Biomedical subjects

Christian Grillon

Publications and source records attributed to Christian Grillon.

30 records · Page 2Linked to original sources

PubMed2004

Deficits in hippocampus-mediated Pavlovian conditioning in endogenous hypercortisolism.

BACKGROUND: Elevated endogenous levels of corticosteroids cause neural dysfunction and loss, especially within the hippocampus, as well as cognitive impairment in hippocampus-mediated tasks. Because Cushing's syndrome patients suffer from hypercortisolism, they represent a unique opportunity to study the impact of elevated glucocorticoids on cognitive functions. The aim of this study was to examine the performance of Cushing's syndrome patients on trace eyeblink conditioning, a cross-species, hippocampal-mediated test of learning and memory. METHODS: Eleven Cushing's syndrome patients and 11 healthy control subjects participated in an eyeblink trace conditioning test (1000-msec trace) and a task of declarative memory for words. Salivary cortisol was collected in both the patients and the control subjects, and urinary free cortisol was collected in the patients only. RESULTS: The patients exhibited fewer conditional responses and remembered fewer words, compared with the control subjects. Cortisol levels correlated with immediate and delayed declarative memory only. Conditional response correlated with delayed recall after controlling for the magnitude of unconditional response. CONCLUSIONS: The integrity of the hippocampus seems to be compromised in Cushing's syndrome patients. Trace eyeblink conditioning might be useful both as a clinical tool to examine changes in hippocampus function in Cushing's disease patients and as a translational tool of research on the impact of chronic exposure of glucocorticoids.

Adult↗

PubMed2004

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.

Adult↗

PubMed2004

Effects of the beta-blocker propranolol on cued and contextual fear conditioning in humans.

RATIONALE: Beta-adrenergic receptors are involved in the consolidation of emotional memories. Yet, a number of studies using Pavlovian cued fear conditioning have been unable to demonstrate an effect of beta-adrenergic blockade on acquisition or retention of fear conditioning. Evidence for the involvement of beta-adrenergic receptors in emotional memories comes mostly from studies using fear inhibitory avoidance in rodents. It is possible that fear inhibitory avoidance is more akin to contextual conditioning than to cued fear conditioning, suggesting that context conditioning may be disrupted by beta-adrenergic blockade. OBJECTIVE: This study investigated the effects of the beta-adrenergic blocker propranolol on cued and contextual fear conditioning in humans. METHODS: Subjects were given either placebo (n=15) or 40 mg propranolol (n=15) prior to differential cued conditioning. A week later, they were tested for retention of context and cued fear conditioning using physiological (startle reflex and electrodermal activity) and subjective measures of emotional arousal. RESULTS: The results were consistent with the hypothesis. The skin conductance level (SCL) and the subjective measure of arousal suggested reduced emotional arousal upon returning to the conditioning context in the propranolol group, compared to the placebo group. The acquisition and retention of cued fear conditioning were not affected by propranolol. CONCLUSIONS: These results suggest that beta-adrenergic receptors are involved in contextual fear conditioning.

Adrenergic beta-Antagonists↗

PubMed2004

Adaptive and maladaptive psychobiological responses to severe psychological stress: implications for the discovery of novel pharmacotherapy.

Post-traumatic stress disorder (PTSD) is one of the few DSM-IV diagnoses contingent upon a psychosocial stressor. In this context, there is an urgent need to acquire a better understanding of both the adaptive and maladaptive psychobiological responses to traumatic stress. Preclinical investigators have utilized a variety of animal models to identify the behavioral and neurobiological features of the organism's response to stress. However, given the complexity of the healthy and pathological human response to physiological and psychological stress, the extent to which the animal data is immediately transferable to human remains to be fully determined. This review draws upon preclinical and clinical literature to examine the transformation of an adaptive human stress response into a maladaptive and debilitating mental disorder. An integrative psychobiological model for PTSD is presented, linking psychological processes and behavioral patterns with current findings in neurocircuitry, neurochemistry and psychophysiology. The implications of this model for the discovery of novel pharmacological approaches to the treatment of severe psychological distress are discussed.

