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Safety signals and human anxiety: a fear-potentiated startle study.

The effect of a safety signal on the magnitude of anticipatory anxiety was investigated using the fear-potentiated startle reflex paradigm in humans. The amplitude of the acoustic startle reflex was measured during the anticipation of unpleasant electric shocks ("threat") and during "safe" conditions. Threat and safe conditions were signaled by three different colored lights. Two lights signaled safe conditions (safe 1, safe 2) and the other light signaled the threat condition (threat). In phase I, the lights alternated, each presentation consisting of one colored light. In phase II, the lights were presented alone or in the two combinations of safe 1 (or safe 2) + threat and safe 1 + safe 2. In both phases, the contingency between the lights and the shock was explained to the subjects. It was emphasized that no shock could be administered when the safe 1 and threat light were simultaneously presented in phase II. Subjects' belief and understanding of the instructions were verified. In Phase I, startle was increased in the threat-alone compared to the safe-alone condition, reflecting increased anticipatory anxiety in the threat-alone condition. In phase II, startle in the safe + threat condition was smaller than in the threat-alone condition, but was larger than in the safe + threat. These results were interpreted as suggesting that the threat signal was still able to elicit anticipatory anxiety despite the fact that it was no longer associated with a threat.

Acoustic Stimulation↗

Ontogenetic dissociation of two classes of habituation.

The rates of decrement of two classes of response (an elicited startle reflex and emitted exploratory behavior) were determined in rats of two different ages (15 and 36 days). The rate of decrement in the startle reflex was not clearly differentiated as a function of age. In contrast, there was no evidence of habituation of exploration in the younger animals, whereas the older rats uniformly showed profound response decrements. This ontogenetic dissociation of the two instances of response decrement indicates that accounts of both instances in terms of a common process called habituation may be unwarranted. In addition, these data, in conjunction with earlier findings, indirectly support the possibility that reflex decrements may be relatively more dependent on brain serotonin whereas decrements in exploration may be more dependent on normal cholinergic activity in brain.

Age Factors↗

Fear-potentiated startle: relationship to the level of state/trait anxiety in healthy subjects.

The startle reflex is potentiated during experimentally induced anxiety (fear-potentiated startle). It is also increased in various anxiety disorders. The present study investigated the relationship between individual differences in fear and anxiety, and startle modulation. The eyeblink component of the acoustic startle reflex was measured in a paradigm involving the anticipation of electric shocks in 22 healthy men who were volunteers. Each subject's fear of shock was assessed with the state portion of the State-Trait Anxiety Inventory (STAI; Spielberger 1983). Fear-potentiated startle, but not baseline startle, differed in the low and high fear subjects. The magnitude of fear-potentiated startle was larger in the high-fear group as compared to the low-fear group. The time-course of startle modulation suggested a longer duration of anticipatory anxiety in the high-fear group. Trait anxiety, which was assessed with the trait portion of the STAI, did not relate to individual differences in either baseline or fear-potentiated startle.

Adolescent↗

Pro-dopamine effects of neurotensin on sensorimotor gating deficits.

Neurotensin is a neuropeptide which coexists with mesolimbic dopamine and has exhibited neuroleptic-like activity in the nucleus accumbens. This study examined the effects of neurotensin infused into the nucleus accumbens on prepulse inhibition (PPI) of the rat's acoustic startle reflex, a measure which is relevant to the sensorimotor gating deficits seen in schizophrenia. Neurotensin (5 micrograms) had no effect on the amplitude of the acoustic startle reflex nor on baseline PPI, but it potentiated the disruption of PPI produced by amphetamine and apomorphine. This is the first report of a pro-dopamine action for intra-accumbens neurotensin, and suggests that a complex behavioral pharmacology is associated with this neuropeptide.

Acoustic Stimulation↗

Noradrenergic influence on the prepulse inhibition of acoustic startle.

Oral administration of p,p'-1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane (DDT), a chemical believed to increase neuronal membrane excitability increased the acoustic startle responsiveness of rats. Inhibition of the acoustic startle response with a brief, prepulse white-noise stimulus was evident at 12.5 to 25 mg/kg of p,p'-DDT, but not at 50 mg/kg. Pretreatment of rats with phenoxybenzamine, an adrenergic receptor antagonist, attenuated the effects of 12.5 mg/kg of p,p'-DDT on the acoustic startle reflex, and decreased the maximum magnitude reduction produced by the prepulse stimulus in DDT-exposed rats. These data extend previous work showing that p,p'-DDT augments startle reactivity in rats and is in accord with the existence of an excitatory norepinephrine(NE)-containing pathway modulating motor outflow in the acoustic startle reflex arc.

