Unconditioned responding (UCR) to a naturally aversive stimulus is associated with defensive responding to a conditioned threat cue (CS+) and a conditioned safety cue (CS−) in trauma‐exposed ...individuals during fear acquisition. However, the relationships of UCR with defensive responses during extinction training, posttraumatic stress disorder (PTSD) symptom severity, and fearful traits in trauma‐exposed individuals are not known. In a sample of 100 trauma‐exposed adults with a continuum of PTSD severity, we recorded startle responses and skin conductance responses (SCR) during fear acquisition and extinction training using a 140 psi, 250‐ms air blast to the larynx as the unconditioned stimulus. We explored dimensional associations of two different measures of UCR (unconditioned startle and unconditioned SCR) with conditioned defensive responding to CS+ and CS−, conditioned fear (CS+ minus CS−), PTSD symptom severity, and a measure of fearful traits (composite of fear survey schedule, anxiety sensitivity index, and Connor‐Davidson resilience scale). Unconditioned startle was positively associated with startle potentiation to the threat cue and the safety cue across both learning phases (CS+ Acquisition, CS− Acquisition, CS+ Extinction Training, CS− Extinction Training) and with fearful traits. Unconditioned SCR was positively associated with SCR to the CS+ and CS− and SCR difference score during Acquisition. Neither type of UCR was associated with PTSD symptom severity. Our findings suggest that UCR, particularly unconditioned startle to a naturally aversive stimulus, may inform research on biomarkers and treatment targets for symptoms of pervasive and persistent fear in trauma‐exposed individuals.
Our study adds evidence that unconditioned aversive responding is associated with persistent defensive responding to conditioned threat and safety cues and with trait‐level fear in daily life, in trauma‐exposed adults. We complement previous evidence that unconditioned responding (UCR) is associated with defensive responding during fear acquisition and provide empirical support for the theory that UCR may inform research on biomarkers and treatment targets for symptoms of pervasive and persistent fear in trauma‐exposed individuals.
Acid sphingomyelinase (ASM) regulates a variety of physiological processes and plays an important role in emotional behavior. The role of ASM in fear-related behavior has not been investigated so ...far. Using transgenic mice overexpressing ASM (ASMtg) and ASM deficient mice, we studied whether ASM regulates fear learning and expression of cued and contextual fear in a classical fear conditioning paradigm, a model used to investigate specific attributes of post-traumatic stress disorder (PTSD). We show that ASM does not affect fear learning as both ASMtg and ASM deficient mice display unaltered fear conditioning when compared to wild-type littermates. However, ASM regulates the expression of contextual fear in a sex-specific manner. While ASM overexpression enhances the expression of contextual fear in both male and female mice, ASM deficiency reduces the expression of contextual fear specifically in male mice. The expression of cued fear, however, is not regulated by ASM as ASMtg and ASM deficient mice display similar tone-elicited freezing levels. This study shows that ASM modulates the expression of contextual fear but not of cued fear in a sex-specific manner and adds a novel piece of information regarding the involvement of ASM in hippocampal-dependent aversive memory.
Generalization of conditioned-fear, a core feature of post-traumatic stress disorder (PTSD), has been the focus of several recent neuroimaging studies. A striking outcome of these studies is the ...frequency with which neural correlates of generalization fall within hubs of well-established functional networks including salience (SN), central executive (CEN), and default networks (DN). Neural substrates of generalization found to date may thus reflect traces of large-scale brain networks that form more expansive neural representations of generalization. The present study includes the first network-based analysis of generalization and PTSD-related abnormalities therein.
fMRI responses in established intrinsic connectivity networks (ICNs) representing SN, CEN, and DN were assessed during a generalized conditioned-fear task in male combat veterans (N = 58) with wide-ranging PTSD symptom severity. The task included five rings of graded size. Extreme sizes served as conditioned danger-cues (CS+: paired with shock) and safety-cues (CS-), and the three intermediate sizes served as generalization stimuli (GSs) forming a continuum-of-size between CS+ and CS-. Generalization-gradients were assessed as behavioral and ICN response slopes from CS+, through GSs, to CS-. Increasing PTSD symptomatology was predicted to relate to less-steep slopes indicative of stronger generalization.
SN, CEN, and DN responses fell along generalization-gradients with levels of generalization within and between SN and CEN scaling with PTSD symptom severity.
Neural substrates of generalized conditioned-fear include large-scale networks that adhere to the functional organization of the brain. Current findings implicate levels of generalization in SN and CEN as promising neural markers of PTSD.