Adaptation, Physiological↗

PubMed2004

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.

Adult↗

PubMed2003

Anxiolytic effects of a novel group II metabotropic glutamate receptor agonist (LY354740) in the fear-potentiated startle paradigm in humans.

RATIONALE: LY354740, a structural analogue of glutamate that shows specificity at the mGluR2/3 receptor, has anxiolytic effects in animal models. OBJECTIVE: This study investigated the anxiolytic effects of LY354740 in humans using the fear-potentiated startle reflex methodology. METHODS: Subjects were given either placebo (n=16), 20 mg LY354740 (n=15), or 200 mg LY354740 (n=13). The fear-potentiated startle tests examined startle potentiation to shock anticipation and to darkness. RESULTS: Consistent with previous results, startle was increased by threat of shock and by darkness. LY354740 did not affect baseline startle. Correspondingly, subjects did not report LY354740 to be sedative. LY354740 significantly reduced the increase in startle magnitude during shock anticipation, but not during darkness. Subjective reports of state anxiety and negative affectivity during the fear-potentiated startle tests were also reduced in a dose-dependent manner by LY354740. CONCLUSIONS: These results suggest that LY354740 has an anxiolytic profile in humans without being sedative.

Administration, Oral↗

PubMed2003

A neuroimaging method for the study of threat in adolescents.

Little is understood about the brain basis of anxiety, particularly among youth. However, threat paradigms with animals are delineating the relationship between anxietylike behaviors and brain function. We adapted a threat paradigm for adolescents using functional magnetic resonance imaging. The aim was to examine amygdala activation to fear. The threat was an aversive air blast directed to the larynx. Participants were explicitly informed that they might receive the air blast when viewing one stimulus (threat condition) and would not receive the blast when viewing the other stimulus (safe condition). Participants provided fear ratings immediately after each trial. Based on the relatively mild nature of the air blast, we expected participants to report varying degrees of fear. Those who reported increased fear showed right amygdala activation during the threat condition and left amygdala activation in the safe condition. These procedures offer a promising tool for studying youth with anxiety disorders.

Adolescent↗

PubMed2003

Emotional arousal does not affect delay eyeblink conditioning.

Arousal can modulate information processing, including associative learning. However, there are conflicting results as to whether arousal affects eyeblink conditioning in humans. One potential problem with previous studies is that they have not taken into account factors that are known to affect conditioning. One such factor is the strength of the unconditioned response (UR). Despite evidence that greater UR leads to greater conditioned responses (CR), prior studies have not examined the role of the UR in CR performance. Prior studies have also usually classified subjects into low and high arousal groups based on a priori categorization without reliance on objective measures of arousal. The present study was designed to examine the impact of arousal on delay eyeblink conditioning. Changes in arousal levels were obtained by having participants view pictures selected for their a priori emotional and arousal values as being pleasant/arousing, unpleasant/arousing, or neutral/not arousing. Each subject viewed pictures of only one category. The spontaneous fluctuation of the skin conductance was taken as an index of physiological arousal. Subjects were divided into low and high arousal groups according to a median-split. Results showed that the rate of CR was positively related to the amplitude of the UR, but was not affected by emotional pictures or by physiological arousal. It is argued that changes in CR during arousal could be due to differences in unconditioned eyeblink strength rather than to changes in associative processes.

Adult↗

PubMed2003

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.

Animals↗

PubMed2002

Startle reactivity and anxiety disorders: aversive conditioning, context, and neurobiology.

