Distal Threat Research Articles

Neural substrates of defensive reactivity in two subtypes of specific phobia

Depending on threat proximity, different defensive behaviours are mediated by a descending neural network involving forebrain (distal threat) vs midbrain areas (proximal threat). Compared to healthy subjects, it can be assumed that phobics are characterized by shortened defensive distances on a behavioural and neural level. This study aimed at characterizing defensive reactivity in two subtypes of specific phobia [snake (SP) and dental phobics (DP)]. Using functional magnetic resonance imaging (fMRI), n = 39 subjects (13 healthy controls, HC; 13 SP; 13 DP) underwent an event-related fMRI task employing an anticipation (5-10 s) and immediate perception phase (phobic pictures and matched neutral stimuli; 1250 ms) to modulate defensive distance. Although no differential brain activity in any comparisons was observed in DP, areas associated with defensive behaviours (e.g. amygdala, hippocampus, midbrain) were activated in SP. Decreasing defensive distance in SP was characterized by a shift to midbrain activity. Present findings substantiate differences between phobia types in their physiological and neural organization that can be expanded to early stages of defensive behaviours. Findings may contribute to a better understanding of the dynamic organization of defensive reactivity in different types of phobic fear.

The origins of ‘5-HT and mechanisms of defence’ by Deakin and Graeff: A personal perspective

In this brief reflection I outline how Fred Graeff and I came to integrate our ideas and findings concerning the behavioural functions of serotonin (5-HT) over 20 years ago in '5-HT and mechanisms of defence', reproduced in this volume (pp. 000-000). The principal insight was that different 5-HT pathways mediate distinct adaptive responses to aversive events of different types. It emerged from a number of strands in neuropsychopharmacology: the functional implications of the still-fresh images of monoamine neuroanatomy of the 1970s; the ethological differentiation of behavioural responses to proximal and distal threats; and the seemingly contradictory effects of 5-HT drugs in unconditioned, Pavlovian and instrumental paradigms of reward and aversion. The article has been cited over 600 times and continues to be cited. The evidence was mainly from the animal literature but included some experimental psychopharmacological tests in humans. Some more recent and notable human corroborations are highlighted in this perspective.

Alcohol stress response dampening: selective reduction of anxiety in the face of uncertain threat.

Problematic alcohol use and stress response dampening (SRD) are intimately interconnected. Recent evidence suggests that alcohol produces selective SRD during uncertain but not certain threat. We systematically varied shock probability in a novel task assessing alcohol SRD during low probable/uncertain threat, while holding temporal precision of threat constant. Intoxicated (0.08% target blood alcohol concentration) and placebo participants completed a cued shock threat task in which probability of shock administration at the offset of brief visual cues varied parametrically. High probability (100%) shock cues represented certain threat as used in earlier research, while lower probability (20% and 60%) shock cues provided novel uncertain threat conditions. Startle potentiation during cues and inter-trial intervals (ITIs) served as the measure of affective response. General linear model analysis indicated that alcohol SRD magnitude increased monotonically as threat uncertainty increased. Alcohol SRD was significantly greater during 20% and 60% shock threat relative to 100% shock threat. Alcohol also significantly reduced startle potentiation during distal threat in shock-free ITIs. Alcohol SRD magnitude during distal/uncertain threat was meaningfully moderated by individual differences in negative affectivity and weekly alcohol consumption. This work advances understanding of which properties of uncertainty are relevant to anxiety and anxiolytic effects of alcohol.

Self, Identity, and Reactions to Distal Threats: The Case of Environmental Behavior

This article examines self-relevant processes that sustain behaviors that have little or no direct implications for people’s well-being. When outcomes are low in direct personal relevance, far in the future, or only weakly linked to one’s present behavior, imagined personal incentives may not be enough to motivate behavior. Under such circumstances, people may nonetheless perform actions that are linked to their identity, self-evaluation, or public image. Using pro-environmental behavior as an exemplar, we examine self-processes that are involved when people engage in behaviors that do not directly affect their personal self-interest.

