Involvement of the human medial cerebellum in long-term habituation of the acoustic startle response

Animal studies have shown an involvement of the cerebellar vermis in long-term habituation of the acoustic startle response, but not in short-term habituation. The aim of the present study was to investigate whether short-term and long-term habituation of the acoustic startle response are impaired in patients with medial cerebellar lesions. Five patients with midline cerebellar lesions due to surgery for astrocytoma and ten healthy, age- and sex-matched subjects were studied. Subjects received 40 acoustic startle stimuli each day on five successive days. Peak amplitudes of the startle response recorded at the orbicularis oculi and the sternomastoid muscles were obtained. Data were analyzed for response decrement within the training session of one day (short-term habituation) and for a decrease in the startle response across the five training days (long-term habituation). Short- and long-term habituation of the startle response recorded at the sternomastoid muscles could be achieved in controls and in cerebellar patients. However, long-term habituation of the blink component of the acoustic startle response recorded at the orbicularis oculi muscles was significantly impaired in patients with cerebellar lesions compared with control subjects, whereas short-term habituation was preserved in both groups. The present findings suggest that the medial cerebellum is involved in long-term habituation of the blink component of the startle response in humans.     

Personality correlates of startle habituation

This study investigated the relationship between extraversion and rates of acoustic startle habituation, a potential biological marker for individual differences. Personality was measured using the Eysenck Personality Questionnaire (EPQ), the Sensation Seeking Scale (SSS), and Tellegen's Multidimensional Personality Questionnaire (MPQ). Higher EPQ Extraversion and higher SSS scores were associated with faster, more rapid startle habituation. Moreover, the relationship between extraversion and faster startle habituation was replicated in a second, follow-up sample. Within the initial study sample, lower scores on the Constraint (CON) factor of the MPQ (reflecting greater impulsiveness, risk-taking, and nonconformity) were also associated with faster startle habituation. Follow-up analyses revealed relationships between EPQ Extraversion, SSS, and low MPQ CON. These results suggest that faster habituation within the CNS may be associated tendencies toward impulsivity and behavioral disinhibition.     

Stimulus specificity in the habituation of the startle response in the rat

A series of experiments evaluated whether the habituation of the startle response of the rat to tactile and auditory cues is stimulus specific. Experiment 1 showed stimulus specificity of a short-term habituation effect, whereby the startle to the second of a pair of stimuli was significantly less when the initial stimulus involved the same rather than the different modality. Experiments 2 and 3 focused on the more persistent decrement in startle that is a result of repeated stimulation, and demonstrated that such long-term habituation to the tactile and auditory stimuli contained a stimulus specific component in addition to a generalized component. The generalized habituation observed between the tactile and auditory stimuli in the three experiments may be due to an auditory accompaniment of the tactile stimulus employed. Discussion emphasized the utility of investigating habituation in a preparation with robust specificity.     

Habituation of the acoustic startle response following lesion of the medial septal nucleus

Adult male rats were subjected to one of three surgical procedures: total lesions of the medial septal nuclei (TMS), partial lesions of the medial septal nuclei (PMS), and lesions of the dorsal fimbria (FM), as an attempt to determine the role of the septo-hippocampal relationship in habituation of the acoustic startle response. The initial startle amplitude of the TMS group was approximately three times that of the other groups, but rapidly decreased to the level of the other experimental groups and thereafter habituated at similar slow rates. Unlike animals with hippocampal lesions, all animals with hippocampal afferent damage displayed overdays savings of habituation. Following nine days without startle stimulation, startle amplitudes of the TMS groups had returned to their initial level while the PMS, FM and Control groups exhibited nonsignificant recovery. Differences in rates of habituation and amplitude of startle responses were attributed to loss of hippocampal input, and increased hippocampal output over intact pathways, respectively.     

