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The Amygdala and the Neural Pathways of Fear
Abstract
Fear and anxiety are evolutionarily developed responses to perceived or anticipated threat. They involve behavioral, autonomic,
and endocrine alterations aimed at increasing an organism's chances of survival. Excessive or uncontrolled fear and anxiety
may lead to anxiety disorders. Animal and human studies indicate the critical role of the amygdala in adaptive and maladaptive
fear. Recent advances elucidating the organization of the neural circuitry and molecular mechanisms of fear provide new insights
in normal as well as pathological fear. In this chapter, we review the microcircuitry of the amygdala with a special emphasis
on its relevance to fear processing and fear learning. We also discuss recent developments in understanding the basic molecular
mechanism of fear. Finally, we address some of the implications of amygdala research for developing novel therapeutic approaches
to maladaptive fear and anxiety.
KeywordsAmygdala–anxiety–extinction–fear–fear conditioning–learning–memory–memory consolidation–memory reconsolidation–synaptic plasticity
... The amygdalar complex is also composed of distinct structures associated with specific neurological functions; however, all three structures contribute to anxiety-related behaviours (Dbiec & Ledoux, 2009;Kinkead et al., 2023;Zhang et al., 2021). Thus, our analysis considered the basolateral (BLA), central (CeA) and medial (MeA) subdivisions of the amygdala (Dbiec & Ledoux, 2009;Zhang et al., 2021; see Figure 3). ...
... The amygdalar complex is also composed of distinct structures associated with specific neurological functions; however, all three structures contribute to anxiety-related behaviours (Dbiec & Ledoux, 2009;Kinkead et al., 2023;Zhang et al., 2021). Thus, our analysis considered the basolateral (BLA), central (CeA) and medial (MeA) subdivisions of the amygdala (Dbiec & Ledoux, 2009;Zhang et al., 2021; see Figure 3). Briefly, the BLA is of interest because this subregion communicates bi-directionally with brain regions affecting cognition, motivation and stress responses; enhanced excitability within this structure underlies behavioural disturbances characteristic of neurodevelopmental disorders such as autism and attention-deficit hyperactivity disorder (Sharp, 2017), and such traits have been reported in GIH-exposed male offspring (Vanderplow et al., 2022). ...
Sleep‐disordered breathing is a respiratory disorder commonly experienced by pregnant women. The recurrent hypoxaemic events associated with sleep‐disordered breathing have deleterious consequences for the mother and fetus. Adult male (but not female) rats born to dams subjected to gestational intermittent hypoxia (GIH) have a higher resting blood pressure than control animals and show behavioural/neurodevelopmental disorders. The origin of this persistent, sex‐specific effect of GIH in offspring is unknown, but disruption of the neuroendocrine stress pathways is a key mechanism by which gestational stress increases disease risk in progeny. Using FosB immunolabelling as a chronic marker of neuronal activation, we determined whether GIH augments basal expression of FosB in the perikaryas of cells in the paraventricular nucleus of the hypothalamus (PVN), a key structure in the regulation of the stress response and blood pressure. From gestational day 10, female rats were subjected to GIH for 8 h/day (light phase) until the day before delivery (gestational day 21); GIH consisted of 2 min hypoxic bouts (10.5% O2) alternating with normoxia. Control rats were exposed to intermittent normoxia over the same period (GNX). At adulthood (10–15 weeks), the brains of male and female rats were harvested for FosB immunohistochemistry. In males, GIH augmented PVN FosB labelling density by 30%. Conversely, PVN FosB density in GIH females was 28% lower than that of GNX females. We conclude that GIH has persistent and sex‐specific impacts on the development of stress pathways, thereby offering a plausible mechanism by which GIH can disturb neural development and blood pressure homeostasis in adulthood.
... Los estudios en humanos que utilizaron imágenes de resonancia magnética funcional (fMRI) adaptaron estas tareas simples de condicionamiento del miedo y demostraron que la amígdala humana también se activa por estímulos condicionados por el miedo, y que esta activación disminuye con la extinción. 22 Además, se encontró que los circuitos de la corteza prefrontal ventromedial (vmPFC)-amígdala, median la extinción del miedo en ratas y humanos. Al aplicar tareas diseñadas para roedores a humanos, se demostró que los circuitos que median la adquisición y extinción del miedo están bien conservados. ...
