Biology of Mood and Anxiety Disorders

The field of non-pharmacological therapies for treatment resistant depression (TRD) is rapidly evolving and new somatic therapies are valuable options for patients who have failed numerous other treatments. A major challenge for clinicians (and patients alike) is how to integrate the results from published clinical trials in the clinical decision-making process. We reviewed the literature for articles reporting results for clinical trials in particular efficacy data, contraindications and side effects of somatic therapies including electroconvulsive therapy (ECT), transcranial magnetic stimulation (TMS), vagal nerve stimulation (VNS) and deep brain stimulation (DBS). Each of these devices has an indication for patients with different level of treatment resistance, based on acuteness of illness, likelihood of response, costs and associated risks. ECT is widely available and its effects are relatively rapid in severe TRD, but its cognitive adverse effects may be cumbersome. TMS is safe and well tolerated, and it has been approved by FDA for adults who have failed to respond to one antidepressant, but its use in TRD is still controversial as it is not supported by rigorous double-blind randomized clinical trials. The options requiring surgical approach are VNS and DBS. VNS has been FDA-approved for TRD, however it is not indicated for management of acute illness. DBS for TRD is still an experimental area of investigation and double-blind clinical trials are underway.

Cristina Cusin

Darin D Dougherty

Biology of Mood & Anxiety Disorders

Somatic therapies for treatment-resistant depression: ECT, TMS, VNS, DBS

难治性抑郁症的体细胞疗法：ECT、TMS、VNS、DBS

Lithium is considered by many as the gold standard medication in the management of bipolar disorder (BD). However, the clinical response to lithium is heterogeneous, and the molecular basis for this difference in response is unknown. In the present study, we sought to determine how the peripheral blood gene expression profiles of patients with bipolar disorder (BD) changed over time following intitiation of treatment with lithium, and whether differences in those profiles over time were related to the clinical response.Illumina Sentrix Beadchip (Human-6v2) microarrays containing > 48,000 transcript probes were used to measure levels of expression of gene-expression in peripheral blood from 20 depressed subjects with BD prior to and every two weeks during 8 weeks of open-label treatment with lithium.Changes in gene-expression were compared between treatment responders (defined as a decrease in the Hamilton Depression Rating Scale of 50% or more) and non-responders. Pathway analysis was conducted using GeneGO Metacore software.127 genes showed a differential response in responders vs. non-responders. Pathway analysis showed that regulation of apoptosis was the most significantly affected pathway among these genes. Closer examination of the time-course of changes among BCL2 related genes showed that in lithium-responders, one month after starting treatment with lithium, several anti-apoptotic genes including Bcl2 and insulin receptor substrate 2 (IRS2) were up-regulated, while pro-apoptotic genes, including BCL2-antagonist/killer 1 (BAK1) and BCL2-associated agonist of cell death (BAD), were down-regulated. In contrast, in lithium non-responders, BCL2 and IRS2 were down-regulated, while BAK1 and BAD up-regulated at the one-month time-point.These results suggest that differential changes in the balance of pro- and anti- apoptotic gene-expression following treatment with lithium may explain some of the heterogeneity in clinical response in BD patients.

Lori Lowthert

Janine Leffert

Aiping Lin

Sheila Umlauf

Kathleen Maloney

Anjana Muralidharan

Boris Lorberg

Shrikant Mane

Hongyu Zhao

Rajita Sinha

Zubin Bhagwagar

Robert Beech

Increased ratio of anti-apoptotic to pro-apoptotic Bcl2 gene-family members in lithium-responders one month after treatment initiation

锂治疗应答者在治疗开始一个月后抗凋亡与促凋亡Bcl2基因家族成员比例增加

Anxiety disorders are characterized by specific emotions, thoughts and physiological responses. Little is known, however, about the relationship between psychological/personality indices of anxiety responses to fear stimuli.We studied this relationship in healthy subjects by comparing scores on psychological and personality questionnaires with results of an experimental fear conditioning paradigm using a visual conditioned stimulus (CS). We measured skin conductance response (SCR) during habituation, conditioning, and extinction; subsequently testing for recall and renewal of fear 24 hours later.We found that multiple regression models explained 45% of the variance during conditioning to the CS+, and 24% of the variance during renewal of fear to the CS+. Factors that explained conditioning included lower levels of conscientiousness, increased baseline reactivity (SCL), and response to the shock (UCR). Low levels of extraversion correlated with greater renewal. No model could be found to explain extinction learning or extinction recall to the CS+.The lack of correlation of fear extinction with personality and neuropsychological indices suggests that extinction may be less determined by trait variables and cognitive state, and may depend more on the subject's current emotional state. The negative correlation between fear renewal and extraversion suggests that this personality characteristic may protect against post-treatment relapse of symptoms of anxiety disorders.

