异。男女神经内分泌水平和认知功能的相关项目稍有不同,但两者的ACTH、PTC与记忆功能相关,E2、T、LH、FSH等性激素与很多方面的认知功能如注意、记忆、思维分析能力、执行功能相关。结论健康成人的神经内分泌功能与神经心理功能之间存在相关性。

抑郁症是精神科的常见病和多发病，病因复杂，涉及多个机制。临床研究一致认为抑郁症的发病涉及神经内分泌的变化，并认为某些神经递质的变化可作为抑郁症神经生物学标志。细胞因子目前成为研究的热点，较多研究表明其与抑郁症的发病有相关性，但具体机制有待进一步的研究。本文就抑郁症神经内分泌及细胞因子方面的研究进展作一综述。

本文回顾了正性和负性情绪对人体神经内分泌和免疫功能的作用以及有关的影响因素。研究显示正性和负性情绪会造成不同的神经内分泌和免疫功能变化,个体的人格特征和遗传因素都与这些变化相关,而正性情绪可以明显消除负性情绪的作用。

生态心理学是西方心理学的一种新取向，它在方法论上倡导将交互作用原则作为主要研究原则，具 体来说，就是主张实际生活环境的研究原则、多元方法选择原则、多元交互解释原则，这些原则带来了心理学研究模式的转向：从探讨思辨中或实验室中的心理向探 讨真实环境中的心理转变；从人的心理内部机制的探求转向对人和环境互动关系的探求；从对理论模型的追问到对理论背景与实验设计之间匹配的关注；从分析性思 维模式为主转向综合性思维模式。

目前,心理学、生物学及社会学等多个学科都在关注负性情绪。本文从生物学的角度,介绍了负性情绪的大脑解剖结构,阐述了神经递质、神经肽、神经甾体与负性情绪的关系,并描述了负性情绪中激素、基因及环境三者之间的相互作用。

焦虑症是临床上较为常见的精神障碍之一,给患者的正常生活带来了极大的影响,当前随着生活节奏的加快,焦虑症患者数量持续增长,尤其是广泛性焦虑障碍、惊恐障碍、社交障碍等患者的数量明显增长,因此焦虑症的治疗逐渐引起了人们的重视。当前认知行为治疗对于焦虑症临床治疗具有显著的疗效,在临床中应用广泛。

Mast cells (MCs) are well studied for their roles in allergic and inflammatory disorders. MCs are also identified in the central nervous system (CNS), but have not been examined much. In recent years, growing evidence has shown that central MCs can modulate brain function and behavior in an endogenous homeostatic way. On the one hand, MCs exert protective effects on the development of related brain regions, the maintenance of neuronal activity, and various behaviors like motivation behavior, emotionality and cognition. The changes in the number and activity of central MCs under stressful conditions have relations with different limbs of stress response of brain and behavior. On the other hand, the hypo-activity or hyper-activity of MCs in immunity-related diseases or MCs transgenic animals both promote deleterious outcomes in brain function and behavior, which may be involved in the pathological process of some neuroimmune disorders. Anatomical and functional studies in vitro indicate that there exist bidirectional interactions between MCs and neural cells, including neurons and glial cells. Firstly, MCs and nerves are apposed with spatial gaps of 20 nm or less, an intimate interaction resembling synaptic junctions. Secondly, MCs and nerves also share common activating signals and receptors. On the one hand, MCs contain a variety of biologically active substances, which regulate the activity of the surrounding brain tissues when released through degranulation upon mast cell activation. On the other hand, there exist different kinds of receptors on mast cell membrane, through which MCs can be affected by neurological and immune signaling molecules in the brain. However, the current findings about the crosstalk between mast cell and the CNS are mainly based on studies in vitro. Until now, we know little about how bidirectional communication between mast cell and the CNS regulate brain and behavior in vivo, and its relationship with pathological processes in some immune related psychosomatic diseases. Further studies are needed to elucidate the neurobiology of brain mast cell, which might open new perspectives for the development of therapeutic targets in some neuropsychological diseases.

强迫症是一种常见的、具有复发性和难治性的精神疾病,它以反复出现的强迫行为和强迫观念为主要特征。以往大量脑成像研究证实了强迫症患者存在皮质-纹状体-丘脑-皮质环路的异常,特别是眶额叶、扣带回、尾状核、丘脑、颞叶、脑岛、胼胝体等组织存在结构和功能异常。近年来的研究还发现强迫症患者的背外侧前额叶、顶叶、枕叶、小脑等脑区也存在着结构和功能障碍。此提示,强迫症患者可能还存在其他环路或系统的异常,就此进行探索有助于深入了解强迫症的病理机制。因此,该文尝试对近年来强迫症的脑结构和功能成像的研究进行综述,以期全面研究分析强迫症的神经生物学基础研究的最新动态,为临床诊断与治疗提供参考。

恐惧性条件化学习的行为范式是研究情绪信息编码和储存的神经生物学机制的一个重要手段。杏仁核,尤其是外侧杏仁核(lateral nucleus of amygdala,LA),在恐惧性条件化的建立、恐惧信息的表达,以及恐惧性事件信息的存贮过程中起着非常重要的作用。本文着重论述外侧杏仁核在恐惧性条件化学习过程中的神经可塑性变化和相关的LTP机制,以及决定这种可塑性变化的分子信号转导通路。

The pervasive hopelessness and high risk of suicide in depressive patients suggested that the self might be abnormal among them. The status of fMRI studies on abnormalities of self-related processing in depression were reviewed in this article.

The hypothalamic-pituitary-adrenal (HPA) axis may mediate the deleterious effects of stress on health. It is sensitive to cognitive and emotional aspects of organism-environment interactions, such as familiarity, control, and social support. Scientific study of how such factors moderate human HPA axis activity has been limited. Their relevance to HPA axis disturbances in psychiatric patients is largely unexplored. To determine whether cognitive manipulation can alter HPA axis activity in laboratory studies and whether patients with panic disorder are differentially sensitive to the manipulated factors. Pharmacological activation paradigm (cholecystokinin-B agonist pentagastrin) by which we examined symptom and endocrine effects on subjects randomly assigned to a standard introduction or a cognitive intervention. Clinical research center. Recruited from university clinic and newspaper advertisements. Fourteen patients with panic disorder and 14 controls, individually matched for age and sex. Intervention Half of each group received a 9-minute cognitive intervention designed to reduce novelty, increase cognitive coping, and provide a sense of control. Corticotropin (ACTH) and cortisol levels. The cognitive intervention significantly reduced cortisol (P = .02) and ACTH (P = .01) levels, despite pentagastrin's robust stimulation of both hormones (P<.001). The intervention effect was evident in patients and controls, who did not differ in basal HPA axis activity or response to pentagastrin. They did differ in panic symptom responses, which were unaffected by the intervention, and in ACTH effects of the intervention. Patients' exaggerated anxiety responses to pentagastrin were normalized by the intervention. Cognitive/emotional manipulation can substantially modulate HPA axis responses to pharmacological activation in humans, and HPA disturbances in panic disorder may be secondary to manipulable cognitive/emotional sensitivities. Further study of such factors as novelty, control, and coping may help clarify the origins of HPA axis disturbance in psychiatric disorders and the mediators linking psychosocial stress to disease.

61A quarter century of neuropsychological research in OCD yielded mixed results.61A comprehensive critical review of the OCD neuropsychological literature is presented.61Central concepts and contemporary controversies are discussed.61Novel insights and recommendation for future research are offered.

The hypothalamic-pituitary-adrenal (HPA) axis may mediate negative health effects of stress. It is sensitive to cognitive/emotional factors like novelty, perceived control, and coping. Psychological intervention that reduces novelty and enhances cognitive coping and sense of control can reduce cortisol responses to pentagastrin, a pharmacological HPA activator. This study attempted to identify the core factors that modulate HPA axis activity in this model. Varying instructions were administered prior to drug exposure in a two-visit (placebo first) pentagastrin infusion paradigm. Healthy subjects ( n = 40) were randomly assigned to one of four instruction groups: 1) standard instruction (SI); 2) full cognitive intervention (CI); 3) the CI control component alone; or 4) the CI novelty reduction/coping components alone. Blood samples were obtained via intravenous catheter before and after pentagastrin. Subjects receiving an intervention had smaller cortisol responses than subjects receiving standard instructions. Coping alone had as strong an impact as the more complex intervention that combined coping and control. Control alone also reduced cortisol but its HPA impact appeared less robust. Brief psychological manipulation can significantly reduce HPA activation in challenge paradigms. Cognitive preparation that focused on side effects, reduced potential surprise, and enhanced cognitive coping modulated HPA axis activity as effectively as a previously tested intervention that combined coping and control manipulations. A sense of control alone also reduced cortisol release. The results support development of control or coping techniques to combat negative health effects of stress that are mediated by HPA axis activation.