Analysis of Variance↗

The effects of intra-accumbens neurotensin on sensorimotor gating.

Neurotensin is a neuropeptide which coexists with mesolimbic dopamine. Previous studies have shown that centrally administered neurotensin can modulate the activity of mesolimbic dopamine with a profile similar to neuroleptics. For example, infusions of neurotensin into the nucleus accumbens inhibit amphetamine-induced hyperlocomotion. Prepulse inhibition (PPI) occurs when a weak prestimulus ('prepulse') inhibits the amplitude of the startle response to an intense stimulus ('pulse'). PPI is an operational measure of sensorimotor gating which is strongly regulated by mesolimbic dopamine. This study examined the effects of various doses of neurotensin infused into the nucleus accumbens of rats on the prepulse inhibition (PPI) of their acoustic startle reflex. Neurotensin (0.25-5.0 microg) was infused into the nucleus accumbens of rats. Animals then received subcutaneous injections of amphetamine (2 mg/kg) or saline and were placed in startle chambers where measures of startle amplitude and PPI were obtained. Neurotensin increased baseline PPI and blocked amphetamine-induced disruption of PPI in a dose-dependent fashion. The lowest dose of neurotensin tested (0.25 microg) significantly increased baseline PPI and both 0.25 and 1.0 microg neurotensin blocked amphetamine-induced decreases in PPI. The 5.0 microg dose of neurotensin had no significant effect on prepulse inhibition. Neurotensin had no effect on the amplitude of the acoustic startle reflex in amphetamine- or saline-treated rats. The results suggest that intra-accumbens neurotensin has a significant, dose-dependent effect on sensorimotor gating in which lower doses (0.25-1.0 microg) exhibit a neuroleptic-like action.

Animals↗

Regulation of prepulse inhibition by ventral pallidal projections.

The acoustic startle reflex is inhibited by the presentation of a weak auditory prestimulus 30-500 ma prior to the starting stimulus. Previous studies have demonstrated that prepulse inhibition (PPI) of acoustic startle is regulated by GABAergic activity in the ventral pallidum. Ventral pallidal efferents include major projections to the pedunculopontine tegmental nucleus (PPTg), subthalamic nucleus (STN), and mediodorsal thalamus (MD). We used lesion and intracerebral infusion techniques to determine the relevance of these projections to the ventral pallidal regulation of PPI. Consistent with previous results, PPTg lesions significantly reduced PPI in all startle sessions, while MD lesions significantly reduced PPI only under certain experimental conditions. STN lesions failed to alter PPI, but they did significantly disrupt amphetamine-induced locomotion, verifying the behavioral effectiveness of these lesions. Infusion of the GABA-A agonist muscimol into either the PPTg or the MD significantly reduced PPI. Ventral pallidal projections to the PPTg and to the MD thus appear to regulate PPI, possibly via a GABAergic mechanism. Pallidal projections to the STN may regulate other behavioral processes such as locomotor activity, but they do not appear to regulate sensorimotor gating of the acoustic startle reflex.

Acoustic Stimulation↗

Cysteamine blocks amphetamine-induced deficits in sensorimotor gating.

Somatostatin is a neuropeptide that has been shown to interact with dopamine. Low concentrations of cysteamine selectively depletes somatostatin and has been used to investigate the role of endogenous somatostatin in lieu of an available selective receptor antagonist. We examined the effects of various doses of subcutaneous cysteamine on baseline and amphetamine-disrupted sensorimotor gating as measured by prepulse inhibition of the acoustic startle reflex. Cysteamine in doses ranging from 50-300 mg/kg reversed decreases in PPI induced by systemic injections of amphetamine (2 mg/kg). Cysteamine had no effect on the amplitude of the acoustic startle reflex itself. The results lend further support to a somatostatin-dopamine interaction within the brain in which endogenous somatostatin facilitates dopaminergic activity. These findings also suggest that endogenous somatostatin might play a significant role in regulation of sensorimotor gating deficits. This has clinical implications as deficient prepulse inhibition is recorded in humans suffering from neuropsychiatric conditions such as schizophrenia.