Acoustic startle responses of protein malnourished rats

Acoustic startle responses were measured as part of a systematic attempt to determine if early protein malnutrition leads to a general hyperreactivity to aversive stimulation. In Experiment 1 startle responses transduced by floor movements were not reliably influenced by protein restriction in the preweaning or postweaning periods. The magnitude of the startle response, however, was positively correlated with body weight, partly as a consequence of the transduction method. Thus, differences in body weight might have obscured diet-related differences in startle amplitude. In Experiment 2 startles were recorded as electromyographic responses of the neck muscles and were larger in rats fed the low protein diet postweaning, especially in rats switched from high to low protein conditions at weaning. There was no indication that rats subjected to preweaning protein malnutrition were hyperreactive to aversive stimulation. In Experiment 1 it was also found that mean startle amplitudes were larger in young adults, 60 or 90 days old, than in 35-day-old rats, partly because there was less habituation in the adults.     

Prepulse inhibition of the startle response with chronic schizophrenia: A replication study

Prepulse inhibition (PPI) deficit, the acoustic startle reflex (ASR) and habituation (HAB) impairment are considered to be endophenotypes for schizophrenia. The recent two studies have reported that a PPI deficit was detected in Japanese schizophrenic patients. We replicated that study using larger samples (115 schizophrenic patients and 111 normal controls) than the original study and a method same as original study. A startle response monitoring system was used to deliver acoustic startle stimuli, and to record and score the electromyographic activity of the orbicularis oculi muscle. We evaluated the startle measures of mean magnitude of ASR, HAB, and PPI at prepulse sound pressure intensities of 82 dB (PPI82), 86 dB (PPI86), and 90 dB (PPI90). ASR was significantly different between schizophrenic patients and controls. HAB and all PPI session data from schizophrenic patients were significantly lower than in controls. In addition, we detected significant differences for ASR, HAB and each PPI (82, 86 and 90 dB) between schizophrenic patients and controls with the use of multiple regression analysis. The gender and smoking state were not correlated with ASR, HAB or any PPI in multiple regression analysis. In conclusion, we were able to replicate the finding of HAB impairment and PPI deficit in chronic Japanese schizophrenic patients.     

Attenuation of the prepulse inhibition of the acoustic startle response within and between sessions

Prepulse inhibition (PPI) and habituation of the acoustic startle response (ASR) are widely used biological markers in the study of psychiatric disorders and have been shown to be homologous across species. Previous studies in humans suggested that PPI is a stable and reliable measure between test sessions, but that PPI decreases within sessions. The purpose of this study was to explore the short- and long-term decrease in PPI as a potential confound in the measurement and interpretation of PPI. We investigated the progression of PPI and habituation of ASR in three test sessions spaced 4 weeks apart in a group of 20 healthy participants. Analysis revealed a significant decrease in the percent PPI within and between the test sessions. Nevertheless, PPI was reliable across three test sessions, indicating that the significant attenuation of PPI over time was a consistent phenomenon. These results suggest that PPI exhibits short- and long-term attenuation.     

Acoustic startle response in patients with orthostatic tremor

Background and aim

Orthostatic tremor is a high frequency tremor predominantly on calf muscles during standing. Brainstem is the most probable generator in the pathogenesis since it comprises bilaterally projecting centers regulating stance or tone. We aimed to investigate the functional role of brainstem through the evaluation of acoustic startle response in primary orthostatic tremor patients.

Patients and method

We included 7 (2 males) consecutive patients and 13 (5 males) healthy volunteers. Diagnosis was confirmed by polymyographic surface electromyography. All subjects underwent acoustic startle response and blink reflex investigations.

Results

Presence rate (71.4% vs. 100%, p = 0.042) and response rate (27.5% vs. 40.5%, p = 0.047) of total acoustic startle response were lower in patient group. Similarly, probability over orbicularis oculi was lower among patients (p = 0.003). However, blink reflex was observed in all patients and healthy volunteers and latencies of startle and blink reflexes were similar between groups.

Conclusions

In our patient group, normal response rate and latencies of R1 and R2 show structural integrity of at least blink reflex circuit at brainstem. On the other hand, suppressed response rates probably reflect decreased excitability of auditory startle reflex pathway.     

