Caractérisation et objectivation de l’acouphène subjectif chronique idiopathique

Objectif: Cette thèse avait pour objectif principal la mise en oeuvre et la validation de la faisabilité, chez l'humain, du paradigme de modulation du réflexe acoustique de sursaut par un court silence (GPIAS) afin de l'utiliser comme mesure objective de l'acouphène. Pour ce faire, trois expériences ont été réalisées. L'expérience 1 avait pour objectif de valider l'inhibition du réflexe de sursaut par un court silence chez des participants humains normo-entendants (sans acouphène) lors de la présentation d'un bruit de fond centré en hautes et en basses fréquences afin de déterminer les paramètres optimaux du paradigme. L'expérience 2 avait pour objectif de valider la précision et la fidélité d'une méthode de caractérisation psychoacoustique de l'acouphène (appariement en intensité et en fréquence). Finalement, l'expérience 3 avait pour objectif d'appliquer le paradigme d'objectivation de l'acouphène par le réflexe de sursaut à des participants atteints d'acouphènes chroniques en utilisant les techniques développées lors des expériences 1 et 2. Méthodologie : L'expérience 1 incluait 157 participants testés dans l'une des conditions de durée du court silence (5, 25, 50, 100, 200 ms) et dans l'un des deux paradigmes (court silence à l'intérieur du bruit de fond ou suivant celui-ci) à l'aide de bruits de fond en hautes et en basses fréquences. L'expérience 2 incluait deux groupes de participants avec acouphène, l'un musicien (n=16) et l'autre sans expérience musicale (n=16) ainsi qu'un groupe de simulateur sans acouphène (n=18). Ils tous ont été évalués sur leur capacité d'appariement en fréquence et en intensité de leur acouphène. Les mesures ont été reprises chez un sous-groupe de participants plusieurs semaines plus tard. L'expérience 3 incluait 15 participants avec acouphène et 17 contrôles évalués à l'aide du paradigme d'inhibition du réflexe de sursaut à l'aide d'un court silence (GPIAS). Les paramètres psychoacoustiques de l'acouphène ont également été mesurés. Toutes les mesures ont été reprises plusieurs mois plus tard chez un sous-groupe de participants. Résultats : Expérience 1 : le paradigme d'inhibition du réflexe acoustique de sursaut par un court silence est applicable chez l'humain normo-entendant. Expérience 2 : les mesures psychoacoustiques informatisées de l'acouphène incluant l'appariement en fréquence et en intensité sont des mesures précises et fidèles du percept de l'acouphène. Expérience 3 : un déficit d'inhibition au paradigme du GPIAS a été retrouvé chez le groupe de participants avec acouphène pour les bruits de fond en hautes et en basses fréquences au test et au retest. Les mesures d'appariement en fréquence ont révélé un acouphène dont la fréquence prédominante était d'environ 16 000 Hz chez la plupart des participants. Discussion : Il est possible d'appliquer le paradigme d'inhibition du réflexe acoustique de sursaut par un court silence à des participants humains atteints d'acouphène, tel qu'il est utilisé en recherche animale pour « objectiver » la présence d'acouphène. Toutefois, le déficit d'inhibition mesuré n'est pas spécifique à la fréquence de l'acouphène lorsque validé à partir des données d'appariement psychoacoustique. Nos résultats soulèvent des questions quant à l'interprétation originale du paradigme pour détecter la présence d'un acouphène chez les animaux.

Primary and secondary neural networks of auditory prepulse inhibition: a functional magnetic resonance imaging study of sensorimotor gating of the human acoustic startle response

Feedforward inhibition deficits have been consistently demonstrated in a range of neuropsychiatric conditions using prepulse inhibition (PPI) of the acoustic startle eye-blink reflex when assessing sensorimotor gating. While PPI can be recorded in acutely decerebrated rats, behavioural, pharmacological and psychophysiological studies suggest the involvement of a complex neural network extending from brainstem nuclei to higher order cortical areas. The current functional magnetic resonance imaging study investigated the neural network underlying PPI and its association with electromyographically (EMG) recorded PPI of the acoustic startle eye-blink reflex in 16 healthy volunteers. A sparse imaging design was employed to model signal changes in blood oxygenation level-dependent (BOLD) responses to acoustic startle probes that were preceded by a prepulse at 120 ms or 480 ms stimulus onset asynchrony or without prepulse. Sensorimotor gating was EMG confirmed for the 120-ms prepulse condition, while startle responses in the 480-ms prepulse condition did not differ from startle alone. Multiple regression analysis of BOLD contrasts identified activation in pons, thalamus, caudate nuclei, left angular gyrus and bilaterally in anterior cingulate, associated with EMGrecorded sensorimotor gating. Planned contrasts confirmed increased pons activation for startle alone vs 120-ms prepulse condition, while increased anterior superior frontal gyrus activation was confirmed for the reverse contrast. Our findings are consistent with a primary pontine circuitry of sensorimotor gating that interconnects with inferior parietal, superior temporal, frontal and prefrontal cortices via thalamus and striatum. PPI processes in the prefrontal, frontal and superior temporal cortex were functionally distinct from sensorimotor gating.