Acoustic Stimulation↗

Fearfulness and startle potentiation during aversive visual stimuli.

Recent experimental research suggests an association between negative affect and potentiation of the human startle reflex, as well as enhancement of this effect among fearful compared to low fear subjects. In the present study, 32 undergraduates were selected for high or low total Fear Survey Schedule scores. Acoustic startle probes were presented while subjects received warned presentations of aversive and neutral photographic slides. High fear but not low fear subjects showed potentiated short-latency cardiac acceleration and blink magnitude, and reduced blink latency, during aversive compared to neutral slides. These results support the hypothesis that affective modulation of startle is enhanced among high fear compared to low fear subjects. Considered in the context of prior findings, the results suggest that this individual difference effect generalizes across psychophysiological components of the startle reflex and diverse procedures for manipulating affect.

Adolescent↗

Habituation of the blink reflex in first-episode schizophrenia, psychotic depression and non-psychotic depression.

OBJECTIVE: Electrophysiological recording of the electrically elicited blink reflex is the most reliable method of investigating habituation of the startle reflex. The purpose of this study was to compare the habituation and the late R3-component of the blink reflex between control subjects (N=19) and first-episode patients with schizophrenia (N=17), psychotic depression (N=23), and severe non-psychotic depression (N=25). METHODS: The blink reflex was evoked by electrical stimulation of the supraorbital nerve, and the deficient habituation of the R2i-component was measured with a computer-assisted integral area measurement. Prefrontal executive function of the patients was assessed with the Wisconsin Card Sorting Test. Current psychiatric symptoms were assessed with the Brief Psychiatric Rating Scale, the Hamilton Depression Scale, the Positive and Negative Syndrome Scale, and the Calgary Depression Scale. RESULTS: Deficient habituation of the blink reflex and occurrence of the late R3 component were associated both with a previous diagnosis of psychotic disorder and with the presence of current psychosis. The sensitivity and specificity of the abnormal habituation of the blink reflex in detecting psychotic disorder were 0.50 and 0.80, respectively. The abnormalities of the blink reflex were not associated with psychotropic medication. In schizophrenic patients, defective habituation of the blink reflex was associated with negative and cognitive symptoms, and in depressive patients with the presence of delusions. CONCLUSIONS: The deficient habituation of the blink reflex and occurrence of the late R3 component seem to be both trait and state markers of a psychotic disorder. The results suggest that schizophrenia and psychotic depression share some common neurobiological mechanisms involved in the modulation of the startle reflex.

Adult↗

PGO waves in rats in the non-paradoxical sleep states.

Experiments were conducted in rats in order to characterize further the occurrence of PGO waves recorded from the region of the locus coeruleus, which were elicited by auditory stimuli. Repeated stimulus presentations at regular interstimulus intervals resulted in a consistent, state-dependent pattern in the occurrence and amplitudes of elicited PGO waves. The probability of eliciting a PGO wave was lowest during paradoxical sleep and highest immediately afterwards. This was followed by a gradual decline in responding during the ensuing period of slow-wave sleep. These results were obtained regardless of at what point in the rats' sleep cycles presentations of the auditory stimuli began. In other experiments, a comparison of elicited PGO waves with the acoustic startle reflex revealed major differences between these 2 responses. PGO waves could be elicited with very low intensity stimuli that were below the threshold for producing a behavioral response, while much louder stimuli were required to elicit a startle. The startle reflex habituated in a linear fashion and did not display state-related changes. It was concluded that elicited PGO waves are an electrophysiological sign of sensory responsiveness, and that their spontaneous appearance during and preceding paradoxical sleep reflects endogenously generated reticular activation.

Acoustic Stimulation↗

Does neonatal brain ischemia induce schizophrenia-like behavior in young adult rats?