Abstract Although the cognitive model of depression has evolved appreciably since its first formulation over 40 years ago, the potential interaction of genetic, neurochemical, and cognitive factors has only recently been demonstrated. Combining findings from behavioral genetics and cognitive neuroscience with the accumulated research on the cognitive model opens new opportunities for integrated research. Drawing on advances in cognitive, personality, and social psychology as well as clinical observations, expansions of the original cognitive model have incorporated in successive stages automatic thoughts, cognitive distortions, dysfunctional beliefs, and information-processing biases. The developmental model identified early traumatic experiences and the formation of dysfunctional beliefs as predisposing events and congruent stressors in later life as precipitating factors. It is now possible to sketch out possible genetic and neurochemical pathways that interact with or are parallel to cognitive variables. A hypersensitive amygdala is associated with both a genetic polymorphism and a pattern of negative cognitive biases and dysfunctional beliefs, all of which constitute risk factors for depression. Further, the combination of a hyperactive amygdala and hypoactive prefrontal regions is associated with diminished cognitive appraisal and the occurrence of depression. Genetic polymorphisms also are involved in the overreaction to the stress and the hypercortisolemia in the development of depression--probably mediated by cognitive distortions. I suggest that comprehensive study of the psychological as well as biological correlates of depression can provide a new understanding of this debilitating disorder.

Background and objectives: Cognitive behavioral therapy (CBT) combines cognitive restructuring with exposure to feared stimuli in the treatment of anxiety disorders. Due to the complexities of cognition emotion interactions during ongoing CBT, the underlying mechanisms remain unclear, which hinders treatment optimization. Methods: We created a laboratory analogue by combining reappraisal, a key ingredient of cognitive restructuring, with Pavlovian conditioning, a key ingredient in behavioral treatments. The novel differential Pavlovian acquisition and extinction task featured social stimuli as conditioned and unconditioned stimuli under unregulated and reappraisal instructions. Results: Findings indicated that reappraising the conditioned stimuli attenuated acquisition (Study 1) and facilitated extinction (Study 2) of conditioned negative valence. In Study 3, highly socially anxious individuals showed deficient extinction learning relative to low socially anxious individuals but compensated, for, this by using reappraisal. Limitations: Diagnostic status of participants was not assessed in structured clinical interviews. Conclusions: Reappraisal of feared stimuli could be useful in prevention and treatment of social anxiety. (C) 2014 Elsevier Ltd. All rights reserved.

Abstract Although cognitive-behavioral psychotherapy (CBT) and pharmacotherapy are evidence-based treatments for pediatric anxiety, many youth with anxiety disorders fail to respond to these treatments. Given limitations of clinical measures in predicting treatment response, identifying neural predictors is timely. In this study, 35 anxious youth (ages 7 19 years) completed an emotional face-matching task during which the late positive potential (LPP), an event-related potential (ERP) component that indexes sustained attention towards emotional stimuli, was measured. Following the ERP measurement, youth received CBT or selective serotonin reuptake inhibitor (SSRI) treatment, and the LPP was examined as a predictor of treatment response. Findings indicated that, accounting for pre-treatment anxiety severity, neural reactivity to emotional faces predicted anxiety severity post- CBT and SSRI treatment such that enhanced electrocortical response to angry faces was associated with better treatment response. An enhanced LPP to angry faces may predict treatment response insofar as it may reflect greater emotion dysregulation or less avoidance and/or enhanced engagement with environmental stimuli in general, including with treatment.

Abstract BACKGROUND: Cognitive behavioral therapy (CBT) is a well-established treatment for anxiety and depression; however, response to CBT is heterogeneous across patients and many remain symptomatic after therapy, raising the need to identify prospective predictors for treatment planning. Altered neural processing of reward has been implicated in both depression and anxiety, and improving hedonic capacity is a goal of CBT. However, little is known about how neural response to reward relates to CBT outcomes in depression and anxiety. The current study used the reward positivity (RewP) event-related potential (ERP) component to examine whether neural reactivity to reward would predict CBT response in a sample of patients with anxiety without depression (n = 30) and comorbid anxiety and depression (CAD, n = 22). METHODS: Participants completed a guessing reward ERP paradigm before completing 12 weeks of standard CBT. RESULTS: The majority of the sample (68%; 35 out of 52 patients) responded to treatment, and those with a reduced RewP at baseline were more likely to respond to treatment. A reduced RewP was also associated with a greater pre-to-post CBT reduction in depressive symptoms among individuals with CAD, but not among individuals with pure anxiety. CONCLUSIONS: CBT may be most beneficial in reducing depressive symptoms for individuals who demonstrate decreased reward reactivity prior to treatment. CBT may target reward brain function, leading to greater improvement in symptoms. These effects may be strongest, and therefore most meaningful, for individuals with reward-processing deficits prior to treatment. 2016 Wiley Periodicals, Inc.

The short-term efficacy and effectiveness of Cognitive-Behavioral Therapy (CBT) for treating anxiety disorders in adults has been well established by a multitude of clinical studies and well-controlled randomized trials. However, though the long-term efficacy of CBT as a treatment modality is fairly well established, the degree of its long-term effectiveness has yet to be fully evaluated. Thus, the present study sought to assess both the immediate and long-term effectiveness of individually-administered CBT for the treatment of anxiety disorders in an outpatient psychological clinic. Individuals with a primary diagnosis of Panic Disorder, Social Phobia, Posttraumatic Stress Disorder, Generalized Anxiety Disorder, or Obsessive-Compulsive Disorder who had received 3 or more sessions of CBT were assessed for symptom severity and improvement prior to initiating treatment, at posttreatment, and at one-year follow-up. Symptom severity and improvement ratings were used to categorize patients as “responders” or “remitters” at posttreatment, and “maintained responders” or “maintained remitters” at follow-up. Findings demonstrated that posttreatment success as responder and remitter was significantly maintained at one-year follow-up. Additionally, pre- and posttreatment severity and posttreatment improvement scores were also predictive of maintenance. Furthermore, effect sizes were used to compare the effectiveness of CBT in the present clinical sample to research treatment outcomes demonstrated by previous efficacy studies.

Major depression occurs in 4.4% to 20% of the general population. Studies suggest that major depression is accompanied by immune dysregulation and activation of the inflammatory response system (IRS). Our objective was to quantitatively summarize the data on concentrations of specific cytokines in patients diagnosed with a major depressive episode and controls. We performed a meta-analysis of studies measuring cytokine concentration in patients with major depression, with a database search of the English literature (to August 2009) and a manual search of references. Twenty-four studies involving unstimulated measurements of cytokines in patients meeting DSM criteria for major depression were included in the meta-analysis; 13 for tumor necrosis factor (TNF)- , 9 for interleukin (IL)-1 , 16 for IL-6, 5 for IL-4, 5 for IL-2, 4 for IL-8, 6 for IL-10, and 4 for interferon (IFN)- . There were significantly higher concentrations of TNF- ( p < .00001), weighted mean difference (WMD) (95% confidence interval) 3.97 pg/mL (2.24 to 5.71), in depressed subjects compared with control subjects (438 depressed/350 nondepressed). Also, IL-6 concentrations were significantly higher ( p < .00001) in depressed subjects compared with control subjects (492 depressed/400 nondepressed) with an overall WMD of 1.78 pg/mL (1.23 to 2.33). There were no significant differences among depressed and nondepressed subjects for the other cytokines studied. This meta-analysis reports significantly higher concentrations of the proinflammatory cytokines TNF- and IL-6 in depressed subjects compared with control subjects. While both positive and negative results have been reported in individual studies, this meta-analytic result strengthens evidence that depression is accompanied by activation of the IRS.

Obsessive-compulsive disorder (OCD) has repeatedly been associated with hyperactivity in fronto-striatal brain regions and regions related to performance monitoring. The aim of the current study was to further investigate electrophysiological correlates of performance monitoring. Specifically, we intended to replicate previous results revealing enhanced error-related negativity (ERN) amplitudes in OCD patients. Furthermore, we examined whether OCD patients also showed alterations regarding the correct-related negativity (CRN), the error positivity (Pe) and behavioural correlates of performance monitoring. Event-related brain potentials (ERPs) were recorded from a group of 20 OCD patients and 20 healthy control participants during a modified flanker task. Force sensitive response buttons were utilized to separate correct trials from incorrect trials with full and partial response activation. Both groups displayed substantial ERN and Pe amplitudes for full and partial errors. On error trials OCD patients showed enhanced ERN amplitudes, but group differences were not significant for the Pe and for behavioural adjustment. Further, the OCD group also exhibited enhanced CRN amplitudes and a correlation of frontal CRN amplitudes with symptom severity. These data provide further support for the view that performance monitoring is overactive in OCD. Further, since the amplitude enhancement is not specific to error processing, but is also observed for correct reactions, a response monitoring or evaluation process that contributes to both ERP components might be overactive in OCD. This is in line with fMRI results that revealed higher error- and conflict-related activity in the medial frontal cortex in OCD patients.