The aim of this article is to review studies on human anxiety using the startle reflex methodology and to apply the literature on context conditioning in rats to interpret the results. A distinction is made between cued fear (as in specific phobia), a phasic response to an explicit threat cue, and anxiety, a more sustained and future-oriented response not linked to a specific discrete cue. Experimentally, contextual fear, as opposed to cued fear, may best reflect the feeling of aversive expectation about potential future dangers that characterizes anxiety. Following a brief description of the neurobiology of cued fear and context conditioning, evidence is presented showing that anxious patients are overly sensitive to threatening contexts. It is then argued that the degree to which contextual fear is prompted by threat depends on whether the danger is predictable or unpredictable. Consistent with animal data, unpredictable shocks in humans result in greater context conditioning compared to predictable shocks. Because conditioning promotes predictability, it is proposed to use conditioning procedures to study the development of appropriate and inappropriate aversive expectations. Cued fear learning is seen as an adaptive process by which undifferentiated fear becomes cue-specific. Deficits in cued fear learning lead to the development of nonadaptive aversive expectancies and an attentional bias toward generalized threat. Lacking a cue for threat, the organism cannot identify periods of danger and safety and remains in a chronic state of anxiety. Factors that may affect conditioning are discussed.

Animals↗

PubMed2002

Associative learning deficits increase symptoms of anxiety in humans.

BACKGROUND: Unpredictability has been postulated to be fundamental to anxiety and mood disorders. The origin of this unpredictability remains obscure. Because classical conditioning promotes predictability, this study investigated whether failure to learn conditioned stimulus (CS)-unconditioned stimulus (US) relationship during fear conditioning increased anxiety and avoidance. METHODS: Healthy subjects participated in two similar differential fear conditioning sessions separated by 1 week (n = 72) or a month (n = 61) in which one of two conditioned stimuli was associated with a shock/US. Following initial acquisition, subjects' awareness of CS-US relationship was assessed. Conditioned responses (CR) to the CS and to the experimental context were examined using the startle reflex and the skin conductance. Avoidance was operationally defined as failure to return for the second session. RESULTS: Only aware subjects showed differential CR. In the unaware subjects, the deficit in differential conditioning was associated with increased signs of anxiety during the first and second sessions. In addition, there was greater avoidance in the unaware subjects. CONCLUSIONS: Deficits in explicit cue fear conditioning can enhance anxiety. These findings are consistent with theories that associate anxiety and mood disorders with perceived unpredictability. Contextual conditioning models may be relevant to study chronic forms of anxiety.

Adolescent↗

PubMed2002

Benzodiazepines have no effect on fear-potentiated startle in humans.

RATIONALE: Pre-clinical and clinical investigations have provided a great deal of evidence that the fear-potentiated startle paradigm represents a valid model for the objective assessment of emotional states of anxiety and fear. OBJECTIVE: The four studies presented in this report sought to further validate the "threat of shock" paradigm as a human analogue to fear-potentiated startle in rats, by examining the effect of benzodiazepine administration on both baseline and fear-potentiated startle. METHODS: Three studies, conducted at Utrecht University, evaluated the effects of oxazepam and of diazepam on baseline and fear-potentiated startle, whereas a fourth study, conducted at Yale University, evaluated the effect of diazepam on baseline, contextual and cue-specific fear-potentiated startle. The threat of shock paradigm consisted of verbal instruction about two visual cues (the threat cue predicted the possible administration of electric shock, the other predicted a safe period), followed by a series of presentations of these cues. During these conditions, acoustic startle stimuli were presented in order to elicit startle responses. The magnitude of the startle response was used to index the degree of fear or alarm experienced during the periods of threat and safety. The fourth study examined the effect of IV administration of diazepam in a similar threat of shock paradigm except that there were two additional context manipulations: electrode placement and darkness. RESULTS: None of the drug manipulations affected specific threat-cue potentiation of startle. However, reductions in baseline startle were observed. Further, startle potentiation by darkness was inhibited by diazepam. CONCLUSIONS: At least one type of fear-potentiated startle, i.e. potentiation by a cue-specific fear manipulation, is not susceptible to benzodiazepine treatment. In contrast, effects of manipulations more akin to anxiety (darkness, context) appear sensitive to benzodiazepines. Human experimental models differentiating between these cue specific and contextual responses are needed to shed more light on differences in the anatomy and pharmacology of anxiety disorders.

Adolescent↗