Perinatal cerebral hypoxia represents a major cause of obstetric complications and the resulting transient oxygen deficiency might belong to early risk factors for schizophrenia. The aim of this study was to evaluate possible long-term behavioral changes induced by one hour of continuous bilateral common carotid artery occlusion in 12-day-old male rats. Post-ischemic behavioral disturbances were evaluated in social (play) behavior on postnatal day 22 (PND 22), open field test (PND 35 and 50) and prepulse inhibition of the acoustic startle reflex (PND 50). Transient ischemia in neonatal rats was not significantly altered in social dyadic interactions evaluated in pre-weaning pups, but resulted in enhanced locomotor activity in pubertal rats (PND 35) and impaired prepulse inhibition of the startle reflex in post-pubertal males (PND 50). These behavioral alterations suggest that perinatal hypoxic/ischemic insults may represent a risk factor for later manifestation of specific features relevant to schizophrenia in predisposed individuals.

Acoustic Stimulation↗

Increased sensitivity to the sensorimotor gating-disruptive effects of apomorphine after lesions of medial prefrontal cortex or ventral hippocampus in adult rats.

Sensorimotor gating of the startle reflex is impaired in humans with schizophrenia and in rats after mesolimbic D2 dopamine receptor activation. The loss of startle gating after D2 activation in rats has been used as an animal model of impaired sensorimotor gating in schizophrenia, because the ability of antipsychotics to restore startle gating in D2-activated rats correlates significantly with antipsychotic clinical potency. Substantial evidence indicates that the pathophysiology of schizophrenia includes structural and functional deficits in prefrontal and temporal regions, particularly the dorsolateral prefrontal cortex and the hippocampus and parahippocampal gyrus. The present study assessed startle gating in adult rats after ibotenic acid lesions of the medial prefrontal cortex or ventral hippocampus. Medial prefrontal cortex lesioned rats exhibited normal startle amplitude and normal sensorimotor gating, as reflected by prepulse inhibition (PPI) of the startle reflex. Hippocampus lesioned rats exhibited elevated startle amplitude, and similar to rats with medial prefrontal cortex lesions, did not show significant changes in basal PPI. Low doses of the mixed dopamine agonist apomorphine did not significantly reduce PPI in sham lesioned rats, but significantly disrupted PPI in both medial prefrontal cortex- and ventral hippo-campus lesioned rats. These data are consistent with the hypothesis that cell damage in frontal and temporal cortex increases the sensitivity to the sensorimotor gating-disruptive effects of dopamine receptor activation.

Animals↗

Fear imagery and the startle-probe reflex.

Blink reflexes to acoustic probes, heart rate, and subjective reports were studied during affective memory imagery. Thirty-six undergraduates memorized 6 pairs of neutral and fearful sentences. After learning each pair, they relaxed and listened to a series of uniform tones, one every 6 s. A change in tone pitch (higher or lower) cued recall of one of the two sentences. At the first cue tone, groups (n = 12) were under different instructions: (a) ignore the sentence and relax, (b) silently articulate the sentence, and (c) imagine the sentence content as a personal experience. At the second cue tone, all subjects performed the imagery task. Startle probes (50-ms, 95-dB white noise) were presented unpredictably during relaxation and recall trials. Probe blink reflexes were larger and cardiac rate faster at fear sentence recall than at neutral sentence recall or relaxation. For probe reflexes, this effect was greater for imagery than for nonsemantic recall tasks.

Adult↗

Selective behaviors altered in plasminogen-deficient mice are reconstituted with intracerebroventricular injection of plasminogen.

In vitro studies demonstrate a role for the plasminogen (Plg) system in neurological function and recently in vivo studies show a role of the Plg system in neurodegeneration after the injection of an excitotoxic agent. Differences in the development of neurological function, however, have not been demonstrated in the Plg-deficient (Plg-/-) mice compared to wild-type (WT) mice. The role of Plg system in neurological function may relate to remodeling which occurs in response to various environmental challenges. In this study, behaviors (open field, grooming, hind-leg gait, water maze, and acoustic startle reflex) were tested in the Plg-deficient and WT mice at 6-8 weeks of age. Grooming, a response to the stress of an open field or fur moistening, was increased in the Plg-/--deficient mice compared to WT mice, and the acoustic startle reflex (ASR) was markedly decreased in the Plg-/- mice. The reduced ASR in Plg-/- mice occurred in mice with a mixed C57BL:129 background or in mice with a C57BL background. Plg was required for the ASR, since a deficiency of the Plg activators, urokinase (uPA) or tissue Plg activator (tPA), did not cause a reduction in the ASR compared to their WT control. Infusion of Plg directly into the brain was effective in restoring the ASR in the Plg-/- mice, but had no effect on the ASR of WT mice. Peripheral bolus injections of Plg or infusion into the jugular vein were ineffective in restoring the ASR in the Plg-/- mice. These results indicate that Plg is required for the appropriate response to the environmental challenge of a sudden loud sound, and that the response can be restored in Plg-/- mice by directly infusing Plg into the brain.