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Abstract Reactive oxygen intermediates (ROIs) play an important role in inflammatory processes as mediators of injury and potentially in signal transduction leading to gene expression. Cyclooxygenase (COX) is a rate-limiting enzyme in prostanoid biosynthesis, and its recently cloned inducible form, COX-2, is induced by proinflammatory cytokines. This study linked ROIs to the signaling pathways that induce COX-2 expression. The hydroxyl radical scavengers DMSO (1%), as well as di- and tetramethylthiourea, inhibited IL-1-, TNF alpha-, and LPS-induced COX-2 expression in rat mesangial cells. The suppression of COX-2 mRNA expression correlated with the COX-2 protein level. In comparison with the prolonged induction of the inducible gene encoding protein-tyrosine phosphatase by hydrogen peroxide, the COX-2 gene was only transiently induced. Protein-tyrosine phosphatase is also induced by heat shock and chemical stress, whereas COX-2 is not. Superoxide was a more potent inducer for COX-2 than hydrogen peroxide. In addition, NADPH stimulated COX-2 expression, and an inhibitor of NADPH oxidase blocked COX-2 expression induced by TNF alpha. COX-2 and KC gene expression costimulated by IL-1 were inhibited differentially by the scavengers. These studies demonstrate that oxidant stress is a specific and important inducer of COX-2 gene expression. This induction may contribute to the deleterious amplification of prostanoids in inflammation and compound the direct effects of ROI production.

61The neural changes following CBT for GAD are not well understood.61Before CBT, GAD participants had less insula activation to happy faces vs. controls.61CBT decreased cingulate and amygdala activation to threat cues in GAD participants.61CBT also increased insula activation to happy faces in GAD participants.61Symptom change following CBT for GAD likely reflects multicomponent neural processes.

A group of 11 women (18-29 years old) in the first episode of depression was evaluated before and after cognitive behavioral therapy (CBT). Depressive scores, assessed by Hamilton Rating Scale (HRSD), and serum IL-6 levels significantly decreased after the seventh session. These results suggest that CBT reduced both depressive symptoms and the inflammatory state in women. (C) 2013 Elsevier Ireland Ltd. All rights reserved.

Stressful challenges are associated with variations in immune parameters, including increased innate immunity/inflammation. Among possible mechanisms through which brain monitors peripheral immune responses, toll-like receptors (TLRs) recently emerged as the first line of defense against invading microorganisms. Their expression is modulated in response to pathogens and other environmental stresses. Taking into account this background, the present study aimed to elucidate whether the toll-like receptor-4 (TLR-4) signaling pathway is activated after repeated restraint/acoustic stress exposure in mice prefrontal cortex (PFC), the potential regulatory mechanism implicated (i.e., bacterial translocation), and its role in conditions of stress-induced neuroinflammation, using a genetic strategy: C3H/HeJ mice with a defective response to lipopolysaccharide stimulation of TLR-4. Stress exposure upregulates TLR-4 pathway in mice PFC. Stress-induced inflammatory nuclear factor B activation, upregulation of the proinflammatory enzymes nitric oxide synthase and cyclooxygenase type 2, and cellular oxidative/nitrosative damage are reduced when the TLR-4 pathway is defective. Conversely, TLR-4 deficient mice presented higher levels of the anti-inflammatory nuclear factor peroxisome proliferator activated receptor-gamma after stress exposure than control mice. The series of experiments using antibiotic intestinal decontamination also suggest a role for bacterial translocation on TLR-4 activation in PFC after stress exposure. Taken together, all the data presented here suggest a bifunctional role of TLR-4 signaling pathway after stress exposure by triggering neuroinflammation at PFC level and regulating gut barrier function/permeability. Furthermore, our data suggest a possible protective role of antibiotic decontamination in stress-related pathologies presenting increased intestinal permeability (leaky gut) such as depression, showing a potential therapeutic target that deserves further consideration.

The measurement of inflammation by biomarkers not only documents clinically relevant infections but also offers an important tool to pin point potentially harmful effects of chronic psychosocial stressors. This article focuses firstly on basic biology of inflammation and lists main biomarkers currently used in psycho-physiologic research. In the second part, the effects of the hypothalamic–pituitary–adrenal (HPA) axis and the autonomic nervous system as pathways modulating stress-related inflammation are discussed. Furthermore, current evidence of how chronic psychosocial stressors are related to alterations in inflammatory activity is presented. In summary, job stress, low socioeconomic status, childhood adversities as well as life events, caregiver stress, and loneliness were all shown to exert effects on immunologic activity.

Cognitive therapy for psychosis has developed over the past 30 years from initial case studies, treatment manuals, pilot randomized controlled studies to fully powered and methodologically rigorous efficacy and, subsequently, effectiveness trials. Reviews and meta-analyses have confirmed the benefits of the interventions. Considered appraisal by government and professional organizations has now led to its inclusion in international treatment guidelines for schizophrenia. Patients consistently ask for access to psychotherapeutic interventions, and it is slowly becoming available in many European countries and other parts of the world, eg, US and the People Republic of China. However, it remains unacceptably difficult to access for the vast majority of people with psychosis who could benefit from it. Psychosis affects people in the prime of their lives and leads to major effects on their levels of distress, well-being, and functioning, and also results in major costs to society. Providing effective interventions at an early stage has the potential to reduce the high relapse rates that occur after recovery from first episode and the ensuing morbidity and premature mortality associated with psychosis.

The present study examined the cortical processes that mediate cognitive regulation in response to emotion-eliciting stimuli, before and after anxious children participated in a cognitive behavioral therapy program. Electroencephalographic activity was recorded from anxious children (n = 24, 8 males) and comparison children (n = 16, 7 males) at pre-and post-treatment sessions. The change in anxiety T-scores from pre- to post-treatment was used to signify clinical improvement among anxious children (Improvers: n = 11 vs. Non-improvers: n = 13). Event-related potential components were recorded while children performed a Go/No-go task using emotional facial expressions. For the P1 component, believed to reflect attention and/or arousal processes, Non-improvers had greater activation levels relative to Improver and comparison groups at both sessions. Greater P1 amplitudes at pre-treatment predicted non-improvement following treatment. For the frontal N2 component, thought to reflect cognitive control processing, Improvers recruited greater activation from pre- to post-treatment, a change in activation that was predictive of treatment outcome. Non-improvers showed increased cortical activation within the time window of the P1, whether at pre- or post-treatment. These data suggest that heightened perceptual vigilance may have led to poorer outcomes. Improvers showed increased prefrontal activation within the time window of the N2 from pre- to post-treatment. These data suggest that increased cognitive control may have led to improved treatment outcomes. In sum, P1 activation may serve as a predictor of treatment outcome, while N2 activation may serve as an indicator of treatment response.

A large amount of research has accumulated on the efficacy and effectiveness of cognitive-behavioral therapy (CBT) for anxiety disorders including posttraumatic stress disorder, obsessive-compulsive disorder, panic disorder, generalized anxiety disorder, social anxiety disorder, and specific phobia. The purpose of the current article is to provide an overview of two of the most commonly used CBT methods used to treat anxiety disorders (exposure and cognitive therapy) and to summarize and discuss the current empirical research regarding the usefulness of these techniques for each anxiety disorder. Additionally, we discuss the difficulties that arise when comparing active CBT treatments, and we suggest directions for future research. Overall, CBT appears to be both efficacious and effective in the treatment of anxiety disorders, but dismantling studies are needed to determine which specific treatment components lead to beneficial outcomes and which patients are most likely to benefit from these treatment components.

In recent years, increased attention has been paid to the inflammatory mechanisms of major depressive disorder (MDD). The aim of the present study was to investigate pro-inflammatory pathways related to the “leaky gut” hypothesis of MDD, which is based on the putative intestinal translocation of Gram-negative bacteria and a subsequent abnormal immune response mediated by the Toll-Like Receptor-4 (TLR-4) pathway. 50 patients with first-episode MDD and 30 healthy control subjects participated in the study. Real-time quantitative PCR was used to measure TLR-4 and TLR-2 RNA from peripheral mononuclear blood cells, as well as the expression of NF-κβ, a key transcription factor of the pro-inflammatory response. TLR-4 protein expression was determined by using flow cytometry. TLR-2 served as a control molecule. Low-grade inflammation was characterized by the measurement of interleukin-6 (IL-6) and C-reactive protein (CRP). Bacterial translocation was investigated by the measurement of the 16S rRNA subunit (16S rDNA) of intestinal microbiota in the blood plasma of the participants. We performed these analyses before (t1) and after (t2) cognitive-behavioral therapy (CBT) in MDD. The healthy control subjects were also assessed two times. We found significantly elevated expressions of all three markers (TLR-4 RNA and protein, NF-κβ RNA) and 16S rDNA in MDD at t1 relative to healthy control subjects. These markers showed a significant decrease during CBT (t1>t2 in MDD). We observed no between-group differences and changes in the case of TLR-2. Greater reduction of pro-inflammatory markers during CBT was associated with more pronounced clinical improvement. IL-6 and CRP displayed a moderately elevated level in MDD and did not change during CBT. In conclusion, TLR-4 signaling is up-regulated in newly diagnosed patients with MDD, which may be related to bacterial translocation or to the presence of various damage-associated molecular patterns. Clinical improvement during psychotherapy is associated with decreased expression of pro-inflammatory markers.