La amígdala es una estructura relacionada con la activación emocional, la percepción del miedo, la sexualidad, la impulsividad, la agresividad y la recompensa y evitación. El daño, anatómico o funcional conlleva a la aparición de signos relacionados, tales como inconciencia ante el peligro, desinhibición, etc. y está asimismo asociada a las toxicomanías y a las epilepsias psicomotoras. Constituye asimismo un blanco terapéutico para la agresividad incontrolada, el stress post- traumático y algunas formas de epilepsia refractaria.
... Lors de la première étape d'évaluation d'un stimulus, les études actuelles font état de l'existence d'une double voie de traitement de l'information(Dbiec & LeDoux, 2009). Une première voie lente dite thalamo-cortico-amygdalienne permettrait un traitement cortical approfondi de l'information. ...
Full text available at : https://theses.hal.science/tel-04146982
Stress is a phenomenon frequently encountered in driving. It can affect the safety and comfort of users. Driving automation offers new ways to improve safety and reduce the danger posed by some human factors. However, it can also result in the concomitant occurrence of non-driving related tasks, and still inevitably requires supervision during phases of manual driving. To mitigate the negative effects of stress, implicit (or subtle) regulation strategies that do not impair the driving task can be used. Because driving automation is increasingly available to a variety of individuals, it is therefore important to consider the individual differences between persons that can influence stress and its regulation. The objectives of this thesis were threefold: (1) to study the effects of stress during an autonomous driving situation with takeover and manual driving phases, (2) to verify the effectiveness of regulation techniques based on the modulation of the physiological response on the level of stress and (3) to consider the individual traits that can influence stress and its regulation in the context of safety and comfort during autonomous driving. To achieve these objectives, we first identified stress regulation techniques applicable to a driving context. Some of these techniques, based on physiological modulation (cardiac and respiratory), were tested both in a laboratory context and in an autonomous driving simulation. A game was designed to induce stress during the supervision task, and behavioral and physiological measures were used to investigate the impact of this stress on individuals and on their performance on the supervision task and on manual driving. In both experiments, individual traits (e.g., personality, driving habits) were considered in the study of stress and regulation techniques. The results showed that stress increased the level of engagement of participants toward the game, despite weakly negative effects on safety (in terms of responses to takeover notifications and driving behavior). The subjective effects of stress and regulation techniques varied according to individual traits related to the interpretation of stressful context, and to the perception of the bracelet used. Regulation was most effective when it allowed the attention to be diverted from the stressors, without being perceived as an additional difficulty. The mechanism of attentional redeployment seemed central to the functioning of cardiac regulation, whereas it seemed to support the effectiveness of physiological modulation in the case of respiratory regulation. These results show that the use of implicit regulation should consider the level of attention that they require to be effective, which may vary between individuals.
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Le stress est un phénomène couramment rencontré lors de la conduite automobile. Il peut affecter la sécurité et le confort des usagers. L’automatisation de la conduite ouvre la voie à une amélioration de la sécurité et à une réduction du facteur humain, mais favorise l’apparition de tâches non liées à la conduite, et nécessite encore de superviser le système lors de phases de reprise de la conduite manuelle. Pour pallier les effets négatifs du stress, des stratégies de régulation implicites (ou subtiles) n’entraînant pas de perturbations de l’usager vis-à-vis de la tâche de conduite peuvent être utilisées. Du fait de l’ouverture de l’automatisation de la conduite à des individus provenant de tous horizons, il est également important de considérer les différences individuelles pouvant influencer le stress et sa régulation. Les objectifs de cette thèse étaient donc triples : (1) étudier les effets du stress pendant la supervision d’un véhicule autonome avec des phases de reprise en main et de conduite manuelle ; (2) vérifier l’efficacité de solutions de régulation basées sur une modulation de la réponse physiologique, sur le niveau de stress ; (3) Prendre en considération des traits individuels pouvant influencer le stress et sa régulation en termes de sécurité et de confort des usagers de véhicules autonomes. Pour atteindre ces objectifs, nous avons d’abord identifié des techniques de régulation du stress applicables en contexte de conduite automobile. Certaines de ces techniques, basées sur la modulation physiologique (cardiaque et respiratoire), ont été testées lors de deux expérimentations : Une en contexte de laboratoire, l’autre en contexte de conduite autonome simulée. Un jeu a été créé pour induire du stress pendant la tâche de supervision, et des mesures comportementales et physiologiques ont été utilisées pour investiguer l’impact de ce stress sur les individus et sur leur performance de supervision et de conduite manuelle. Dans ces deux expérimentations, des traits individuels (e.g. Personnalité, habitudes de conduite) ont été pris en compte dans l’étude du stress et des techniques de régulation. Les résultats obtenus montrent que le stress augmentait l’engagement des participants envers le jeu, et présentait des effets faibles sur la diminution de la sécurité (en termes de réponses aux alarmes de reprise en main et de comportement de conduite). Les effets subjectifs du stress et des techniques de régulation variaient selon des traits individuels liés à la prise en compte et à l’interprétation des éléments stressants du contexte et des bracelets utilisés. La régulation était plus efficace lorsqu’elle permettait de détourner l’attention des stresseurs, sans que cela ne soit perçu comme une difficulté supplémentaire. Ce mécanisme de détournement attentionnel semblait central pour le fonctionnement de la régulation basée sur le cardiaque, tandis qu’il semblait plutôt appuyer l’efficacité de la modulation physiologique dans le cas de la régulation respiratoire. Ces résultats montrent que le recours aux techniques de régulation implicite doit se faire en tenant compte du niveau d’attention qu’elles requièrent malgré tout pour être efficaces, ce niveau d’attention pouvant varier entre les individus.