Towards a translational model of panic attack.

years ago, Deakin and Graeff proposed that whereas generalized anxiety disorder is produced by the overactivity of 5-HT excitatory projections from dorsal raphe nucleus to the areas of prefrontal cortex and amygdala which process distal threat, panic attacks are a dysfunction of 5-HT inhibitory projections from dorsal raphe nucleus to the dorsal periaqueductal gray matter, thereby releasing the responses to proximal threat, innate fear or anoxia. Besides, they suggested that the decrease in 5-HT1A neurotransmission in the hippocampus results in learned helplessness and depression. Accordingly, the Deakin Graeff hypothesis provided a unified frame to the widespread use of 5-HT selective reuptake inhibitors in generalized anxiety, panic disorder and depression. Competitor hypotheses implicate panic attacks with the abnormal functioning of locus coeruleus, basolateral amygdala, dorsomedial hypothalamus or an as-yet-unknown suffocation alarm system. Conversely, cognitive psychologists suggest that panic attacks result from the catastrophic (cortical) interpretation of bodily symptoms. In any event, translational models of panic attack are expected to reproduce the main features of clinical panic, namely, the patient's higher sensitivity to both lactate and CO2, the drug specific sensitivity, the lack of stress hormone responses during panic attacks, the higher vulnerability of women and the high comorbidity with agoraphobia, major depression and childhood separation anxiety. Therefore, here we review the main steps in the experimental approach to anxiety disorders which are paving the route towards a translational model of panic attack. Keywords: Panic, Anxiety, Stress, Suffocation, Serotonin, Periaqueductal Gray Matter

Refluxo gastroesofágico participando da cascata cognitiva do pânico

O transtorno do pânico (TP) é um transtorno ansioso não-fóbico que acomete de 1,5% a 4% da população mundial. É caracterizado por ataques imotivados de mal-estar psíquico e sintomas somáticos, além de ansiedade antecipatória à crise, com prejuízo funcional ao indivíduo. O objetivo deste relato de caso é descrever a associação entre transtorno do pânico e doença do refluxo gastroesofágico (DRGE). MCL, 25 anos, apresentava crises de pânico frequentes, pouco responsivas ao tratamento durante 6 meses, mesmo com readequação da farmacoterapia. Iniciou-se investigação, sendo fechado o diagnóstico de DRGE, cujo tratamento culminou em remissão das crises de pânico. A dor torácica aguda da DRGE era interpretada como ameaça proximal, ocasionando dúvidas sobre passar mal e hiperventilação, servindo como gatilho da cascata cognitiva do pânico, no mesencéfalo dorsal. A inflamação da mucosa esofágica funciona como ameaça distal, estimulando a amígdala e causando ansiedade antecipatória, mantendo a elevação dos hormônios de estresse. Segundo o modelo de Deakin-Graeff, embora a 5-HT iniba o ataque de pânico e facilite a ansiedade antecipatória, no TP esta última é estimulada por meio do núcleo dorsal da rafe. Portanto, casos que incluem a associação TP e DRGE devem ser mais bem examinados, para que haja diagnóstico e tratamento adequados.

The dorsal raphe nucleus exerts opposed control on generalized anxiety and panic-related defensive responses in rats

It has been proposed that the ascending dorsal raphe (DR)-serotonergic (5-HT) pathway facilitates conditioned avoidance responses to potential or distal threat, while the DR-periventricular 5-HT pathway inhibits unconditioned flight reactions to proximal danger. Dysfunction on these pathways would be, respectively, related to generalized anxiety (GAD) and panic disorder (PD). To investigate this hypothesis, we microinjected into the rat DR the benzodiazepine inverse receptor agonist FG 7142, the 5-HT 1A receptor agonist 8-OH-DPAT or the GABA A receptor agonist muscimol. Animals were evaluated in the elevated T-maze (ETM) and light/dark transition test. These models generate defensive responses that have been related to GAD and PD. Experiments were also conducted in the ETM 14 days after the selective lesion of DR serotonergic neurons by 5,7-dihydroxytriptamine (DHT). In all cases, rats were pre-exposed to one of the open arms of the ETM 1 day before testing. The results showed that FG 7142 facilitated inhibitory avoidance, an anxiogenic effect, while impairing one-way escape, an anxiolytic effect. 8-OH-DPAT, muscimol, and 5,7-DHT-induced lesions acted in the opposite direction, impairing inhibitory avoidance while facilitating one-way escape from the open arm. In the light/dark transition, 8-OH-DPAT and muscimol increased the time spent in the lighted compartment, an anxiolytic effect. The data supports the view that distinct DR-5-HT pathways regulate neural mechanisms underlying GAD and PD.