Animals↗

Noise-induced psychogenic tremor associated with post-traumatic stress disorder.

Tremors in post-traumatic stress disorders have not been previously well characterized. A 67-year-old man has a 46-year history of a noise-induced exaggerated startle reflex followed by a large amplitude rest, postural and kinetic tremor that may persist for up to 3 days. This tremor is superimposed on a continuous mild organic postural/kinetic tremor whose electrophysiological characteristics are different from those of the overlying tremor. We attribute the exaggerated startle reflex and the noise-induced tremor to Post-Traumatic Stress Disorder (PTSD) and postulate a psychogenic origin for the noise-induced tremor. The patient also believes the noise-induced tremor to be psychologically based and to be produced by the fear and anxiety he experiences when he hears loud, unexpected noises. The sudden onset of the noise-induced tremor, its intermittent character, its temporary disappearance on distraction despite the patient's inability to suppress it, inconsistencies in handwriting and figure drawing, and the fact that the noise-induced tremor is stimulus specific and persists long after the offending stimulus (noise) is no longer present all suggest a tremor of psychogenic origin.

Accidents↗

On association between cortical 5-HT2A receptors and behavior in rats with experimental thyroid disturbances.

Thyroid hormones (TH) were hypothesized to affect behavior via neurotransmission alterations. The present study was aimed to reveal effects of chronic TH deficit and excess on some types of adaptive behavior (catalepsy, acoustic startle reflex, open-field performance), sexual arousal and cerebral 5-HT2A serotonin receptors of adult Wistar rats. Administration of thyroxine synthesis inhibitor, propylthiouracil (PTU, 50 mg/l, 28 days), in drinking water produced substantial decrease in plasma thyroxine level and body weight gain, attenuated significantly acoustic startle reflex amplitude, sexual motivation and plasma testosterone surge in response to receptive female introduction, increased predisposition to catalepsy without considerable effects on open-field performance. L-thyroxine treatment (T4, 0.5 mg/l, 28 days) caused significant plasma thyroxine augmentation, somatic growth retardation and disturbances in sexual but not in other types of behavior studied. TH dysfunctions markedly increased number of DOI-induced wet dog shakes reflecting high functional activity of 5-HT2A receptors without any effect on cortical 5-HT2A receptor mRNA level. The involvement of cerebral 5-HT2A receptors alterations at posttranslational level in mechanisms of TH effects on sexual arousal was suggested. The data attract particular attention to undesirable effects of PTU and L-thyroxine treatment on behavior.

Animals↗

Automatic quantification of withdrawal from 5-day diazepam in rats: ultrasonic distress vocalizations and hyperreflexia to acoustic startle stimuli.

The purpose of the present work was to develop an objective and precise method to quantify withdrawal responses from anxiolytics relying on ethologically valid responses. Behavioral effects of diazepam withdrawal in rats are automatically measured that appear to correspond to clinically relevant disturbances in affective and sensory-motor functions. Ultrasonic vocalizations and startle reflexes in response to acoustic stimuli were measured as indices of withdrawal 24 h after 5 days of 2.5, 5 or 10 mg/kg diazepam, b.i.d., IP in male Long-Evans rats. About 60% of male rats emit 22-26 kHz ultrasonic calls when exposed to acoustic startle stimuli (18 presentations, 9 at 105 dB and 9 at 115 dB, each 30 s apart on average). Diazepam-withdrawn rats exhibited startle responses with larger maximal and average amplitude and emitted more frequent 22-26 kHz ultrasonic vocalizations than vehicle-treated control animals. The magnitude of the withdrawal changes in ultrasonic calls and in startle reflex amplitude increased significantly already at the low 2.5 mg/kg diazepam dose in spite of considerable individual variability. The increased ultrasound rates during diazepam withdrawal contrast with the suppressive effects of acutely administered diazepam in drug-naive rats. The current methodology offers the opportunity to more adequately characterize withdrawal from anxiolytic substances in a quantitative, objective and automated manner.

Acoustic Stimulation↗