... The study shows that the ERP measures in the cued GO/ NOGO task could serve as a reliable functional neuromarkers for the detection of cognitive control dysfunction [20,21,22,23] which is disturbed in PTSD. ...
Introduction
There is a lack in the worldwide literature of reports on the Neuromarkers of Post-Traumatic Stress Disorder (PTSD) in patients after bilateral hand amputation The aim of this study was to test a hypothesis regarding developing Post-Traumatic Stress Disorder (PTSD) in a patient after bilateral hand amputation with the use of Event Related Potentials (ERPs). On the basis of previous research, the amplitudes of P3 ERP components elicited in the cued GO/NOGO tasks have been chosen as candidates for neuromarkers of PTSD.
Case study
A 24-year-old patient had undergone bilateral hand amputation 12 months previously. The patient was repeatedly operated on (he had undergone successful bilateral hand replantation) and despite the severity of the injuries, he recovered. However, the patient complained of flashbacks, anxiety and sleep difficulties. Specialist tests showed the presence of PTSD. The patient participated in the cued GO/NOGO task (Kropotov, 2009) with recording 19-channel EEG. P3 GO and NOGO waves in this task were found to be significantly smaller, in comparison to a group of healthy control subjects of the same age (N=23) taken from the HBI normative database (https://www.hbimed.com/). This observed pattern of ERP waves in the patient corresponds to the pattern found in PTSD patients.
Conclusions
ERPs in a GO/NOGO task can be used in the assessment of the functional brain changes induced by chronic PTSD.
... This increase in size is associated with the partitioning and maturation of individual brain structures. For example, in the amygdala, a key structure for processing threat [25], the different nuclei become subdivided between PN7 and 14 [26]. The cellular composition of brain structures also changes: for example, mitral cells are set up in the olfactory bulb during embryogenesis (e.g., present at birth), while 89% of the granular cells are integrated to the olfactory bulb after birth [23]. ...
Purpose of Review
Early life experiences have long-lasting influence on a child. For an infant, the quality of caregiving is one of the most critical factors supporting growth and development. Adverse social events in infancy have the potency to alter the child’s developmental trajectory and elevate the lifetime risk for a range of psychiatric disorders. Although clinical studies associate early childhood adversities with lifetime risk for mental disorders, the knowledge of underlying neural and molecular alterations leading to these disorders comes mostly from animal studies. In this article, we overview selected animal models of early life social adversity, including maternal abuse and neglect, and maternal trauma and fear.
Recent Findings
We first characterize the major behavioral and neural changes normally occurring in early life. We then present several animal models of maternally mediated early life adversity that contribute to reorient the developmental changes toward pathological outcomes. These models yielded to recently identified neurobiological mechanisms, including epigenetic alterations, through which these adversities lead to a lasting dysregulation of the stress response system, aberrant fear learning and memory, and increased anxiety or depression-like behaviors.
Summary
We conclude by emphasizing the unique role of the caregiver’s influences on the developing brain in infancy. Understanding of the infant’s mechanisms of vulnerability and resilience to maltreatment is essential for the advancement of novel therapeutic and preventive approaches.
Objective
To explore a novel model for war-related posttraumatic stress disorder (PTSD) symptomatology including emotion regulation processes, namely experiential avoidance (EA) and uncompassionate self-responding (USR), mediating the impact of childhood threat memories, combat exposure distress, combat and noncombat threats, and peritraumatic depersonalization/derealization (PDD) on PTSD symptomatology.
Method
A sample of 650 male Portuguese Overseas War veterans filled self-report instruments.