On serotonin and experimental anxiety.

This review describes the development of a research line on the role of serotonin (5-HT) in experimental anxiety that was initiated in 1969, in the laboratory founded by P.B. Dews, W.H. Morse and R.T. Kelleher at the Harvard Medical School, and has evolved until this date. Initially, it was found that two non-selective 5-HT receptor antagonists released punished responding in pigeons with a magnitude comparable to that of benzodiazepine anxiolytics. This result was one of the key evidences that led to the concept that 5-HT enhanced anxiety by acting both in the forebrain and in the periaqueductal gray matter (PAG). Further evidence supported this hypothesis regarding the forebrain, but results with electrical stimulation and intracerebral drug injection into the PAG indicated that 5-HT inhibited aversive behavior evoked from this area. As a result, it has been suggested that 5-HT has a dual role in the regulation of defense, namely enhancing learned responses to potential or distal threat through actions in the forebrain while inhibiting unconditioned responses to proximal threat by acting on the PAG. The former would be related to generalized anxiety and the latter to panic disorder. To test this hypothesis, a new animal model, named the elevated T-maze, has been designed. It consists of one arm enclosed by walls that is perpendicular to two open arms elevated from the floor. The same rat performs two tasks, namely inhibitory avoidance of the elevated open arms, representing conditioned anxiety and one-way escape from one of the open arms, representative of unconditioned fear. The differential effects of drugs acting on 5-HT observed in the two tasks of the ETM generally support the hypothesis under scrutiny.

Animal models of 'anxiety': where next?

Numerous procedures have been developed to facilitate preclinical research on the behavioural pharmacology of anxiety and, as a result of this application, are often referred to as animal models of 'anxiety'. This is an unfortunate misnomer, not only because of the apparent inability of many tests to detect novel anxiolytics consistently, but also because the term implies that anxiety is a unitary emotion. Such difficulties have arisen largely as a consequence of test development strategies which, by emphasizing pharmacological (i.e. benzodiazepine) validation, have yielded models predictive of a specific type of anxiolytic activity. The present review argues that the refinement of existing tests as well as the development of new procedures requires urgent attention to the much neglected issue of behavioural validation. From an evolutionary perspective, normal human anxiety may be conceptualized as a repertoire of defence reactions tailored to meet different forms of threats, and disorders of anxiety as the inappropriate activation or exaggeration of these usually adaptive response patterns. In this context, consideration of the defensive reactions typically observed in our animal models reveals substantially greater commonality in the behavioural effects of benzodiazepine and 5-HT1A anxiolytics than would otherwise be apparent. Therefore, with the exception of the conventional plus-maze paradigm (discussed at some length), better correspondence is seen in tests involving unconditioned response to potential threat (e.g. social interaction, distress vocalizations and light/dark exploration) than in tests of conditioned fear reactions. Even within the latter grouping, however, greater commonality is seen in procedures based on reactions to proximal threat (e.g. freezing, startle, ultrasonic vocalizations, burying) than those involving reactions to distal threat (e.g. avoidance/flight). Significantly, very similar findings have been reported in tests specifically designed to study defensive reactions (e.g. rat and mouse defence test batteries) or which incorporate a more detailed knowledge of defence into established procedures (e.g. ethological plus-maze and defensive burying paradigms). Furthermore, recent evidence also suggests that drugs with proved clinical efficacy in panic attacks/panic disorder have reliably stronger effects on flight responses than other components of the defensive repertoire. It is concluded that a focus on defensive behaviour patterns improves test validity (predictive/face/construct), offers a more rational basis for test selection in drug development programmes, and provides a firmer theoretical framework for future methodological and therapeutic advance.