Learning by conditioning is a key ability of animals and humans for acquiring novel behavior necessary for survival in a changing environment. Aberrant conditioning has been considered a crucial factor in the etiology and maintenance of panic disorder with agoraphobia (PD/A). Cognitive-behavioral therapy (CBT) is an effective treatment for PD/A. However, the neural mechanisms underlying the effects of CBT on conditioning processes in PD/A are unknown. In a randomized, controlled, multicenter clinical trial in medication-free patients with PD/A who were treated with 12 sessions of manualized CBT, functional magnetic resonance imaging (fMRI) was used during fear conditioning before and after CBT. Quality-controlled fMRI data from 42 patients and 42 healthy subjects were obtained. After CBT, patients compared to control subjects revealed reduced activation for the conditioned response (CS+ > CS–) in the left inferior frontal gyrus (IFG). This activation reduction was correlated with reduction in agoraphobic symptoms from t1 to t2. Patients compared to control subjects also demonstrated increased connectivity between the IFG and regions of the “fear network” (amygdalae, insulae, anterior cingulate cortex) across time. This study demonstrates the link between cerebral correlates of cognitive (IFG) and emotional (“fear network”) processing during symptom improvement across time in PD/A. Further research along this line has promising potential to support the development and further optimization of targeted treatments.

Background Aberrant amygdala-prefrontal interactions at rest and during emotion processing are implicated in the pathophysiology of generalized social anxiety disorder (gSAD), a common disorder...

Epigenetics is a burgeoning area of biomedical research into the mechanisms by which genes are regulated-how the activity of producing proteins is controlled. Although molecular epigenetic research is highly biochemical, it is of interest to sociologists because some epigenetic changes are environmentally mediated and can persist across the life span or into further generations. Environmental epigenetic research tracks mechanisms by which social forces-from pollution to nutrition to mothering to traumatic experience-become molecularly embodied, affect gene expression, and induce durable changes in behavior and health. We begin with an introduction to the science of environmental epigenetics focused on articulating the logic of experimentation and explanation in this field. Turning to sociologists' key interests, we review the growing literature on epigenetics of socioeconomic status. Finally, we consider how epigenetics offers opportunities and challenges for sociological research on both empirical and theoretical grounds.

The purpose of the present pilot study was to explore the moderating role of basal inflammation on the effects of behavioral pain treatment in 41 patients with long-standing pain. Baseline pro-inflammatory status moderated behavioral treatment outcomes: higher pre-treatment levels of Tumor Necrosis Factor (TNF)- and Interleukin (IL)-6 were related to less improvement in pain intensity, psychological inflexibility and in mental health-related quality of life. The treatment outcomes improved in the subgroup that had low levels of pro-inflammatory cytokines at baseline, while the subjects with higher pro-inflammatory status did not. Altogether, results indicate that low-grade inflammation may influence the behavioral treatment outcomes and provide a possible explanation of the heterogeneity in treatment response.

Posttraumatic stress disorder (PTSD) is characterized by a reduced expression of FKBP5, a key modulator of the glucocorticoid receptor. Smaller hippocampal volume has also been documented in PTSD. In this study we explored FKBP5 gene expression, brain structure and cognitive flexibility in patients with PTSD before and after cognitive behavioral therapy (CBT) We measured peripheral FKBP5 RNA, volumes of the hippocampus, amygdala, and medial orbitofrontal cortex and cognitive flexibility in 39 patients with PTSD before and after CBT. The control subjects were 31 trauma-exposed individuals without PTSD who were also assessed twice. At baseline, patients with PTSD showed lower FKBP5 gene expression and smaller hippocampal and medial orbitofrontal cortex, but not amygdala, volumes relative to control subjects. At follow-up, we found significantly increased FKBP5 expression and increased hippocampal volume in patients with PTSD. At follow-up, patients did not differ from control subjects in hippocampal volume. Improvement in PTSD symptoms was predicted by increased FKBP5 expression and increased hippocampal volume, but the primary predictor was FKBP5 expression. There was a positive correlation between the performance on a partial reversal task which tests cognitive flexibility and treatment responsiveness. Clinical improvement in individuals with PTSD was associated with increased expression of FKBP5, increased hippocampal volume and better cognitive flexibility. The three variables were positively correlated.

Abstract A thorough investigation of the neural effects of psychotherapy is needed in order to provide a neurobiological foundation for widely used treatment protocols. This paper reviews functional neuroimaging studies on psychotherapy effects and their methodological background, including the development of symptom provocation techniques. Studies of cognitive behavioural therapy (CBT) effects in obsessive-compulsive disorder (OCD) were consistent in showing decreased metabolism in the right caudate nucleus. Cognitive behavioural therapy in phobia resulted in decreased activity in limbic and paralimbic areas. Interestingly, similar effects were observed after successful intervention with selective serotonin reuptake inhibitors (SSRI) in both diseases, indicating commonalities in the biological mechanisms of psycho- and pharmacotherapy. These findings are discussed in the context of current neurobiological models of anxiety disorders. Findings in depression, where both decreases and increases in prefrontal metabolism after treatment and considerable differences between pharmacological and psychological interventions were reported, seem still too heterogeneous to allow for an integrative account, but point to important differences between the mechanisms through which these interventions attain their clinical effects. Further studies with larger patient numbers, use of standardised imaging protocols across studies, and ideally integration with molecular imaging are needed to clarify the remaining contradictions. This effort is worthwhile because functional imaging can then be potentially used to monitor treatment effects and aid in the choice of the optimal therapy. Finally, recent advances in the functional imaging of hypnosis and the application of neurofeedback are evaluated for their potential use in the development of psychotherapy protocols that use the direct modulation of brain activity as a way of improving symptoms.

OBJECTIVE: Classical conditioning features prominently in many etiological accounts of panic disorder. According to such accounts, neutral conditioned stimuli present during panic attacks acquire panicogenic properties. Conditioned stimuli triggering panic symptoms are not limited to the original conditioned stimuli but are thought to generalize to stimuli resembling those co-occurring with panic, resulting in the proliferation of panic cues. The authors conducted a laboratory-based assessment of this potential correlate of panic disorder by testing the degree to which panic patients and healthy subjects manifest generalization of conditioned fear. METHOD: Nineteen patients with a DSM-IV-TR diagnosis of panic disorder and 19 healthy comparison subjects were recruited for the study. The fear-generalization paradigm consisted of 10 rings of graded size presented on a computer monitor; one extreme size was a conditioned danger cue, the other extreme a conditioned safety cue, and the eight rings of intermediary size created a continuum of similarity from one extreme to the other. Generalization was assessed by conditioned fear potentiating of the startle blink reflex as measured with electromyography (EMG). RESULTS: Panic patients displayed stronger conditioned generalization than comparison subjects, as reflected by startle EMG. Conditioned fear in panic patients generalized to rings with up to three units of dissimilarity to the conditioned danger cue, whereas generalization in comparison subjects was restricted to rings with only one unit of dissimilarity. CONCLUSIONS: The findings demonstrate a marked proclivity toward fear overgeneralization in panic disorder and provide a methodology for laboratory-based investigations of this central, yet understudied, conditioning correlate of panic. Given the putative molecular basis of fear conditioning, these results may have implications for novel treatments and prevention in panic disorder.

Although cognitive behavioral therapy (CBT) is an effective treatment for obsessive–compulsive disorder (OCD), the treatment mechanisms remain poorly understood. This study aimed to investigate the effects ofCBTon changes in the intrinsic whole‐brain functional network ofOCDpatients. Twenty drug‐naive and noncomorbidOCDpatients were recruited, and resting‐state functional magnetic resonance imaging was performed before and after 1202weeks ofCBT. Moreover, 20 healthy controls were scanned twice with a 12‐week interval. A graph‐theory degree centrality (DC) approach and functional connectivity method were used to analyze the whole‐brain functional network hub and connectivity changes inOCDpatients before and afterCBTtreatment. A significant group02×02time interaction onDCwas found in the left dorsolateral prefrontal cortex (DLPFC); theDCin the leftDLPFCwas significantly reduced afterCBTtreatment. Resting‐state functional connectivity (RSFC) between the leftDLPFCand right orbitofrontal cortex was increased in theOCDpatients at baseline, and normalized afterCBTtreatment.RSFCchanges between the leftDLPFCand default mode network (DMN) positively correlated with changes in clinical symptoms inOCDpatients. These findings suggest thatCBTcan modulate changes in intrinsic functional network hubs in the cortico–striato–thalamo‐cortical circuit inOCDpatients. Cognitive control network andDMNconnectivity may be a potential imaging biomarker for evaluatingCBTtreatment forOCD.