The cardiovascular startle response: Anxiety and the benzodiazepine receptor complex

Benzodiazepine receptor (BZR) agonists are prototypic anxiolytic agents, whereas BZR inverse agonists exert anxio-genic effects. The effects of these compounds offer a potentially important pharmacological model system to examine the central mechanisms of anxiety. In accord with its putative anxiogenic properties, we previously found that the BZR partial inverse agonist, FG 7142, enhances the cardiovascular defensive response to a nonsignal acoustic stimulus in rats. In contrast, we found in the present study that this agent attenuates both the somatic and cardiovascular components of the acoustic startle response. BZR agonists and inverse agonists are known to modulate the basal forebrain cortical cholinergic system, and we consider the potential involvement of this system in the disparate psychophysiological actions of FG 7142 and in anxiety states in general.     

Influence of functional tryptophan hydroxylase 2 gene variation and sex on the startle response in children, young adults, and older adults

Serotonin, a key regulator of emotional behavior, is synthesized by tryptophan hydroxylase (TPH). Allelic variation of TPH2 gene expression influences serotonin synthesis in the brain and therefore may modulate emotional processing. Here, we investigated the influence of the −703 G/T polymorphism in the regulatory promoter region of the TPH2 gene on the startle response in three different age samples: children (N = 110), young adults (N = 209), and older adults (N = 95). Startle magnitudes to intense noise bursts were recorded during baseline and while participants viewed unpleasant, pleasant or neutral pictures. There was a significant TPH2 × sex interaction effect in young adults with male T allele carriers showing stronger overall startle responses compared to male G/G homozygotes while in young women this effect appeared to be reversed. The difference between TPH2 genotype groups also reached significance in the female subsample when including menstrual cycle phase. In contrast, there was no effect of TPH2 or a TPH2 × sex interaction effect in children or in older adults.     

Age, sex and strain differences in activity and habituation in SHR and WKY rats

The highly inbred strain of Wistar-Kyoto spontaneously hypertensive rat (SHR) and its normotensive, genetic control (WKY) were examined with respect to strain differences in spontaneous activity scores in a novel environment (small activity cage) and in ability to habituate to that environment. These behaviors were examined in experimentally naive rats, 197 SHR and WKY, males and females, at varying ages from 4 to 56 weeks, in order to determine whether there are sex and age differences in addition to the well-known strain differences in these behaviors. Total activity scores, determined in a 15 min test in the activity cage, were higher in SHR than WKY rats; females were significantly more active than males in either strain, and activity scores varied significantly with age both within strains and between strains. Ability to habituate to the test cage was determined by repeating the 15 min activity test at hourly intervals for three additional trials on the same day. The results indicate that the SHR, males and females and at all ages tested, habituate poorly if at all to the test cage as compared with WKY rats. Moreover, despite the variability of baseline activity scores (first trial) observed across ages, sexes and strains, the habituation patterns of either strain remained relatively fixed throughout the first year of life.     

The effect of startle reflex habituation on cardiac defense: Interference between two protective reflexes

The present study investigated the relationship between blink startle and cardiac defense, two protective reflexes that are said to be elicited by the transient and the sustained components, respectively, of high intensity stimuli. Three groups of participants were presented with three intense long lasting noise stimuli (500ms) after habituation training with 12 brief (50ms) high intensity noise bursts (High group), low intensity noise bursts (Low group) or high intensity visual stimuli (Light group). The transition from habituation to defense stimuli resulted in increased blink startles in groups Low and Light, but not in group High. A cardiac defense reflex, characterised by a short and long delayed increase in heart rate, was observed in group Light, but not in groups Low and High. This pattern of results indicates that habituation to startle eliciting stimuli will impair defense reflexes elicited on subsequent test trials and suggests some interrelation between the two reflex systems.     