Environmental enrichment and chronic restraint stress in ICR mice: Effects on prepulse inhibition of startle and Y-maze spatial recognition memory

In most studies regarding the improving or therapeutical effects induced by enriched environment (EE), EE was performed after the stress treatment or in patients with certain diseases. In the current study, the effects of chronic restraint stress (6 h/day) in mice living in an enriched environment or standard environment (SE) were tested. Mice were randomly divided into 4 groups: non-stressed or stressed mice housed in SE or EE conditions (SE, stress + SE, EE, stress + EE). Prepulse inhibition (PPI) of startle was tested after the 2 weeks or 4 weeks stress and/or EE treatment and 1 or 2 weeks withdrawal from the 4 weeks treatment. After the 4 weeks treatment, spatial recognition memory in Y-maze was also tested. The results showed that EE increased PPI in stressed and non-stressed mice after 2 weeks treatment. No effect of EE on PPI was found after the 4 weeks treatment. 4 weeks chronic restraint stress increased PPI in mice housed in standard but not EE conditions. Stressed mice showed deficits on the 1 h delay version of the Y-maze which could be prevented by living in an enriched environment. Our results indicated that living in an enriched environment reversed the impairing effects of chronic restraint stress on spatial recognition memory. However, EE did not change the effects of stress on PPI. (C) 2010 Elsevier B.V. All rights reserved.

Maternal separation followed by isolation-housing differentially affects prepulse inhibition of the acoustic startle response in C57BL/6 mice

Exposure to chronic stress is associated with an increased incidence of neuropsychiatric dysfunction. The current study evaluated two competing hypotheses, the cumulative stress and the match/mismatch hypothesis of neuropsychiatric dysfunction, using two paradigms relating to exposure to “stress”: pre-weaning maternal separation and post-weaning isolation-housing. C57BL/6 offspring were reared under four conditions: typical animal facility rearing (AFR, control), early handling (EH, daily 15 min separation from dam), maternal separation (MS, daily 4 hr separation from dam), and maternal and peer separation (MPS, daily 4 hr separation from dam and from littermates). After weaning, mice were either housed socially (2–3/cage) or in isolation (1/cage) and then tested for prepulse inhibition in adulthood. Isolation-housed MPS subjects displayed greater deficits in prepulse inhibition relative to socially-housed MPS subjects while socially-housed AFR subjects displayed greater deficits in prepulse inhibition relative to isolation-housed AFR subjects. The results indicate that these treatment conditions represent a potentially valuable model for evaluating the match/mismatch hypothesis in regards to neuropsychiatric dysfunction.

Combined prenatal and chronic postnatal vitamin D deficiency in rats impairs prepulse inhibition of acoustic startle

There is growing evidence that 1,25-dihydroxyvitamin D-3 is involved in normal brain development. The aim of this study was to examine the impact of prenatal and postnatal hypovitaminosis D on prepulse inhibition (PPI) of acoustic startle in adult rats. We compared six groups of rats: control rats with normal vitamin D throughout life and normal litter size (Litter); control rats with normal vitamin D but with a reduced litter size of two (Control); offspring from reduced litters of vitamin D deplete mothers who were repleted at birth (Birth), repleted at weaning (Weaning) or remained on a deplete diet until 10 weeks of age (Life); or control rats that were placed on a vitamin D-deficient diet from 5 to 10 weeks of age (Adult). All rats were tested in acoustic startle chambers at 5 and 10 weeks of age for acoustic startle responses and for PPI. There were no significant group differences at 5 weeks of age on the acoustic startle response or on PPI. At 10 weeks of age, rats in the Life group only had impaired PPI despite having normal acoustic startle responses. We conclude that combined prenatal and chronic postnatal hypovitaminosis D, but not early life hypovitaminosis D, alters PPI. (C) 2004 Elsevier Inc. All rights reserved.