Karen G Martínez

Melissa Castro-Couch

José A Franco-Chaves

Brenda Ojeda-Arce

Gustavo Segura

Mohammed R Milad

Gregory J Quirk

Correlations between psychological tests and physiological responses during fear conditioning and renewal

恐惧条件作用和恢复期间心理测试与生理反应之间的相关性

Abstract Bipolar disorder (BD) is a multi-factorial disorder caused by genetic and environmental influences. It has a large genetic component, with heritability estimated between 59-93%. Recent genome-wide association studies (GWAS) using large BD patient populations have identified a number of genes with strong statistical evidence for association with susceptibility for BD. Among the most significant and replicated genes is ankyrin 3 ( ANK3 ), a large gene that encodes multiple isoforms of the ankyrin G protein. This article reviews the current evidence for genetic association of ANK3 with BD, followed by a comprehensive overview of the known biology of the ankyrin G protein, focusing on its neural functions and their potential relevance to BD. Ankyrin G is a scaffold protein that is known to have many essential functions in the brain, although the mechanism by which it contributes to BD is unknown. These functions include organizational roles for subcellular domains in neurons including the axon initial segment and nodes of Ranvier, through which ankyrin G orchestrates the localization of key ion channels and GABAergic presynaptic terminals, as well as creating a diffusion barrier that limits transport into the axon and helps define axo-dendritic polarity. Ankyrin G is postulated to have similar structural and organizational roles at synaptic terminals. Finally, ankyrin G is implicated in both neurogenesis and neuroprotection. ANK3 and other BD risk genes participate in some of the same biological pathways and neural processes that highlight several mechanisms by which they may contribute to BD pathophysiology. Biological investigation in cellular and animal model systems will be critical for elucidating the mechanism through which ANK3 confers risk of BD. This knowledge is expected to lead to a better understanding of the brain abnormalities contributing to BD symptoms, and to potentially identify new targets for treatment and intervention approaches.

Melanie P. Leussis

Jon Morrow Madison

Tracey L Petryshen

Ankyrin 3: genetic association with bipolar disorder and relevance to disease pathophysiology

锚蛋白3：与双相情感障碍的遗传关联及其与疾病病理生理的相关性

Family, twin and epidemiologic studies all point to an important genetic contribution to the risk to develop mood and anxiety disorders. While some progress has been made in identifying relevant pathomechanisms for these disorders, candidate based strategies have often yielded controversial findings. Hopes were thus high when genome-wide genetic association studies became available and affordable and allowed a hypothesis-free approach to study genetic risk factors for these disorders. In an unprecendented scientific collaborative effort, large international consortia formed to allow the analysis of these genome-wide association datasets across thousands of cases and controls ([1] and see also http://www.broadinstitute.org/mpg/ricopili/). Now that large meta-analyses of genome-wide association studies (GWAS) have been published for bipolar disorder and major depression it has become clear that main effects of common variants are difficult to identify in these disorders, suggesting that additional approaches maybe needed to understand the genetic basis of these disorders [2,3].