Iron deficiency affects acoustic startle response and latency, but not prepulse inhibition in young adult rats

Iron deficiency is associated with alterations in dopamine and serotonin transporters as well as changes in dopamine receptor (DR) density, monoamine concentrations, and in vivo extracellular contents of monoamines in terminal fields. Human infants with iron deficiency have both delayed maturation as well as lengthened central conduction times in auditory evoked potential studies. The current study utilizes the magnitude of the acoustic startle response (ASR), prepulse inhibition (PPI), and mean latency to maximum startle response (T(max)), to examine the functional integrity of response to environmental cues. Male and female rats consumed iron deficient (ID) or iron adequate (CN) diets from weaning until adulthood. ID rats of both sexes had 20-60% reductions in ASR when compared to CN rats but there was no effect on PPI. T(max) was significantly longer by 10-20% in females, but not males. Dopamine transporter density was significantly lower in putamen, nucleus accumbens, and olfactory tubercle in males, but not female rats while the serotonin transporter was significantly different from control animal density in five of 14 brain regions. Norepinephrine transporter density was lower in the locus ceruleus of ID male rats but was unaffected in ID female rats. Regression modeling of ASR with brain monoamine transporters and receptors showed hematocrit, norepinephrine transporter (NET) in dentate gyrus, and D1R in the nucleus accumbens account for nearly 49% of the variance in ASR. T(max) was not significantly associated with any of the independent variables. We conclude that iron deficiency affects the startle response, but not the inhibitory circuits involved in prepulse inhibition. Importantly, sex also strongly influenced these behavioral responses. Future studies, perhaps pharmacologic in nature, are necessary to ascertain whether iron deficiency modifies the contribution of monoaminergic systems to responses to environmental stimuli.     

Relationship between prepulse inhibition of acoustic startle response and schizotypy in healthy Japanese subjects

Prepulse inhibition (PPI) of the acoustic startle reflex (ASR) is the most common psychophysiological index of sensorimotor gating. Several studies have investigated the relationship of PPI of ASR to schizotypy in Caucasians. However, little has been reported on this relationship in Asians. We investigated a possible relationship between PPI of ASR and schizotypy in 79 healthy Japanese subjects. Schizotypy was assessed by the Schizotypal personality Questionnaire (SPQ). PPI was evaluated at signal‐to‐noise ratios (SnRs: difference between background noise intensity and prepulse intensity) of +12, +16, and +20 dB. The total SPQ score, cognitive/perceptual score, and interpersonal score correlated negatively with PPI at SnR of +16 and +20 dB. We conclude that PPI is associated with the trait of schizotypy in healthy Asian subjects.     

MR/Har and MNRA/Har Maudsley rat strains: Differences in acoustic startle habituation

Female Maudsley Reactive (MR/Har) and Nonreactive (MNRA/Har) rats were tested for initial acoustic startle reactivity and within-session startle habituation. Subjects were exposed in each of five weekly sessions to 12 acoustic startle noise bursts at a 20-s interstimulus interval, a procedure in which genetically heterogeneous Sprague Dawley rats have been shown to exhibit robust within-session habituation. Although initial startle reactivity was comparable in the two strains, significant differences in withinssession habituation were observed. Specifically, MR/Har rats were observed to exhibit substantial within-session habituation to these acoustic stimuli, while rats of the MNRA/Har strain exhibited little, if any, habituation to these repeated acoustic stimuli. The basis for this dramatic difference in within-session startle habituation in these Maudsley rats is at present unexplained and under investigation.This work was supported in part by the WSU Biomedical Research Award Program, the American Heart Association of Michigan Grant-in-Aid Program, the Pharmaceutical Manufacturers Association Research Starter Grant and MH 42501-01 to R.L.C., and the National Science Foundation to G.M.H.     

Enhancement of the acoustic startle response by stimulation of an excitatory pathway from the central amygdala/basal nucleus of Meynert to the pontine reticular formation