Effect of adrenalectomy and corticosterone replacement on prepulse inhibition and locomotor activity in mice

1 Stress is a risk factor in psychiatric illnesses such as schizophrenia. The aim of the present study was to investigate the effect of different circulating levels of the adrenal steroid corticosterone (CORT) on locomotor hyperactivity and prepulse inhibition of acoustic startle, two behavioural animal models of aspects of schizophrenia. 2 Male C57BL/6J mice (n = 10 per group) were anaesthetised with isoflurane and sham-operated or adrenalectomised (ADX). ADX mice were implanted with 50 mg pellets consisting of 100% cholesterol, or 2, 10 or 50 mg of CORT mixed with cholesterol. CORT pellet implantation dose dependently increased plasma CORT levels 3 weeks after surgery. Starting 1 week after surgery, mice were tested for prepulse inhibition after injection of saline or 5 mg kg(-1) of haloperidol. 3 In intact mice and in mice implanted with 10 mg of CORT, haloperidol treatment significantly increased prepulse inhibition (average values from 38 - 42 to 52%). Similar results were observed when testing the mice for amphetamine-induced locomotor hyperactivity (5 mg kg(-1)). In contrast, there was no significant effect of haloperidol in mice implanted either with cholesterol or 2 or 50 mg of CORT. 4 These results in behavioural animal models of schizophrenia suggest an important role of the stress hormone CORT in modulating dopaminergic activity in this illness.

Interaction of corticosterone and nicotine in regulation of prepulse inhibition in mice

The aim of the present Study was to investigate if different levels of circulating corticosterone (CORT) modulate the effect of nicotine on prepulse inhibition (PPI), a measure of sensorimotor gating that is disrupted in schizophrenia and other mental illnesses. Four groups of mice were investigated: sham-operated, adrenalectomized (ADX) and implanted with a cholesterol pellet, ADX and implanted with a 10 mg CORT pellet, or ADX and 50 mg, of CORT. Different CORT levels or doses of nicotine did not significantly affect startle responses. Baseline PPI was significantly reduced in mice implanted with the highest dose of CORT. In ADX mice implanted with cholesterol, nicotine treatment influenced PPI depending on the prepulse intensity. In ADX mice implanted with 50 mg of CORT, treatment with 10 mg/kg of nicotine caused a significant increase in PPI at all prepulse intensities. Binding studies showed that corticosterone treatment had significantly affected nicotinic acetylcholine receptor (nAChR) density in the mouse brain. Treatment with 50 mg CORT decreased I-125-epibatidine binding in the globus pallidus and I-125-alpha-bungarotoxin binding in the claustrum. These results suggest a possible interaction of corticosterone and nicotine at the level of the alpha4- and alpha7-type nAChR in the regulation of PPI. In situations of high circulating levels of corticosterone, nicotine may be beneficial to restore disruption of PPI. (C) 2004 Elsevier Ltd. All rights reserved.

Effects of amisulpride, risperidone and chlorpromazine on auditory and visual latent inhibition, prepulse inhibition, executive function and eye movements in healthy volunteers.

In view of the evidence that cognitive deficits in schizophrenia are critically important for long-term outcome, it is essential to establish the effects that the various antipsychotic compounds have on cognition, particularly second-generation drugs. This parallel group, placebo-controlled study aimed to compare the effects in healthy volunteers (n = 128) of acute doses of the atypical antipsychotics amisulpride (300 mg) and risperidone (3 mg) to those of chlorpromazine (100 mg) on tests thought relevant to the schizophrenic process: auditory and visual latent inhibition, prepulse inhibition of the acoustic startle response, executive function and eye movements. The drugs tested were not found to affect auditory latent inhibition, prepulse inhibition or executive functioning as measured by the Cambridge Neuropsychological Test Battery and the FAS test of verbal fluency. However, risperidone disrupted and amisulpride showed a trend to disrupt visual latent inhibition. Although amisulpride did not affect eye movements, both risperidone and chlorpromazine decreased peak saccadic velocity and increased antisaccade error rates, which, in the risperidone group, correlated with drug-induced akathisia. It was concluded that single doses of these drugs appear to have little effect on cognition, but may affect eye movement parameters in accordance with the amount of sedation and akathisia they produce. The effect risperidone had on latent inhibition is likely to relate to its serotonergic properties. Furthermore, as the trend for disrupted visual latent inhibition following amisulpride was similar in nature to that which would be expected with amphetamine, it was concluded that its behaviour in this model is consistent with its preferential presynaptic dopamine antagonistic activity in low dose and its efficacy in the negative symptoms of schizophrenia.

