Johanna M.P. Baas

A review of the modulation of the startle reflex by affective states and its application in psychiatry.

OBJECTIVE To provide an overview of startle reflex methodologies applied to the examination of emotional and motivational states in humans and to review the findings in different forms of psychopathology. METHODS Pertinent articles were searched mostly via MEDLINE and PsycINFO. RESULTS The startle reflex is a non-invasive translational tool of research that bridges the gap between animal and human investigations. Startle is used to study fear and anxiety, affective disturbances, sensitization, motivational states, and homeostasis. CONCLUSIONS The startle reflex is highly sensitive to various factors that are of interest in the studies of emotional disorders and has promoted new areas of investigations in psychiatry. However, research in psychiatry is still in its infancy and most findings await replication. Future progress will benefit from the development of innovative and powerful designs tailored to investigate specific disorders. SIGNIFICANCE The startle reflex has utility as a research tool to examine trauma-related disorders, fear learning, drug addiction, and to contrast affective states and emotional processing across diagnostic groups, but its usefulness as a diagnostic tool is limited.

Anxious responses to predictable and unpredictable aversive events

Anxiety induced by 2 types of predictable and unpredictable aversive stimuli, an unpleasant shock or a less aversive airblast to the larynx, were investigated in a between-group design. Participants anticipated predictable (signaled) or unpredictable (not signaled) aversive events, or no aversive event. Unpredictable, relative to predictable, contexts potentiated the startle reflex in the shock group but not in the airblast group. These data suggest that unpredictability can lead to a sustained level of anxiety only when the pending stimulus is sufficiently aversive. Because predictable and unpredictable danger may induce different types of aversive responses, the proposed design can serve as a useful tool for studying the neurobiology and psychopharmacology of fear and anxiety.

A single administration of testosterone reduces fear-potentiated startle in humans

BACKGROUND Ample evidence from animal research indicates that the gonadal steroid hormone testosterone has fear-reducing properties. Human data on this topic, however, are scarce and far less unequivocal. The present study therefore aimed to scrutinize anxiolytic effects of a single dose of testosterone, using a direct physiological index of fear in humans. METHODS Twenty healthy female participants were tested in a double-blind, placebo-controlled crossover design involving sublingual administration of a single dose of testosterone. Four hours after intake, we assessed effects on baseline startle and fear-potentiated startle in a verbal threat-of-shock paradigm. RESULTS In accordance with predictions, testosterone administration resulted in reduced fear-potentiated startle, without affecting baseline startle. CONCLUSIONS This study provides direct evidence that a single dose of testosterone reduces fear in humans. The relationship of this effect to previous research on anxiolytic effects of benzodiazepines, as well as possible mechanisms of action, is discussed.

Context Conditioning and Behavioral Avoidance in a Virtual Reality Environment: Effect of Predictability

BACKGROUND Sustained anxiety can be modeled using context conditioning, which can be studied in a virtual reality environment. Unpredictable stressors increase context conditioning in animals. This study examined context conditioning to predictable and unpredictable shocks in humans using behavioral avoidance, potentiated startle, and subjective reports of anxiety. METHODS Subjects were guided through three virtual rooms (no-shock, predictable, unpredictable contexts). Eight-sec duration colored lights served as conditioned stimuli (CS). During acquisition, no shock was administered in the no-shock context. Shocks were paired with the CS in the predictable context and were administered randomly in the unpredictable context. No shock was administered during extinction. Startle stimuli were delivered during CS and between CS to assess cued and context conditioning, respectively. To assess avoidance, subjects freely navigated into two of the three contexts to retrieve money. RESULTS Startle between CS was potentiated in the unpredictable context compared to the two other contexts. Following acquisition, subjects showed a strong preference for the no-shock context and avoidance of the unpredictable context. CONCLUSIONS Consistent with animal data, context conditioning is increased by unpredictability. These data support virtual reality as a tool to extend research on physiological and behavioral signs of fear and anxiety in humans.

Exogenous testosterone attenuates the integrated central stress response in healthy young women.

Animal research has shown that the androgen steroid testosterone, the end product of the hypothalamic-pituitary-gonadal (HPG) axis, down regulates the integrated stress response at multiple levels. These effects have been demonstrated at the level of the amygdala and the bed nucleus of the stria terminalis, and along the different nodes of the hypothalamic-pituitary-adrenal (HPA) axis. The present study was designed to assess effects of exogenous testosterone upon reactivity of the autonomic nervous system and modulation of the acoustic startle reflex in humans. Twenty healthy female participants received double-blind, placebo-controlled sublingual administrations of .5mg testosterone. Measurements were made of phasic electrodermal activity, cardiac responses, and startle reflexes to acoustic probes while participants were exposed to pictures with strongly aversive, neutral, or positive content. Subjective reports of mood and picture evaluations were also obtained. Results support the hypothesis of a generally decreased responsiveness of the stress system by showing reduced skin conductance responses as well as reduced affective startle modulation in anxiety-prone participants after administration of testosterone. Candidate neurobiological mechanisms of action are outlined and discussed, and it is argued that androgens promote dynamic regulation of the stress system through actions upon central neuropeptidergic pathways that control corticotropin releasing hormone (CRH) and arginine vasopressin (AVP) expression. The present findings highlight the importance of further investigation of the possible role of the HPG axis in disorders that are associated with HPA axis dysfunctions.