Results
The model explained 59% of the variance of PTSD symptomatology. Both EA and USR mediated the effects of noncombat threats and PDD on PTSD. Additionally, EA mediated combat exposure distress and USR mediated childhood threat memories. Combat exposure distress, combat and noncombat threats, and PDD showed direct effects on PTSD symptomatology.
Conclusion
The findings help to better understand the relationship between predictive factors of war-related PTSD in clinical and research settings, providing novel insights on the effects of combat exposure distress, and the different effects of combat and noncombat-related threats on PTSD.
Background
Patients with specific phobia (SP) show altered brain activation when confronted with phobia-specific stimuli. It is unclear whether this pathogenic activation pattern generalizes to other emotional stimuli. This study addresses this question by employing a well-powered sample while implementing an established paradigm using nonspecific aversive facial stimuli.
Methods
N = 111 patients with SP, spider subtype, and N = 111 healthy controls (HCs) performed a supraliminal emotional face-matching paradigm contrasting aversive faces versus shapes in a 3-T magnetic resonance imaging scanner. We performed region of interest (ROI) analyses for the amygdala, the insula, and the anterior cingulate cortex using univariate as well as machine-learning-based multivariate statistics based on this data. Additionally, we investigated functional connectivity by means of psychophysiological interaction (PPI).
Results
Although the presentation of emotional faces showed significant activation in all three ROIs across both groups, no group differences emerged in all ROIs. Across both groups and in the HC > SP contrast, PPI analyses showed significant task-related connectivity of brain areas typically linked to higher-order emotion processing with the amygdala. The machine learning approach based on whole-brain activity patterns could significantly differentiate the groups with 73% balanced accuracy.
Conclusions
Patients suffering from SP are characterized by differences in the connectivity of the amygdala and areas typically linked to emotional processing in response to aversive facial stimuli (inferior parietal cortex, fusiform gyrus, middle cingulate, postcentral cortex, and insula). This might implicate a subtle difference in the processing of nonspecific emotional stimuli and warrants more research furthering our understanding of neurofunctional alteration in patients with SP.
Moral judgments can be the result of cognitive deliberations, which develop with age and socialization. Rationality began in humans with the development of the cerebral cortex. Alternatively, they can be the based-on survival mechanisms emanating in the sympathetic nervous based on innate, survival mechanisms (fight, flight, freeze) and the amygdala. Common examples are road rage (e.g., I was right while the other driver was wrong, cut me off, and could have killed me) and hold-your-ground state laws for self-defense (the victim was justified in killing the intruder, even though the intruder had no weapon when reaching into their coat pocket). Moral decision making can be based on an innate survival mechanism. Those who did this did not survive and were not our ancestors. This chapter reviews the research on signal detection theory, how aggression is favored over conciliation, as cognitive reasoning breaks down. Physiological studies involving the sympathetic and parasympathetic nervous system are reviewed in terms of the amygdala and emotional intelligence.
Contextual behavioral science can build on the impressive body of knowledge about conditions that nurture children's development by providing an empirically based theory of the role of language in family interactions. This chapter presents an introduction on the efforts to learn about how best to support the most precious resource, children, would benefit by a consideration of any practice that might move ones toward this goal. It describes the processes in more detail within the context of a parent-child-school situation. The chapter describes a sampling of activities from an acceptance and commitment therapy (ACT)-based parenting program to illustrate how specific methods can influence parents' cognitive/ verbal processes. These methods, derived from key relational frame theory (RFT) principles, aim to reduce coercion and, at the same time, increase the incidence of nurturing parenting behaviors.
Adolescence is a time of critical brain changes that pave the way for adult learning processes. However, the extent to which learning in adolescence is best characterized as a transitional linear progression from childhood to adulthood, or represents a period that differs from earlier and later developmental stages, remains unclear. Here we examine behavioral literature on associative fear conditioning and complex choice behavior with rodent models. Many aspects of fear conditioning are intact by adolescence and do not differ from adult patterns. Sufficient evidence, however, suggests that adolescent learning cannot be characterized simply as an immature precursor to adulthood. Across different paradigms assessing choice behavior, literature suggests that adolescent animals typically display more impulsive patterns of responding compared to adults. The extent to which the development of basic conditioning processes serves as a scaffold for later adult decision making is an additional research area that is important for theory, but also has widespread applications for numerous psychological conditions.