The amygdala plays key roles in fear and anxiety. Studies of the amygdala have largely focused on neuronal function and connectivity. Astrocytes functionally interact with neurons, but their role in ...the amygdala remains largely unknown. We show that astrocytes in the medial subdivision of the central amygdala (CeM) determine the synaptic and behavioral outputs of amygdala circuits. To investigate the role of astrocytes in amygdala-related behavior and identify the underlying synaptic mechanisms, we used exogenous or endogenous signaling to selectively activate CeM astrocytes. Astrocytes depressed excitatory synapses from basolateral amygdala via A
adenosine receptor activation and enhanced inhibitory synapses from the lateral subdivision of the central amygdala via A
receptor activation. Furthermore, astrocytic activation decreased the firing rate of CeM neurons and reduced fear expression in a fear-conditioning paradigm. Therefore, we conclude that astrocyte activity determines fear responses by selectively regulating specific synapses, which indicates that animal behavior results from the coordinated activity of neurons and astrocytes.
Multicellular organisms have co-evolved with complex consortia of viruses, bacteria, fungi and parasites, collectively referred to as the microbiota
. In mammals, changes in the composition of the ...microbiota can influence many physiologic processes (including development, metabolism and immune cell function) and are associated with susceptibility to multiple diseases
. Alterations in the microbiota can also modulate host behaviours-such as social activity, stress, and anxiety-related responses-that are linked to diverse neuropsychiatric disorders
. However, the mechanisms by which the microbiota influence neuronal activity and host behaviour remain poorly defined. Here we show that manipulation of the microbiota in antibiotic-treated or germ-free adult mice results in significant deficits in fear extinction learning. Single-nucleus RNA sequencing of the medial prefrontal cortex of the brain revealed significant alterations in gene expression in excitatory neurons, glia and other cell types. Transcranial two-photon imaging showed that deficits in extinction learning after manipulation of the microbiota in adult mice were associated with defective learning-related remodelling of postsynaptic dendritic spines and reduced activity in cue-encoding neurons in the medial prefrontal cortex. In addition, selective re-establishment of the microbiota revealed a limited neonatal developmental window in which microbiota-derived signals can restore normal extinction learning in adulthood. Finally, unbiased metabolomic analysis identified four metabolites that were significantly downregulated in germ-free mice and have been reported to be related to neuropsychiatric disorders in humans and mouse models, suggesting that microbiota-derived compounds may directly affect brain function and behaviour. Together, these data indicate that fear extinction learning requires microbiota-derived signals both during early postnatal neurodevelopment and in adult mice, with implications for our understanding of how diet, infection, and lifestyle influence brain health and subsequent susceptibility to neuropsychiatric disorders.
Rationale
To improve outcomes for patients undergoing extinction-based therapies (e.g., exposure therapy) for anxiety disorders such as post-traumatic stress disorder (PTSD), there has been interest ...in identifying pharmaceutical compounds that might facilitate fear extinction learning and recall. Oxytocin (OT) is a mammalian neuropeptide that modulates activation of fear extinction-based neural circuits and fear responses. Little is known, however, about the effects of OT treatment on conditioned fear responding and extinction in humans.
Objectives
The purpose of the present study was to assess the effects of OT in a fear-potentiated startle task of fear conditioning and extinction.
Methods
A double-blind, placebo-controlled study of 44 healthy human participants was conducted. Participants underwent a conditioned fear acquisition procedure, after which they were randomized to treatment group and delivered OT (24 IU) or placebo via intranasal (IN) spray. Forty-five minutes after treatment, participants underwent extinction training. Twenty-four hours later, subjects were tested for extinction recall.
Results
Relative to placebo, the OT group showed increased fear-potentiated startle responding during the earliest stage of extinction training relative to placebo; however, all treatment groups showed the same level of reduced responding by the end of extinction training. Twenty-four hours later, the OT group showed significantly higher recall of extinction relative to placebo.
Conclusions
The current study provides preliminary evidence that OT may facilitate fear extinction recall in humans. These results support further study of OT as a potential adjunctive treatment for extinction-based therapies in fear-related disorders.
Background
Fear of cancer recurrence (FCR) is more intense in younger women. Because FCR is a powerful determinant of quality of life, identifying those at risk for persistently elevated FCR can ...inform timing of interventions.
Methods
A total of 965 women with stage 0 to stage III breast cancer enrolled in the Young Women's Breast Cancer Study, a prospective cohort of women diagnosed with breast cancer at age ≤40 years, completed the 3‐item Lasry Fear of Recurrence Index. Group‐based trajectory modeling was used to classify distinct FCR patterns from baseline through 5 years post‐diagnosis. Multinomial logistic regression was used to identify patient, disease, and treatment characteristics associated with each trajectory.
Results
Five FCR trajectories were identified with the majority of participants having moderate (33.1%) or high FCR (27.6%) that improved over time. A total of 6.9% participants had moderate FCR that worsened, whereas 21.7% had high FCR at baseline that remained high throughout. In the fully adjusted multinomial model, stages II and III (vs stage I) were associated with lower odds (of being in the high/stable trajectory). White (vs non‐White) were associated with higher odds of being in a trajectory that improved over time.
Conclusions
Although FCR improves over time for many young women with breast cancer, approximately one‐third had FCR that was severe and did not improve or worsened over 5 years after diagnosis. Ongoing monitoring is warranted, with early referral to mental health professionals indicated for those at highest risk for unresolved FCR.