Elisabeth B Binder

The genetic basis of mood and anxiety disorders – changing paradigms

情绪和焦虑障碍的遗传基础——不断变化的范式

Coordination of activity between the amygdala and ventromedial prefrontal cortex (vmPFC) is important for fear-extinction learning. Aberrant recruitment of this circuitry is associated with anxiety disorders. Here, we sought to determine if individual differences in future threat uncertainty sensitivity, a potential risk factor for anxiety disorders, underly compromised recruitment of fear extinction circuitry. Twenty-two healthy subjects completed a cued fear conditioning task with acquisition and extinction phases. During the task, pupil dilation, skin conductance response, and functional magnetic resonance imaging were acquired. We assessed the temporality of fear extinction learning by splitting the extinction phase into early and late extinction. Threat uncertainty sensitivity was measured using self-reported intolerance of uncertainty (IU).During early extinction learning, we found low IU scores to be associated with larger skin conductance responses and right amygdala activity to learned threat vs. safety cues, whereas high IU scores were associated with no skin conductance discrimination and greater activity within the right amygdala to previously learned safety cues. In late extinction learning, low IU scores were associated with successful inhibition of previously learned threat, reflected in comparable skin conductance response and right amgydala activity to learned threat vs. safety cues, whilst high IU scores were associated with continued fear expression to learned threat, indexed by larger skin conductance and amygdala activity to threat vs. safety cues. In addition, high IU scores were associated with greater vmPFC activity to threat vs. safety cues in late extinction. Similar patterns of IU and extinction learning were found for pupil dilation. The results were specific for IU and did not generalize to self-reported trait anxiety.Overall, the neural and psychophysiological patterns observed here suggest high IU individuals to disproportionately generalize threat during times of uncertainty, which subsequently compromises fear extinction learning. More broadly, these findings highlight the potential of intolerance of uncertainty-based mechanisms to help understand pathological fear in anxiety disorders and inform potential treatment targets.

Jayne Morriss

Anastasia Christakou

Carien M. van Reekum

Intolerance of uncertainty predicts fear extinction in amygdala-ventromedial prefrontal cortical circuitry

不确定性厌恶预测杏仁核-腹内侧前额叶皮层电路中的恐惧消退

Post-traumatic stress disorder (PTSD) is accompanied by disturbed sleep and an impaired ability to learn and remember extinction of conditioned fear. Following a traumatic event, the full spectrum of PTSD symptoms typically requires several months to develop. During this time, sleep disturbances such as insomnia, nightmares, and fragmented rapid eye movement sleep predict later development of PTSD symptoms. Only a minority of individuals exposed to trauma go on to develop PTSD. We hypothesize that sleep disturbance resulting from an acute trauma, or predating the traumatic experience, may contribute to the etiology of PTSD. Because symptoms can worsen over time, we suggest that continued sleep disturbances can also maintain and exacerbate PTSD. Sleep disturbance may result in failure of extinction memory to persist and generalize, and we suggest that this constitutes one, non-exclusive mechanism by which poor sleep contributes to the development and perpetuation of PTSD. Also reviewed are neuroendocrine systems that show abnormalities in PTSD, and in which stress responses and sleep disturbance potentially produce synergistic effects that interfere with extinction learning and memory. Preliminary evidence that insomnia alone can disrupt sleep-dependent emotional processes including consolidation of extinction memory is also discussed. We suggest that optimizing sleep quality following trauma, and even strategically timing sleep to strengthen extinction memories therapeutically instantiated during exposure therapy, may allow sleep itself to be recruited in the treatment of PTSD and other trauma and stress-related disorders.

Edward F. Pace-Schott

Anne Germain

Mohammed R. Milad

Sleep and REM sleep disturbance in the pathophysiology of PTSD: the role of extinction memory

睡眠和快速眼动睡眠障碍在创伤后应激障碍病理生理学中的作用：消退记忆的角色

Previous research reported that individual differences in the stress response were moderated by an interaction between individuals' life stress experience and the serotonin transporter-linked polymorphic region (5-HTTLPR), a common polymorphism located in the promoter region of the serotonin transporter gene (SLC6A4). Furthermore, this work suggested that individual differences in SLC6A4 DNA methylation could be one underlying mechanism by which stressful life events might regulate gene expression. The aim of this study was to understand the relation between early and recent life stress experiences, 5-HTTLPR genotype, and SLC6A4 methylation. In addition, we aimed to address how these factors influence gene expression and cortisol response to an acute psychosocial stressor, operationalized as the Trier Social Stress Test (TSST). In a sample of 105 Caucasian males, we collected early and recent life stress measures and blood samples to determine 5-HTTLPR genotype and SLC6A4 methylation. Furthermore, 71 of these participants provided blood and saliva samples before and after the TSST to measure changes in SLC6A4 and NR3C1 gene expression and cortisol response. Compared to S-group individuals, LL individuals responded with increased SLC6A4 mRNA levels to the TSST (t(66) = 3.71, P < .001) and also showed increased global methylation as a function of ELS (r (32) = .45, P = .008) and chronic stress (r (32) = .44, P = .010). Compared to LL individuals, S-group individuals showed reduced SLC6A4 mRNA levels (r (41) = −.31, P = .042) and increased F3 methylation (r (67) = .30, P = .015) as a function of ELS; as well as increased F1 methylation as a function of chronic stress and recent depressive symptoms (r = .41, P < .01), which correlated positively with NR3C1 expression (r (42) = .31, P = .040). Both early and recent life stress alter DNA methylation as a function of 5-HTTLPR genotype. Some of these changes are also reflected in gene expression and cortisol response, differentially affecting individuals' stress response in a manner that may confer susceptibility or resilience for psychopathology upon experiencing stressful life events.