Objective: Although exposure-based cognitive-behavioral therapy (CBT) is an effective treatment option for panic disorder with agoraphobia, the neural substrates of treatment response remain unknown. Evidence suggests that panic disorder with agoraphobia is characterized by dysfunctional safety signal processing. Using fear conditioning as a neurofunctional probe, the authors investigated neural baseline characteristics and neuroplastic changes after CBT that were associated with treatment outcome in patients with panic disorder with agoraphobia.Method: Neural correlates of fear conditioning and extinction were measured using functional MRI before and after a manualized CBT program focusing on behavioral exposure in 49 medication-free patients with a primary diagnosis of panic disorder with agoraphobia. Treatment response was defined as a reduction exceeding 50% in Hamilton Anxiety Rating Scale scores.Results: At baseline, nonresponders exhibited enhanced activation in the right pregenual anterior cingulate cortex, the hippocampus, and the amygdala in response to a safety signal. While this activation pattern partly resolved in nonresponders after CBT, successful treatment was characterized by increased right hippocampal activation when processing stimulus contingencies. Treatment response was associated with an inhibitory functional coupling between the anterior cingulate cortex and the amygdala that did not change over time.Conclusions: This study identified brain activation patterns associated with treatment response in patients with panic disorder with agoraphobia. Altered safety signal processing and anterior cingulate cortex-amygdala coupling may indicate individual differences among these patients that determine the effectiveness of exposure-based CBT and associated neuroplastic changes. Findings point to brain networks by which successful CBT in this patient population is mediated.

Abstract Objective: Generalized anxiety disorder (GAD) is a prevalent and debilitating psychiatric condition of adolescence. Two effective forms of treatment are cognitive behavioral therapy (CBT) and selective serotonin reuptake inhibitors (SSRIs). This pilot study examined changes in brain function following each type of treatment in GAD. Method: Subjects were 14 youths with GAD (7 had CBT, 7 received fluoxetine) and 10 age- and gender-matched healthy peers. Functional magnetic resonance imaging (fMRI) scans were acquired before and after treatment for patients and over two comparable time points for controls. During fMRI acquisition, a probe detection task with emotional (angry, happy) and neutral faces allowed for assessment of neural response to threat. Following previous research, region of interest analyses were performed in the right ventrolateral prefrontal cortex (VLPFC). Results: fMRI results showed increased right VLPFC activation, relative to controls, in the medication (t(15)?=?3.01, p?<?0.01) and CBT (t(15)?=?3.22, p?<?0.01) groups following treatment. Conclusions: This study shows significant increase in right VLPFC activation in response to angry faces following treatment with CBT or fluoxetine for GAD. This is consistent with previous research indicating that the VLPFC may facilitate effective responding to underlying neural correlates of anxiety in other brain regions, such as the amygdala.

Randomized controlled trials have yielded promising results for internet-delivered cognitive behavior therapy (iCBT) for patients with social anxiety disorder (SAD). The present study investigated anxiety-related neural changes after iCBT for SAD. The amygdala is a critical hub in the neural fear network, receptive to change using emotion regulation strategies and a putative target for iCBT. Twenty-two subjects were included in pre- and post-treatment functional magnetic resonance imaging at 3T assessing neural changes during an affective face processing task. Treatment outcome was assessed using social anxiety self-reports and the Clinical Global Impression-Improvement (CGI-I) scale. ICBT yielded better outcome than ABM (66% vs. 25% CGI-I responders). A significant differential activation of the left amygdala was found with relatively decreased reactivity after iCBT. Changes in the amygdala were related to a behavioral measure of social anxiety. Functional connectivity analysis in the iCBT group showed that the amygdala attenuation was associated with increased activity in the medial orbitofrontal cortex and decreased activity in the right ventrolateral and dorsolateral (dlPFC) cortices. Treatment-induced neural changes with iCBT were consistent with previously reported studies on regular CBT and emotion regulation in general.

The rise of molecular epigenetics over the last few years promises to bring the discourse about the sociality and susceptibility to environmental influences of the brain to an entirely new level. Epigenetics deals with molecular mechanisms such as gene expression, which may embed in the organism emories of social experiences and environmental exposures. These changes in gene expression may be transmitted across generations without changes in the DNA sequence. Epigenetics is the most advanced example of the new postgenomic and context-dependent view of the gene that is making its way into contemporary biology. In my article I will use the current emergence of epigenetics and its link with neuroscience research as an example of the new, and in a way unprecedented, sociality of contemporary biology. After a review of the most important developments of epigenetic research, and some of its links with neuroscience, in the second part I reflect on the novel challenges that epigenetics presents for the social sciences for a re-conceptualization of the link between the biological and the social in a postgenomic age. Although epigenetics remains a contested, hyped, and often uncritical terrain, I claim that especially when conceptualized in broader non-genecentric frameworks, it has a genuine potential to reformulate the ossified biology/society debate.

Abstract The psychology of extinction has been studied for decades. Approximately 10 years ago, however, there began a concerted effort to understand the neural circuits of extinction of fear conditioning, in both animals and humans. Progress during this period has been facilitated by a high degree of coordination between rodent and human researchers examining fear extinction. Here we review the major advances and highlight new approaches to understanding and exploiting fear extinction. Research in fear extinction could serve as a model for translational research in other areas of behavioral neuroscience.

Rodent studies implicate the prelimbic (PL) region of the medial prefrontal cortex in the expression of conditioned fear. Human studies suggest that the dorsal anterior cingulate cortex (dACC) plays a role similar to PL in mediating or modulating fear responses. This study examined the role of dACC during fear conditioning in healthy humans with magnetic resonance imaging (MRI). Novel analyses were conducted on data from two cohorts that had previously undergone scanning to study fear extinction. Structural and functional brain data were acquired with MRI; the functional MRI (fMRI) component employed an event-related design. Skin conductance response (SCR) was the index of conditioned responses. We found that: 1) cortical thickness within dACC is positively correlated with SCR during conditioning; 2) dACC is activated by a conditioned fear stimulus; and 3) this activation is positively correlated with differential SCR. Moreover, the dACC region implicated in this research corresponds to the target of anterior cingulotomy, an ablative surgical treatment for patients with mood and anxiety disorders. Convergent structural, functional, and lesion findings from separate groups of subjects suggest that dACC mediates or modulates fear expression in humans. Collectively, these data implicate this territory as a potential target for future anti-anxiety therapies.

Abstract Cognitive-behavioral therapy (CBT) is effective for obsessive compulsive disorder (OCD); however, little is understood about its mechanisms related to brain network connectivity. We examined connectivity changes from resting-state functional magnetic resonance imaging data pre-to-post-CBT in 43 OCD participants, randomized to receive either 4 weeks of intensive CBT or 4 weeks waitlist followed by 4 weeks of CBT, and 24 healthy controls before and after 4 weeks of no treatment. Network-based-statistic analysis revealed large-magnitude increases in OCD connectivity in eight networks. Strongest increases involved connectivity between the cerebellum and caudate/putamen, and between the cerebellum and dorsolateral/ventrolateral prefrontal cortices. Connectivity increases were associated with increased resistance to compulsions. Mechanisms of CBT may involve enhanced cross-network integration, both within and outside of classical cortico-striatal-thalamo-cortical regions; those involving cerebellar to striatal and prefrontal regions may reflect acquisition of new non-compulsive goal-directed behaviors and thought patterns. Our findings have implications for identifying targets for enhancing treatment efficacy and monitoring treatment progress.