Lay Summary
Fear of recurrence is common among young women with breast cancer.
The authors followed a large cohort of young women diagnosed with breast cancer when they were 40 years of age and younger, and found 5 distinct trajectories that show moderate and severe fears do not always improve over time and may require targeted mental health intervention.
Fear of recurrence is prevalent among young women with breast cancer. The authors identify 5 distinct trajectories that show moderate and severe fears do not always resolve over time and may require customized interventions.
The past two decades have brought dramatic progress in the neuroscience of anxiety due, in no small part, to animal findings specifying the neurobiology of Pavlovian fear‐conditioning. Fortuitously, ...this neurally mapped process of fear learning is widely expressed in humans, and has been centrally implicated in the etiology of clinical anxiety. Fear‐conditioning experiments in anxiety patients thus represent a unique opportunity to bring recent advances in animal neuroscience to bear on working, brain‐based models of clinical anxiety. The current presentation details the neural basis and clinical relevance of fear conditioning, and highlights generalization of conditioned fear to stimuli resembling the conditioned danger cue as one of the more robust conditioning markers of clinical anxiety. Studies testing such generalization across a variety of anxiety disorders (panic, generalized anxiety disorder, and social anxiety disorder) with systematic methods developed in animals will next be presented. Finally, neural accounts of overgeneralization deriving from animal and human data will be described with emphasis given to implications for the neurobiology and treatment of clinical anxiety.
Historicizing Fear is a historical interrogation of the use of fear as a tool to vilify and persecute groups and individuals from a global perspective, offering an unflinching look at racism, fearful ...framing, oppression, and marginalization across human history. The book examines fear and Othering from a historical context, providing a better understanding of how power and oppression are used in the present day. Contributors ground their work in the theory of Othering—the reductive action of labeling a person as someone who belongs to a subordinate social category defined as the Other—in relation to historical events, demonstrating that fear of the Other is universal, timeless, and interconnected. Chapters address the music of neo-Nazi white power groups, fear perpetuated through the social construct of black masculinity in a racially hegemonic society, the terror and racial cleansing in early twentieth-century Arkansas, the fear of drug-addicted Vietnam War veterans, the creation of fear by the Tang Dynasty, and more. Timely, provocative, and rigorously researched, Historicizing Fear shows how the Othering of members of different ethnic groups has been used to propagate fear and social tension, justify state violence, and prevent groups or individuals from gaining equality. Broadening the context of how fear of the Other can be used as a propaganda tool, this book will be of interest to scholars and students of history, anthropology, political science, popular culture, critical race issues, social justice, and ethnic studies, as well as the general reader concerned with the fearful framing prevalent in politics. Contributors: Quaylan Allen, Melanie Armstrong, Brecht De Smet, Kirsten Dyck, Adam C. Fong, Jeff Johnson, Łukasz Kamieński, Guy Lancaster, Henry Santos Metcalf, Julie M. Powell, Jelle Versieren
Abstract Background context Psychological factors including fear avoidance beliefs are believed to influence the development of chronic low back pain (LBP). Purpose The purpose of this study was to ...determine the prognostic importance of fear avoidance beliefs as assessed by the Fear Avoidance Beliefs Questionnaire (FABQ) and the Tampa Scale of Kinesiophobia for clinically relevant outcomes in patients with nonspecific LBP. Design/setting The design of this study was a systematic review. Methods In October 2011, the following databases were searched: BIOSIS, CINAHL, Cochrane Library, Embase, OTSeeker, PeDRO, PsycInfo, PubMed/Medline, Scopus, and Web of Science. To ensure the completeness of the search, a hand search and a search of bibliographies was conducted and all relevant references included. A total of 2,031 references were retrieved, leaving 566 references after the removal of duplicates. For 53 references, the full-text was assessed and, finally, 21 studies were included in the analysis. Results The most convincing evidence was found supporting fear avoidance beliefs to be a prognostic factor for work-related outcomes in patients with subacute LBP (ie, 4 weeks–3 months of LBP). Four cohort studies, conducted by disability insurance companies in the United States, Canada, and Belgium, included 258 to 1,068 patients mostly with nonspecific LBP. These researchers found an increased risk for work-related outcomes (not returning to work, sick days) with elevated FABQ scores. The odds ratio (OR) ranged from 1.05 (95% confidence interval CI 1.02–1.09) to 4.64 (95% CI, 1.57–13.71). The highest OR was found when applying a high cutoff for FABQ Work subscale scores. This may indicate that the use of cutoff values increases the likelihood of positive findings. This issue requires further study. Fear avoidance beliefs in very acute LBP (<2 weeks) and chronic LBP (>3 months) was mostly not predictive. Conclusions Evidence suggests that fear avoidance beliefs are prognostic for poor outcome in subacute LBP, and thus early treatment, including interventions to reduce fear avoidance beliefs, may avoid delayed recovery and chronicity.
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