Elif A Duman

Turhan Canli

Influence of life stress, 5-HTTLPR genotype, and SLC6A4 methylation on gene expression and stress response in healthy Caucasian males

生命压力、5-HTTLPR基因型及SLC6A4甲基化对健康高加索男性基因表达和应激反应的影响

There is growing interest in the use of neuroimaging for the direct treatment of mental illness. Here, we present a new framework for such treatment, neurocognitive therapeutics. What distinguishes neurocognitive therapeutics from prior approaches is the use of precise brain-decoding techniques within a real-time feedback system, in order to adapt treatment online and tailor feedback to individuals' needs. We report an initial feasibility study that uses this framework to alter negative attention bias in a small number of patients experiencing significant mood symptoms. The results are consistent with the promise of neurocognitive therapeutics to improve mood symptoms and alter brain networks mediating attentional control. Future work should focus on optimizing the approach, validating its effectiveness, and expanding the scope of targeted disorders.

David M Schnyer

Christopher G Beevers

Megan T deBettencourt

Stephanie M Sherman

Jonathan D Cohen

Kenneth A Norman

Nicholas B Turk-Browne

Neurocognitive therapeutics: from concept to application in the treatment of negative attention bias

神经认知疗法：从概念到应用于负性注意偏向的治疗

Aberrant amygdala-prefrontal interactions at rest and during emotion processing are implicated in the pathophysiology of generalized social anxiety disorder (gSAD), a common disorder characterized by fears of potential scrutiny. Cognitive behavioral therapy (CBT) is first-line psychotherapy for gSAD and other anxiety disorders. While CBT is generally effective, there is a great deal of heterogeneity in treatment response. To date, predictors of success in CBT for gSAD include reduced amygdala reactivity and increased activity in prefrontal regulatory regions (e.g., anterior cingulate cortex, "ACC") during emotion processing. However, studies have not examined whether tonic (i.e., at rest) coupling of amygdala and these prefrontal regions also predict response to CBT.Twenty-one patients with gSAD participated in resting-state functional magnetic resonance imaging (fMRI) before 12 weeks of CBT. Overall, symptom severity was significantly reduced after completing CBT; however, the patients varied considerably in degree of symptom change. Whole-brain voxel-wise findings showed symptom improvement after CBT was predicted by greater right amygdala-pregenual ACC ("pgACC") connectivity and greater left amygdala-pgACC coupling encompassing medial prefrontal cortex. In support of their predictive value, area under receiver operating characteristic curve was significant for the left and right amygdala-pgACC in relation to treatment responders.Improvement after CBT was predicted by enhanced resting-state bilateral amygdala-prefrontal coupling in gSAD. Preliminary results suggest baseline individual differences in a fundamental circuitry that may underlie emotion regulation contributed to variation in symptom change after CBT. Findings offer a new approach towards using a biological measure to foretell who will most likely benefit from CBT. In particular, the departure from neural predictors based on illness-relevant stimuli (e.g., socio-emotional stimuli in gSAD) permits the development of biomarkers that reflect commonalities in the neurobiology of anxiety and mood disorders.

Heide Klumpp

Michael K Keutmann

Daniel A Fitzgerald

Stewart A Shankman

K Luan Phan

Resting state amygdala-prefrontal connectivity predicts symptom change after cognitive behavioral therapy in generalized social anxiety disorder

静息状态下杏仁核-前额叶连接预测广泛性社交焦虑障碍认知行为治疗后的症状变化

出版信息	出版商: BioMed Central Ltd，出版周期: ，期刊类型: journal，开源期刊: 否
基本数据	创刊年份: 2013，原创研究文献占比: ，自引率:， Gold OA占比:

Biology of Mood and Anxiety Disorders

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