The acoustic startle response (ASR) is a simple motor reaction to intense and sudden acoustic stimuli. The neural pathway underlying the ASR in rats is already fairly well understood. As the ASR is subject to a variety of modulations, this reaction can serve as a model for vertebrate neuroethologists to investigate the neural mechanisms mediating sensorimotor transfer and their extrinsic modulation. We report here on experiments in rats which were undertaken in order to investigate the neural mechanisms underlying the enhancement of the ASR. An increased amplitude of the ASR can be observed during states of conditioned and unconditioned fear. By employing neuroanatomical tract tracing methods, we describe a pathway from neurons of the medial division of the central amygdaloid nucleus (cA) and the basal nucleus of Meynert (B) to the caudal pontine reticular nucleus (PnC), an important relay station in the acoustic startle pathway. Extracellular recordings from acoustically responsive neurons in the PnC showed that electrical stimulation of the cA/B facilitates the tone evoked response of these neurons. Behavioural tests following chemical stimulation of the cA/B with NMDA (N-methyl-d-aspartate) in awake rats indicated that activation of this pathway increases the ASR. The lack of sufficient spatial resolution of our stimulation techniques did not allow us to differentiate the relative contributions of the cA and the B to this effect. As the amygdaloid complex has been implicated in emotional behaviour, particularly in the mediation of fear, these findings substantiate the concept that the amygdaloid complex plays a key role for the enhancement of the ASR by conditioned and unconditioned fear.     

Lesions of the inferior olive do not affect long- or short-term habituation of the acoustic startle response in rats

Short- and long-term habituation of the acoustic startle response were assessed in a group of inferior olive-lesioned rats. Neither short- and long-term habituation, nor the performance of the reflex, were affected by the lesion. Since the cerebellar vermis is essential for long-term habituation of this reflex, we suggest that climbing fibres are not involved in this form of learning, which would therefore be mediated by the other cerebellar input, presumably the mossy fibres.     

Effects of bilateral frontal lesions on habituation of the head-shake response in the rat

This experiment investigated the effects of bilateral frontal cortical lesions on the frequency and shape of the habituation curve of the head-shake response, elicited by stimulating the ear with a stream of air, in the rat. The results from an initial procedural-control group indicated that the damage done to the ear by mounting the rats in a stereotaxic was sufficient to increase responding. The results from the basic experiment, using a before-after design, indicated that bilateral frontal cortical lesions led to an overall increase in responding but had no effect on the shape of the habituation curve over trials. The responding of control animals given bilateral cortical lesions in the occipito-parietal area had no effect on responding. The results suggest that the frontal cortex, at least in the rat, is not involved in habituation of all responses.     

Habituation and sensitization of the rat startle response: effects of raphe lesions

In the first experiment raphe lesioned, sham operated and nonoperated rats were presented with 150 tones (50 at each of 3 intensities) a day for 5 days. No differences were found among the groups in the rate of startle response habituation either within or between sessions. However, overall levels of startle were much greater following raphe lesions and a tone by tone analysis indicated that this was caused by heightened tone-elicited sensitization in the raphe group. Further tests of startle sensitization in Experiment 2 found the raphe group to be more sensitized than the other groups by loud tones and footshocks but not by different levels of background white noise. The results support the theory that repetitive stimulus exposure produces both habituation and sensitization and that different neural systems may underly these two processes.     

Enhancement of the acoustic startle reflex by an alarm pheromone in male rats

Recently, we reported that an alarm pheromone released from the perianal region of male rats aggravated stress-induced hyperthermia and increased defensive and risk assessment behaviors in recipient male rats. Based on these results, we hypothesized that the primary effect of the alarm pheromone is to increase anxiety; however, there is still no clear evidence for this pheromone effect. Therefore, we examined this issue by assessing the effect of the alarm pheromone on the acoustic startle reflex (ASR), which is a useful index for studying negative emotions such as anxiety in rats. The alarm pheromone enhanced the ASR for 105-dB auditory stimuli, but not for those of 90 and 120 dB, when these three intensities of sound were used randomly. The same results were obtained when one of these three intensities was used repeatedly. In addition, pretreatment with diazepam (i.p.) at doses of 0.7 and 2.0 mg/kg suppressed the ASR of the pheromone recipients, whereas the lower dose (0.2 mg/kg) slightly attenuated the pheromone effect and the control injection (vehicle) had no effect. These results indicate that the alarm pheromone enhances the ASR by increasing anxiety in recipient rats, suggesting that the primary effect of the alarm pheromone is to increase the anxiety level.