Cognitive behavioural therapy (CBT) is a successful treatment of obsessive compulsive disorder (OCD). It is known to induce changes in cerebral metabolism; however, the dynamics of these changes and their relation to clinical change remain largely unknown, precluding the identification of individualized response biomarkers. In order to study the dynamics of treatment response, we performed systematic clinical and functional magnetic resonance imaging (fMRI) evaluation of 35 OCD patients immediately before a 3-month course of CBT, halfway through and at its end, as well as 6 months after. To sensitize fMRI probing, we used an original exposure task using neutral, generic and personalized obsession-inducing images. As expected, CBT produced a significant improvement in OCD. This improvement was continuous over the course of the therapy; therefore, outcome could be predicted by response at mid-therapy (r2= 0.67,p< 0.001). Haemodynamic response to the task was located in the anterior cingulate and orbitofrontal cortices and was stronger during exposure to personalized obsession-inducing images. In addition, both the anxiety ratings and the haemodynamic response to the obsession-inducing images in the anterior cingulate and the left but not the right orbitofrontal clusters decreased with symptom improvement. Interestingly, haemodynamic activity continued to decrease after stabilization of clinical symptoms. Using an innovative and highly sensitive exposure paradigm in fMRI, we showed that clinical and haemodynamic phenotypes have similar time courses during CBT. Our results, which suggest that the initial CBT sessions are crucial, prompt us to investigate the anatomo-functional modifications underlying the very first weeks of the therapy.

61Depression is associated with deregulation of immune system.61CBT was more effective than NCT regarding the severity of depressive symptoms.61CBT decreased serum levels of IL-6 to post-intervention.61CBT decreased serum levels of TNF-α to post-intervention.

The neurophysiological bases of cognitive-behavioral therapy (CBT) for obsessive ompulsive disorder (OCD) are incompletely understood. Previous studies, though sparse, implicate metabolic changes in pregenual anterior cingulate cortex (pACC) and anterior middle cingulate cortex (aMCC) as neural correlates of response to CBT. The goal of this pilot study was to determine the relationship between levels of the neurochemically interlinked metabolites glutamate + glutamine (Glx) and N-acetyl-aspartate + N-acetyl-aspartyl-glutamate (tNAA) in pACC and aMCC to pretreatment OCD diagnostic status and OCD response to CBT. Proton magnetic resonance spectroscopic imaging (1H MRSI) was acquired from pACC and aMCC in 10 OCD patients at baseline, 8 of whom had a repeat scan after 4 weeks of intensive CBT. pACC was also scanned (baseline only) in 8 age-matched healthy controls. OCD symptoms improved markedly in 8/8 patients after CBT. In right pACC, tNAA was significantly lower in OCD patients than controls at baseline and then increased significantly after CBT. Baseline tNAA also correlated with post-CBT change in OCD symptom severity. In left aMCC, Glx decreased significantly after intensive CBT. These findings add to evidence implicating the pACC and aMCC as loci of the metabolic effects of CBT in OCD, particularly effects on glutamatergic and N-acetyl compounds. Moreover, these metabolic responses occurred after just 4 weeks of intensive CBT, compared to 3 months for standard weekly CBT. Baseline levels of tNAA in the pACC may be associated with response to CBT for OCD. Lateralization of metabolite effects of CBT, previously observed in subcortical nuclei and white matter, may also occur in cingulate cortex. Tentative mechanisms for these effects are discussed. Comorbid depressive symptoms in OCD patients may have contributed to metabolite effects, although baseline and post-CBT change in depression ratings varied with choline-compounds and myo-inositol rather than Glx or tNAA.

Neuropsychopharmacology, the official publication of the American College of Neuropsychopharmacology, publishing the highest quality original research and advancing our understanding of the brain and behavior.

78 CBT is an effective treatment for OCD, but its brain mechanism is unknown. 78 We acquired MRSI of the brain in children with OCD before and after CBT. 78 After CBT, metabolite levels changed in the cingulate and thalamus of OCD patients. 78 Some metabolite changes correlated with symptomatic response to CBT. 78 Results were interpreted using the Glutamatergic Hypothesis of Pediatric OCD.

objective to perform a systematic review of controlled trials and meta-analysis that involved cognitive and/or behavioral treatment for obsessive-compulsive disorder. method: a systematic review of randomized controlled trials and meta-analysis published on the last decade and indexed on medline and psycinfo. results: studies have confirmed that exposure and response prevention and cognitive therapy are effective methods for the treatment of obsessive-compulsive disorder in children, adolescents and adults. among adults, the combined use of serotonin-reuptake inhibitors and exposure and response prevention or cognitive therapy was not associated with any additional therapeutic effect. among children, the combination of serotonin-reuptake inhibitors and exposure and response prevention are superior to either treatment alone. exposure and response prevention associated with cognitive therapy may result in significant benefits to patients with predominant obsessive thoughts and its group modality also reduces obsessive-compulsive symptoms. conclusion: at the present time, cognitive and behavioral therapies have shown to be highly effective psychotherapeutic approaches for the treatment of obsessive-compulsive disorder. nevertheless, more studies are still needed, mainly those focusing on long-term follow-up, group-treatment and the combined use with serotonin-reuptake inhibitors.

Abstract Top of page Abstract ERP Componentry Factor Analysis, Source Localization, and Correlations with fMRI-Based Measures Reward Positivity and Other Reward-Related Constructs The Reward Positivity and Risk for Depression Future Directions Summary References Feedback indicating monetary loss elicits an apparent negative deflection in the event-related potential (ERP) that has been referred to as the feedback error-related negativity, medial frontal negativity, feedback-related negativity, and feedback negativity ll conceptualizations that suggest a negative ERP component that is greater for loss than gain. In the current paper, I review a programmatic line of research indicating that this apparent negativity actually reflects a reward-related positivity (RewP) that is absent or suppressed following nonreward. I situate the RewP within a broader nomological network of reward processing and individual differences in sensitivity to rewards. Further, I review work linking reductions in the RewP to increased depressive symptoms and risk for depression. Finally, I discuss future directions for research on the RewP.

Event-related potentials (ERPs) provide economical neural indices of information-processing abnormalities in relation to depression and depression risk. Early ERP studies of depression focused on cognitive deficits, more recent studies have examined ERPs to emotionally and motivationally relevant stimuli. Both the late positive potential (LPP), a measure of sustained processing of motivationally salient stimuli, and the reward positivity (RewP), an index of reactivity to receipt of reward, appear to be diminished in individuals with major depressive disorder (MDD) and depressive symptoms, suggesting that depression is associated with emotional disengagement and deficits in reward processing.

Major depressive disorder (MDD) is characterized by the presence of disturbances in emotional processing. However, the neural correlates of these alterations, and how they may be affected by therapeutic interventions, remain unclear. The present study addressed these issues in a preliminary investigation using functional magnetic resonance imaging (fMRI) to examine neural responses to positive, negative, and neutral pictures in unmedicated MDD patients ( N = 22) versus controls ( N = 14). After this initial scan, MDD patients were treated with cognitive behavioral therapy (CBT) and scanned again after treatment. Within regions that showed pre-treatment differences between patients and controls, we tested the association between pre-treatment activity and subsequent treatment response as well as activity changes from pre- to post-treatment. This study yielded three main findings. First, prior to treatment and relative to controls, patients exhibited overall reduced activity in the ventromedial prefrontal cortex (PFC), diminished discrimination between emotional and neutral items in the amygdala, caudate, and hippocampus, and enhanced responses to negative versus positive stimuli in the left anterior temporal lobe (ATL) and right dorsolateral PFC. Second, CBT-related symptom improvement in MDD patients was predicted by increased activity at baseline in ventromedial PFC as well as the valence effects in the ATL and dorsolateral PFC. Third, from pre- to post-treatment, MDD patients exhibited overall increases in ventromedial PFC activation, enhanced arousal responses in the amygdala, caudate, and hippocampus, and a reversal of valence effects in the ATL. The study was limited by the relatively small sample that was able to complete both scan sessions, as well as an inability to determine the influence of comorbid disorders within the current sample. Nevertheless, components of the neural networks corresponding to emotion processing disturbances in MDD appear to resolve following treatment and are predictive of treatment response, possibly reflecting improvements in emotion regulation processes in response to CBT.

http://www.nature.com/doifinder/10.1038/tp.2014.109

61Patients with prolonged grief disorder (PGD) had participated in a randomized controlled trial.61They were followed up 1.5 years after integrative cognitive behavioral therapy for PGD.61Post and follow-up ES for prolonged grief symptoms were large.61The pre to post-improvement in overall mental health was maintained.61This is the largest PGD treatment sample followed up for this long so far.

Fear conditioning and extinction are basic forms of associative learning that have gained considerable clinical relevance in enhancing our understanding of anxiety disorders and facilitating their treatment. Modern neuroimaging techniques have significantly aided the identification of anatomical structures and networks involved in fear conditioning. On closer inspection, there is considerable variation in methodology and results between studies. This systematic review provides an overview of the current neuroimaging literature on fear conditioning and extinction on healthy subjects, taking into account methodological issues such as the conditioning paradigm.