The Benzodiazepine Alprazolam Dissociates Contextual Fear from Cued Fear in Humans as Assessed by Fear-potentiated Startle

BACKGROUND The startle reflex is potentiated by aversive states. It has been proposed that phasic startle potentiation to a threat cue and sustained startle potentiation to contextual stimuli reflect distinct processes mediated by different brain structures. The present study tested the hypothesis that alprazolam would reduce the sustained startle potentiation to contextual threats but not the startle potentiation to a threat cue. METHODS Sixteen healthy subjects received each of four treatments: placebo, .5 mg of alprazolam, 1 mg of alprazolam, and 50 mg of diphenhydramine (Benadryl) in a crossover design. Participants were exposed to three conditions, including one in which predictable aversive shocks were signaled by a cue, a second in which shocks were administered unpredictably, and a third condition in which no shocks were anticipated. Acoustic startle were delivered regularly across conditions. RESULTS Phasic startle potentiation to the threat cue in the predictable condition was not affected by alprazolam. In contrast, the sustained increase in startle in the predictable and unpredictable conditions was reduced significantly by the high dose of alprazolam. CONCLUSIONS Startle responses to an explicit threat cue and to an aversive context are psychopharmacologically distinct, suggesting that they may represent functionally dissociable aversive states.

On the processing of spatial frequencies as revealed by evoked-potential source modeling

OBJECTIVES AND METHODS Visually evoked potentials (VEPs) are known to be sensitive to spatial frequency, especially in the time range between 50 and 100 ms post-stimulus. In two experiments we localized the cortical activity elicited by stimuli of varying spatial frequency in scalp-recorded brain potentials, using multi-electrode recordings and dipole-source analysis. RESULTS Low spatial frequencies (<1 c/d) activated relatively lateral occipital areas, the orientation of the neural ensembles involved being predominantly perpendicular to the scalp surface. In contrast, high spatial frequencies (>4 c/d) induced activation of more medial occipital areas with the predominant orientation of the sources being much more parallel to the scalp surface. Furthermore, at about 100 ms latency the lateral-occipital response to low spatial frequencies was stronger in the right hemisphere; no such asymmetry was found for the responses to the high spatial frequencies. These findings were consistent across varying recording conditions, individual subjects, subject populations, stimulus characteristics (grating orientation, grating vs. checkerboard), and task conditions (active vs. passive). CONCLUSION The results indicate that there are differences in sensitivity to specific spatial frequencies between primary and secondary visual areas, as well as between the right and the left hemispheres.

Fear conditioning in virtual reality contexts: a new tool for the study of anxiety

BACKGROUND Context conditioning has been suggested to model clinical anxiety, but context, as manipulated in animal models, has not been translated to human studies. A virtual environment might prove to be the ideal tool for innovative experimental paradigms to study explicitly cued fear and contextual anxiety in humans. METHODS Subjects were guided through a virtual environment that consisted of two rooms connected by a street scene. In each of the rooms, a blue and a yellow panel on a wall served as explicit conditioned stimuli (CS). The panels were displayed several times. One of the panels (CS+) was associated with a shock in one of the rooms (shock room). No shock was administered in the other room (safe room). Acoustic startle stimuli were administered in the presence and in the absence of the panels to assess explicit cued conditioning to the CS and context conditioning to the rooms, respectively. RESULTS Startle was potentiated by the CS+ in both rooms, which suggests generalization of fear across contexts. After acquisition, startle was potentiated in the shock room, compared with the safe room, in the absence of the CS+. CONCLUSIONS These results support the future use of virtual reality to design new conditioning experiments to study both fear and anxiety.

Threat-induced cortical processing and startle potentiation

This paper presents cortical responses as reflected in event- related potentials (ERP) in an instructed fear paradigm. Safe cues and threat cues that predict shock were presented at an unprecedented fast rate (mean SOA of 2.1 s). Startle and subjective measures confirmed that threat relative to safe cues elicited fear. Several ERP correlates of fear processing were predicted and confirmed: modulation of exogenous sensory components, frontal selection positivity, and increase of P3. Furthermore, a frontal negative slow wave was observed. These results are discussed in relation to attentional selection models and emotional processing.

Stimulus-preceding negativity induced by fear: a manifestation of affective anticipation

The Stimulus-Preceding Negativity (SPN), a slow cortical potential, has been studied in relation to anticipatory attention. A review of the literature suggests that most instances of SPN are observed in anticipation of motivational stimuli, such as aversive stimuli and stimuli that provide Knowledge of Results. In the present study, SPN was recorded in 12 subjects in a threat-of-shock experiment. This manipulation induced fear, as shown by subjective ratings and potentiation of the eyeblink startle. The fear-induced SPN showed a frontocentral maximum and coarse source analysis suggested that it was generated in midline frontal areas, possibly by the anterior cingulate cortex. It is concluded that the fear-induced SPN is a manifestation of affective anticipation. Possible thalamocortical and amygdalocortical contributions to its generation are discussed.