Normal levels of prepulse inhibition in the euthymic phase of bipolar disorder.

BACKGROUND:Deficits in prepulse inhibition (PPI) of the acoustic startle response have been suggested as a potentially useful endophenotype for schizophrenia spectrum disorders and may explain certain symptoms and cognitive deficits observed in the psychoses. PPI deficits have also been found in mania, but it remains to be confirmed whether this dysfunction is present in the euthymic phase of bipolar disorder.METHOD: Twenty-three adult patients with DSM-IV bipolar disorder were compared to 20 controls on tests of acoustic startle reactivity and PPI of the startle response. Sociodemographic and treatment variables were recorded and symptom scores assessed using the Hamilton Depression Inventory and the Young Mania Rating Scale.RESULTS:Overall, the patient and control groups demonstrated similar levels of startle reactivity and PPI, although there was a trend for the inter-stimulus interval to differentially affect levels of PPI in the two groups.CONCLUSIONS: In contrast to bipolar patients experiencing a manic episode, general levels of PPI were normal in this euthymic sample. Further studies are required to confirm this finding and to determine the mechanisms by which this potential disruption/normalization occurs. It is suggested that an examination of PPI in a high-risk group is required to fully discount dysfunctional PPI as a potentially useful endophenotype for bipolar disorder.

A fast cholinergic modulation of the primary acoustic startle circuit in rats

Cochlear root neurons (CRNs) are the first brainstem neurons which initiate and participate in the full expression of the acoustic startle reflex. Although it has been suggested that a cholinergic pathway from the ventral nucleus of the trapezoid body (VNTB) conveys auditory prepulses to the CRNs, the neuronal origin of the VNTB-CRNs projection and the role it may play in the cochlear root nucleus remain uncertain. To determine the VNTB neuronal type which projects to CRNs, we performed tract-tracing experiments combined with mechanical lesions, and morphometric analyses. Our results indicate that a subpopulation of non-olivocochlear neurons projects directly and bilaterally to CRNs via the trapezoid body. We also performed a gene expression analysis of muscarinic and nicotinic receptors which indicates that CRNs contain a cholinergic receptor profile sufficient to mediate the modulation of CRN responses. Consequently, we investigated the effects of auditory prepulses on the neuronal activity of CRNs using extracellular recordings in vivo. Our results show that CRN responses are strongly inhibited by auditory prepulses. Unlike other neurons of the cochlear nucleus, the CRNs exhibited inhibition that depended on parameters of the auditory prepulse such as intensity and interstimulus interval, showing their strongest inhibition at short interstimulus intervals. In sum, our study supports the idea that CRNs are involved in the auditory prepulse inhibition of the acoustic startle reflex, and confirms the existence of multiple cholinergic pathways that modulate the primary acoustic startle circuit. © 2013 Springer-Verlag Berlin Heidelberg.

Committee report: Guidelines for human startle eyeblink electromyographic studies

The human startle response is a sensitive, noninvasive measure of central nervous system activity that is Currently used in a wide variety of research and clinical settings. In this article, we raise methodological issues and present recommendations for optimal methods of startle blink electromyographic (EMG) response elicitation, recording, quantification, and reporting. It is hoped that this report Will foster more methodological validity and reliability in research using the startle response, Lis well Lis increase the detail with which relevant methodology is reported in publications using this measure.

Effects of reflex stimulus intensity and stimulus onset asynchrony on prepulse inhibition and perceived intensity of the blink-eliciting stimulus

Prepulse inhibition of the blink reflex is widely applied to investigate information processing deficits in schizophrenia and other psychiatric patient groups. The present experiment investigated the hypothesis that prepulse inhibition reflects a transient process that protects preattentive processing of the prepulse. Participants were presented with pairs of blinkeliciting noises, some preceded by a prepulse at a variable stimulus onset asynchrony (SOA), and were asked to rate the intensity of the second noise relative to the first. Inhibition of blink amplitude was greater for a 110-dB (A) noise than for a 95-dB(A) noise with a 120-ms SOA, whereas there was no difference with a 30-ms SOA. The perceived intensity was also lower for the 110-dB(A) noise than for the 95-dB(A) noise with the 120-ms SOA, but not with the 30-ms SOA. The parallel results support a relationship between prepulse inhibition of response amplitude and perceived intensity. However, the prepulse did not reduce intensity ratings relative to control trials in some conditions, suggesting that prepulse inhibition is not always associated with an attenuation of the perceived impact of the blink-eliciting stimulus.