BackgroundBiased causal attribution is a critical factor in the cognitive model of depression. Whereas depressed patients interpret events negatively, healthy people show a self-serving bias (internal attribution of positive events and external attribution of negative events).MethodsUsing fMRI, depressed patients (n = 15) and healthy controls (n = 15) were confronted with positive and negative social events and made causal attributions (internal vs. external). Functional data were analyzed using a mixed effects model.ResultsBehaviourally, controls showed a self-serving bias, whereas patients demonstrated a balanced attributional pattern. Analysis of functional data revealed a significant group difference in a fronto-temporal network. Higher activation of this network was associated with non self-serving attributions in controls but self-serving attributions in patients. Applying a psycho-physiological interaction analysis, we observed reduced coupling between a dorsomedial PFC seed region and limbic areas during self-serving attributions in patients compared to controls.LimitationsResults of the PPI analysis are preliminary given the liberal statistical threshold.ConclusionsThe association of the behaviourally less frequent attributional pattern with activation in a fronto-temporal network suggests that non self-serving responses may produce a self-related response conflict in controls, while self-serving responses produce this conflict in patients. Moreover, attribution-modulated coupling between the dorsomedial PFC and limbic regions was weaker in patients than controls. This preliminary finding suggests that depression may be associated with disturbances in fronto-limbic coupling during attributional decisions. Our results implicate that treatment of major depression may benefit from approaches that facilitate reinterpretation of emotional events in a more positive, more self-serving way.

Abstract Anxiety disorders are a significant problem in the community, and recent neuroimaging research has focused on determining the brain circuits that underlie them. Research on the neurocircuitry of anxiety disorders has its roots in the study of fear circuits in animal models and the study of brain responses to emotional stimuli in healthy humans. We review this research, as well as neuroimaging studies of anxiety disorders. In general, these studies have reported relatively heightened amygdala activation in response to disorder-relevant stimuli in post-traumatic stress disorder, social phobia, and specific phobia. Activation in the insular cortex appears to be heightened in many of the anxiety disorders. Unlike other anxiety disorders, post-traumatic stress disorder is associated with diminished responsivity in the rostral anterior cingulate cortex and adjacent ventral medial prefrontal cortex. Additional research will be needed to (1) clarify the exact role of each component of the fear circuitry in the anxiety disorders, (2) determine whether functional abnormalities identified in the anxiety disorders represent acquired signs of the disorders or vulnerability factors that increase the risk of developing them, (3) link the findings of functional neuroimaging studies with those of neurochemistry studies, and (4) use functional neuroimaging to predict treatment response and assess treatment-related changes in brain function.

Building upon various lines of research, we posited that methylation of the oxytocin receptor gene (OXTR) would mediate the effect of adult adversity on increased commitment to negative schemas and in turn the development of depression. We tested our model using structural equation modeling and longitudinal data from a sample of 100 middle-aged, African American women. The results provided strong support for the model. Analysis of the 12 CpG sites available for the promoter region of the OXTR gene identified four factors. One of these factors was related to the study variables, whereas the others were not. This factor mediated the effect of adult adversity on schemas relating to pessimism and distrust, and these schemas, in turn, mediated the impact of OXTR methylation on depression. All indirect effects were statistically significant, and they remained significant after controlling for childhood trauma, age, romantic relationship status, individual differences in cell types, and average level of genome-wide methylation. These finding suggest that epigenetic regulation of the oxytocin system may be a mechanism whereby the negative cognitions central to depression become biologically embedded.

Excessive attention toward aversive information may be a core mechanism underlying emotional disorders, but little is known about whether this is predictive of response to treatments. We evaluated whether enhanced attention toward aversive stimuli, as indexed by an event-related potential component, the late positive potential (LPP), would predict response to cognitive behavioral therapy (CBT) in patients with social anxiety disorder and/or major depressive disorder. Thirty-two patients receiving 12 weeks of CBT responded to briefly-presented pairs of aversive and neutral pictures that served as targets or distracters while electroencephaolography was recorded. Patients with larger pre-treatment LPPs to aversive relative to neutral distracters (when targets were aversive) were more likely to respond to CBT, and demonstrated larger reductions in symptoms of depression and anxiety following treatment. Increased attention toward irrelevant aversive stimuli may signal attenuated top-down control, so treatments like CBT that improve this control could be beneficial for these individuals.

Posttraumatic stress disorder (PTSD) is characterized by hyperarousal, flashbacks, avoidance, and memory dysfunctions. Although psychotherapy improves the clinical symptoms, its effect on memory has not been explored. In addition, there is no information about gene expression changes related to hippocampal functions. We assessed PTSD patients (n=20) using the Wechsler Memory Scale-Revised (WAIS-R) and a paired associates learning (PAL) test, as well as changes in blood FK506 binding protein (FKBP5) mRNA expression before and after cognitive behavioral therapy (CBT). Results revealed that before CBT PTSD patients were impaired on WAIS-R delayed recall, attention/concentration, and PAL compared with trauma-exposed control subjects (n=20). These memory dysfunctions showed a significant improvement after CBT. Better performance on the PAL test correlated with enhanced blood FKBP5 mRNA expression. These results suggest that elevated FKBP5 expression during CBT is related to improved associative memory linked to the hippocampal formation.

Surprisingly little research supports the hypothesis that depressions characterized by objective measures of neurobiological dysregulation respond poorly to psychotherapy. Moreover, relevant studies testing this hypothesis have been compromised by low rates of neurobiological abnormality in outpatient samples. The authors therefore investigated response to cognitive behavior therapy in relation to pretreatment measures of hypothalamic-pituitary-adrenocortical (HPA) activity in hospitalized, yet unmedicated, patients.The subjects were 29 unmedicated, hospitalized patients with major depression (DSM-III-R and Schedule for Affective Disorders and Schizophrenia/Research Diagnostic Criteria), nonpsychotic/nonbipolar subtype. After a 7- to 14-day evaluation, urinary free cortisol levels and dexamethasone suppression tests (DSTs) were obtained. Patients were treated for an average of 3 weeks with intensive individual cognitive behavior therapy. Response was assessed in relation to clinical severity of illness and pretreatment HPA parameters.Response to inpatient cognitive behavior therapy was inversely associated with pretreatment urinary free cortisol concentrations, although not strongly correlated with DST results. Overall, 12 (92%) of 13 cortisol suppressors on the DST who had normal urinary free cortisol concentrations responded to treatment, compared with only seven (44%) of the 16 patients characterized by nonsuppression of cortisol and/or elevated urinary free cortisol excretion. The relation between response to cognitive behavior therapy and HPA activity was not explained by clinical measures of symptom severity.Results are consistent with the hypothesis that patients with increased HPA function are less responsive to psychotherapy and, hence, might require somatic interventions. It is proposed that the negative impact of hypercortisolism on neurocognitive function mediates this relationship.

The Hsp90 cochaperone FK506 binding protein 5 (FKBP5) is an established regulator of the glucocorticoid receptor (GR), and numerous genetic studies have linked it to stress-related diseases such as major depression or posttraumatic stress disorder. However, translational studies including genetic animal models are lacking. Mice deficient of FKBP5 were generated and analyzed in comparison with wildtype littermates. They were subjected to several test paradigms characterizing their emotionality, stress reactivity, and coping behavior as well as hypothalamus-pituitary-adrenal axis function and regulation. Moreover, protein expression of GR and FKBP5 was determined in different brain structures 8 days after stress exposure. The combined dexamethasone/corticotropin-releasing hormone test was performed both in mice and healthy human subjects of different FKBP5 genotypes. The GR function was evaluated by reporter gene assays. Under basal conditions, deletion of FKBP5 did not change exploratory drive, locomotor activity, anxiety-related behavior, stress-coping, or depression-like behavior. After exposure to different acute stressors of sufficient intensity, however, it led to a more active coping behavior. Moreover, loss of FKBP5 decreased hypothalamus-pituitary-adrenal axis reactivity and GR expression changes in response to stressors. In mice and humans, the FKBP5 genotype also determined the outcome of the dexamethasone/corticotropin-releasing hormone test. This study in mice and humans presents FKBP5 as a decisive factor for the physiological stress response, shaping neuroendocrine reactivity as well as coping behavior. This lends strong support to the concept emerging from human studies of FKBP5 as important factor governing gene 揺nvironment interactions relevant for the etiology of affective disorders.

Do genetic or epigenetic factors play a role in making some individuals more vulnerable than others to loss of attachment figures or other traumatic experiences? DNA was obtained from growth phase entrained Epstein-Barr Virus (EBV) transformed lymphoblast cell lines from 143 adopted participants. Genotype of the serotonin transporter linked polymorphic region (5HTTLPR) was determined, and methylation ratios for each of the C-phosphate-G (CpG) residues were assessed using quantitative mass spectroscopy. Unresolved loss or trauma was established using the Berkeley Adult Attachment Interview. Higher levels of methylation of the 5HTT promoter associated CpG island were associated with increased risk of unresolved responses to loss or other trauma in carriers of the usually protective 5HTTLPR ll variant. The ss variant of 5HTTLPR predicted more unresolved loss or trauma, but only in case of lower levels of methylation. Higher levels of methylation of the ss variant were associated with less unresolved loss or other trauma. Associations between 5HTTLPR polymorphisms and psychological problems are significantly altered by environmentally induced methylation patterns. Methylation may serve as the interface between adverse environment and the developing organism.