Fear extinction, which involves learning to suppress the expression of previously learned fear, requires N-methyl-D-aspartate receptors (NMDARs) and is mediated by the amygdala and ventromedial prefrontal cortex (vmPFC). Like other types of learning, extinction involves acquisition and consolidation phases. We recently demonstrated that NR2B-containing NMDARs (NR2Bs) in the lateral amygdala (LA) are required for extinction acquisition, but whether they are involved in consolidation is not known. Further, although it has been shown that NMDARs in the vmPFC are required for extinction consolidation, whether NR2Bs in vmPFC are involved in consolidation is not known. In this report, we investigated the possible role of LA and vmPFC NR2Bs in the consolidation of fear extinction using the NR2B-selective antagonist ifenprodil. We show that systemic treatment with ifenprodil immediately after extinction training disrupts extinction consolidation. Ifenprodil infusion into vmPFC, but not the LA, immediately after extinction training also disrupts extinction consolidation. In contrast, we also show pre-extinction training infusions into vmPFC has no effect. These results, together with our previous findings showing that LA NR2Bs are required during the acquisition phase in extinction, indicate a double dissociation for the phase-dependent role of NR2Bs in the LA (acquisition, not consolidation) and vmPFC (consolidation, not acquisition).
Memory consolidation refers to a process by which newly learned information is made resistant to disruption. Traditionally, consolidation has been viewed as an event that occurs once in the life of a memory. However, considerable evidence now indicates that consolidated memories, when reactivated through retrieval, become labile (susceptible to disruption) again and undergo reconsolidation. Because memories are often interrelated in complex associative networks rather than stored in isolation, a key question is whether reactivation of one memory makes associated memories labile in a way that requires reconsolidation. We tested this in rats by creating interlinked associative memories using a second-order fear-conditioning task. We found that directly reactivated memories become labile, but indirectly reactivated (i.e., associated) memories do not. This suggests that memory reactivation produces content-limited rather than wholesale changes in a memory and its associations and explains why each time a memory is retrieved and updated, the entire associative structure of the memory is not grossly altered.
Immediately after experiencing a traumatic event, many people have symptoms of posttraumatic stress disorder (PTSD). If trauma victims restrict their routine and systematically avoid reminders of the incident, symptoms of PTSD are more likely to become chronic. Several clinical studies have shown that programs of cognitive-behavioral therapy (CBT) can be effective in the management of patients with PTSD. Prolonged exposure (PE) therapy-a specific form of exposure therapy-can provide benefits, as can stress inoculation training (SIT) and cognitive therapy (CT). PE is not enhanced by the addition of SIT or CT. PE therapy is a safe treatment that is accepted by patients, and benefits remain apparent after treatment programs have finished. Nonspecialists can be taught to practice effective CBT. For the treatment of large numbers of patients, or for use in centers where CBT has not been routinely employed previously, appropriate training of mental health professionals should be performed. Methods used for the dissemination of CBT to nonspecialists need to be modified to meet the requirements of countries affected by the Asian tsunami. This will entail the use of culturally sensitive materials and the adaptation of training methods to enable large numbers of mental health professionals to be trained together.
A number of programs have been developed to treat posttraumatic stress disorder (PTSD) and acute stress disorder (ASD). Few of these programs have substantial empirical support for their efficacy. Most programs with established efficacy are based on techniques of cognitive behavioral therapy (CBT), including exposure therapy, cognitive therapy, and anxiety management training or, in the case of Eye Movement Desensitization and Reprocessing, incorporate techniques similar to those used in CBT approaches. This chapter describes the major treatment approaches that have been empirically evaluated and reviews the treatment outcome literature for these programs. It concludes that there is substantial evidence for the efficacy of CBT approaches, particularly those that incorporate exposure to the traumatic memory. However, the literature provides little guidance to select among the available treatments as those studies that directly compare two or more treatments show largely equivalent outcomes.
Objective: Most research on the effects of severe psychological stress has focused on stress-related psychopathology. Here, the author develops psychobiological models of resilience to extreme stress. Method: An integrative model of resilience and vulnerability that encompasses the neurochemical response patterns to acute stress and the neural mechanisms mediating reward, fear conditioning and extinction, and social behavior is proposed. Results: Eleven possible neurochemical, neuropeptide, and hormonal mediators of the psychobiological response to extreme stress were identified and related to resilience or vulnerability. The neural mechanisms of reward and motivation (hedonia, optimism, and learned helpfulness), fear responsiveness (effective behaviors despite fear), and adaptive social behavior (altruism, bonding, and teamwork) were found to be relevant to the character traits associated with resilience. Conclusions: The opportunity now exists to bring to bear the full power of advances in our understan...