Objective: The authors investigated the effects of recently identified genome-wide significant schizophrenia genetic risk variants on cognition and brain structure.Method: A panel of six single-nucleotide polymorphisms (SNPs) was selected to represent genome-wide significant loci from three recent genome-wide association studies (GWAS) for schizophrenia and was tested for association with cognitive measures in 346 patients with schizophrenia and 2,342 healthy comparison subjects. Nominally significant results were evaluated for replication in an independent case-control sample. For SNPs showing evidence of association with cognition, associations with brain structural volumes were investigated in a large independent healthy comparison sample.Results: Five of the six SNPs showed no significant association with any cognitive measure. One marker in the major histocompatibility complex (MHC) region, rs6904071, showed independent, replicated evidence of association with delayed episodic memory and was significant when both samples were combined. In the combined sample of up to 3,100 individuals, this SNP was associated with widespread effects across cognitive domains, although these additional associations were no longer significant after adjusting for delayed episodic memory. In the large independent structural imaging sample, the same SNP was also associated with decreased hippocampal volume.Conclusions: The authors identified a SNP in the MHC region that was associated with cognitive performance in patients with schizophrenia and healthy comparison subjects. This SNP, rs6904071, showed a replicated association with episodic memory and hippocampal volume. These findings implicate the MHC region in hippocampal structure and functioning, consistent with the role of MHC proteins in synaptic development and function. Follow-up of these results has the potential to provide insights into the pathophysiology of schizophrenia and cognition.

Different genotypic combinations ofCOMTandDRD2can generate multiple subgroups with different levels of dopamine signaling. Its modulations on brain properties can be investigated by analyzing the combined gene effects ofCOMTandDRD2. However, the inherent association between modulation patterns of the dopamine system on structural and functional properties of the brain remains unknown. In 294 healthy young adults, we investigated both additive and non-additive interactions ofCOMTandDRD2on gray matter volume (GMV) and resting-state functional connectivity (rsFC) using a voxel-based analysis. We found a significant non-additiveCOMT DRD2interaction in the right dorsal anterior cingulate cortex (dACC), exhibiting an inverted U-shape modulation by dopamine signaling. We also found a significant non-additiveCOMT DRD2interaction in the rsFC between the right dACC and precuneus, displaying a U-shape modulation by dopamine signaling. Moreover, this rsFC was negatively correlated with the GMV of the right dACC. Although the additive interaction did not pass corrections for multiple comparisons, we also found a trend towards an inverse modulation pattern and a negative correlation between the GMV and rsFC of the right inferior frontal gyrus. No genotypic differences were detected in any assessments of the cognition, mood and personality. These findings suggest that healthy young adults without optimal dopamine signaling may maintain their normal behavioral performance via a functional compensatory mechanism in response to structural deficit due to genetic variation. The online version of this article (doi:10.1007/s00429-015-1134-4) contains supplementary material, which is available to authorized users.

N2 - Cognitive behavioral therapy (CBT), an effective treatment for depression, targets self-referential processing of emotional stimuli. We examined the effects of CBT on brain functioning during self-referential processing in depressive patients using functional magnetic resonance imaging (fMRI). Depressive patients (n = 23) and healthy participants (n = 15) underwent fMRI scans during a self-referential task using emotional trait words. The depressive patients had fMRI scans before and after completing a total of 12 weekly sessions of group CBT for depression, whereas the healthy participants underwent fMRI scans 12 weeks apart with no intervention. Before undergoing CBT, the depressive patients showed hyperactivity in the medial prefrontal cortex (MPFC) during self-referential processing of negative words. Following CBT, MPFC and ventral anterior cingulate cortex (vACC) activity during self-referential processing among depressive patients was increased for positive stimuli, whereas it was decreased for negative stimuli. Improvements in depressive symptoms were negatively correlated with vACC activity during self-referential processing of negative stimuli. These results suggest that CBT-related improvements in depressive symptoms are associated with changes in MPFC and vACC activation during self-referential processing of emotional stimuli. The Author (2013). Published by Oxford University Press.

Amygdala is considered as the core pathogenesis of generalized social anxiety disorder (GSAD). However, it is still unclear whether effective group cognitive behavioral therapy (CBT) could modulate the function of amygdala-related network. We aimed to examine the resting-state functional connectivity (rsFC) of the amygdala before and after group CBT. Fifteen patients with GSAD were scanned on a 3T MR system before and after 8 weeks of group CBT. For comparison, nineteen healthy control participants also underwent baseline fMRI scanning. We used bilateral amygdala as seed regions and the rsFC maps of the right and left amygdala were created separately in a voxel-wise way. Clusters survived two-tailed Gaussian Random Field (GRF) correction at p <0.05 (voxel z value >2.3). Compared with baseline, patients with CBT showed significantly decreased connectivity of the left amygdala with the right putamen, the left dorsal medial prefrontal cortex (dmPFC) and the right dorsal anterior cingulate cortex (dACC). Especially, the changes of the connectivity between the left amygdala and the dACC positively correlated with changes of the anxiety symptom in patients. Furthermore, in relative to controls, patients showed higher connectivity of left amygdala with dmPFC and dACC at baseline, while normal after CBT. Short-term group CBT could down-regulate the abnormal higher connectivity of prefrontal-amygdala network, along with clinical improvement. This may provide a potential biomarker to monitor the treatment effect of CBT in GSAD patients.

Many psychiatric disorders are associated with abnormal self-processing. While these disorders also have a wide-range of complex, and often heterogeneous sets of symptoms involving different cognitive, emotional and motor domains, an impaired sense of self can contribute to many of these. Research investigating self-processing in healthy subjects has facilitated identification of changes in specific neural circuits which may cause altered self-processing in psychiatric disorders. While there is evidence for altered self-processing in many psychiatric disorders, here we will focus on four of the most studied ones, schizophrenia, autism spectrum disorder (ASD), unipolar depression and borderline personality disorder (BPD). We review evidence for dysfunction in two different neural systems implicated in self-processing, namely the cortical midline system (CMS) and the mirror-neuron system (MNS), as well as contributions from altered inter-hemispheric communication (IHC). We conclude that while abnormalities in frontal-parietal activity and/or connectivity in the CMS are common to all four disorders there is more disruption of integration between frontal and parietal regions resulting in a shift towards parietal control in schizophrenia and ASD which may contribute to the greater severity and delusional aspects of their symptoms. Abnormalities in the MNS and in IHC are also particularly evident in schizophrenia and ASD and may lead to disturbances in sense of agency and the physical self in these two disorders. A better future understanding of how changes in the neural systems sub-serving self-processing contribute to different aspects of symptom abnormality in psychiatric disorders will require that more studies carry out detailed individual assessments of altered self-processing in conjunction with measurements of neural functioning.

The pervasive hopelessness and high risk of suicide in depressive patients suggested that the self might be abnormal among them.The status of fMRI studies on abnormalities of self-related processing in depression were reviewed in this article.

Epigenetic signatures such as methylation of the monoamine oxidase A (MAOA) gene have been found to be altered in panic disorder (PD). Hypothesizing temporal plasticity of epigenetic processes as a mechanism of successful fear extinction, the present psychotherapy-epigenetic study for we believe the first time investigatedMAOAmethylation changes during the course of exposure-based cognitive behavioral therapy (CBT) in PD.MAOAmethylation was compared betweenN=28 female Caucasian PD patients (discovery sample) andN=28 age- and sex-matched healthy controls via direct sequencing of sodium bisulfite-treated DNA extracted from blood cells.MAOAmethylation was furthermore analyzed at baseline (T0) and after a 6-week CBT (T1) in the discovery sample parallelized by a waiting time in healthy controls, as well as in an independent sample of female PD patients (N=20). Patients exhibited lowerMAOAmethylation than healthy controls (P<0.001), and baseline PD severity correlated negatively withMAOAmethylation (P=0.01). In the discovery sample,MAOAmethylation increased up to the level of healthy controls along with CBT response (number of panic attacks; T0–T1: +3.37±2.17%), while non-responders further decreased in methylation (612.00±1.28%P=0.001). In the replication sample, increases inMAOAmethylation correlated with agoraphobic symptom reduction after CBT (P=0.02–0.03). The present results support previous evidence forMAOAhypomethylation as a PD risk marker and suggest reversibility ofMAOAhypomethylation as a potential epigenetic correlate of response to CBT. The emerging notion of epigenetic signatures as a mechanism of action of psychotherapeutic interventions may promote epigenetic patterns as biomarkers of lasting extinction effects.