Prepulse Intensity Research Articles

Impaired Sensorimotor Gating in Unmedicated Adults with Obsessive–Compulsive Disorder

Functional and structural imaging studies suggest that obsessive-compulsive disorder (OCD) symptoms arise from dysfunction in cortico-striato-thalamo-cortical circuits. It has therefore been hypothesized that neurophysiological tasks subserved by these circuits should be abnormal in OCD patients. One neurocognitive probe associated with this circuitry is prepulse inhibition (PPI) of the acoustic startle response. PPI deficits are thought to reflect abnormalities in processing and integration of sensory and motor information. Two prior studies found that OCD patients had PPI deficits at single prepulse (PP) intensities. However, most patients in these studies were taking psychotropic medications at the time of PPI testing, and preclinical studies have demonstrated effects of psychotropic medications on PPI. We examined PPI in 22 unmedicated OCD patients and 22 matched healthy controls at three different PP intensities (74, 78, and 86 dB). OCD patients had significantly less PPI across all three PP intensities compared with controls. Exploratory analyses indicated that OCD patients with a history of tics had lower levels of PPI. Our results demonstrate that unmedicated OCD patients have impaired sensorimotor gating as measured by PPI. This indicates that PPI deficits are present in OCD patients and are not the result of medication effects. Our findings also suggest that OCD patients with a history of tics may have greater impairment in sensorimotor gating than the general OCD population. Future studies should be designed to examine whether PPI deficits characterize tic-related OCD.

Soft-X-ray lasing in nickel-like barium at 9.2 nm using the grazing-incidence scheme

We report on the experimental demonstration of saturated X-ray lasing on the 4d→4p, J=0–1 line of nickel-like barium (Ba, Z=56) at a wavelength of 9.2nm, using a main pulse energy of 9J in a 1.5-ps duration pulse from a Nd:glass chirped-pulse amplification laser. Gain saturation was achieved by applying a triple-pulse scheme in which a weak (few-percent) prepulse, preceding the main pulse by 2.4ns, is followed by a second, relatively intense (16%) prepulse ~50ps before the main pulse. For handling convenience, compound targets of BaF2 were used, either in the form of windows or coated onto glass slides.

X-ray source generation under laser-Ar cluster interaction

BrightK-shell X-ray emissions are generated through the interaction between intense femtosecond laser pulses and Ar clusters. The total yield ofK-shell X-ray photons reaches 1 1011 photons/shot with a conversion efficiency of 2.8 10-5 in 4. When Ar clusters are irradiated by a laser pulse with intense prepulse, the yield ofK-shell X-ray photos will decrease due to prepulse ionization. Keeping high-density plasmas interacting with the main pulse is essential for obtaining the highest X-ray yield.

Independent genetic loci for sensorimotor gating and attentional performance in BXD recombinant inbred strains

A startle reflex in response to an intense acoustic stimulus is inhibited when a barely detectable pulse precedes the startle stimulus by 30-500 ms. It has been theorized that this phenomenon, named prepulse inhibition (PPI) of a startle response, is an automatic early-stage gating process contributing to the ability to focus attention. Deficits in PPI may therefore contribute to deficits in attentional processing. Both deficits are observed in schizophrenia spectrum disorders. Here, we investigated whether there is overlap in genetic control of PPI and attentional processing phenotypes in the panel of BXD recombinant inbred strains of mice. Using an individually titrated prepulse intensity to handle differences in perceived prepulse intensities among strains, we identified a significant quantitative trait locus (QTL) for PPI at the mid-distal end of chromosome 17. A measure of attentional processing in the five-choice serial reaction time task, response variability, mapped to a different locus on proximal-mid chromosome 16. In addition, the estimated genetic and environmental correlations between PPI and several attentional phenotypes were low and not significant. Taken together, the observation of separate genetic loci for PPI and attention and the absence of genetic and environmental correlations indicate that differences in sensorimotor gating do not contribute to differences in attentional performance. Therefore, it is worth pursuing the causative genes residing in both attention and PPI QTL, as these may contribute to separate molecular pathways implicated in neuropsychiatric diseases, such as schizophrenia.

Allopregnanolone infused into the dorsal (CA1) hippocampus increases prepulse inhibition of startle response in Wistar rats

The hippocampus is a brain structure that has traditionally been associated with the pathophysiology and neuropathology of schizophrenia. Also, one of the animal models of schizophrenia most widely accepted and validated is the deterioration of prepulse inhibition (PPI). The hippocampus (both dorsal and ventral) seems to be a brain structure important for the PPI since it appears to contribute to sensorimotor gating. A possible role of neurosteroids in schizophrenia has recently been suggested, as clozapine and olanzapine treatments increase brain and plasma levels of the neurosteroid allopregnanolone (AlloP). The aim of the present work is to investigate the effects of the intrahippocampal administration of neurosteroids on prepulse inhibition. For this purpose, we have bilaterally injected AlloP (0.2 μg/0.5 μl) and pregnenolone sulphate (PregS, 5 ng/0.5 μl) into the dorsal CA1 hippocampus, and we have evaluated PPI behavior. Results show that intrahippocampal AlloP increases PPI ability regardless of prepulse intensity (5, 10 or 15 db above background). Intrahippocampal PregS administration, at the dose tested, does not significantly affect PPI performance. The increase in PPI due to intrahippocampal AlloP administration points out the important role of the hippocampus in central sensorimotor gating mechanisms and on the effects of neurosteroids on this behavior. The present findings may contribute to the study of the neurobiological basis of schizophrenia.

Guidance of a Laser Beam Through an Axially Non-Uniform Plasma Channel in the Weakly Relativistic Limit

The guiding of a laser beam in a plasma channel formed by a short ionizing pulse is investigated in the weakly relativistic limit. The plasma channel formed is axially non-uniform due to self defocusing of the prepulse. When a second delayed laser pulse propagates through the plasma channel formed by the prepulse, the competition between refraction and diffraction results into alternate convergence and divergence of the guided beam. Second-order nonlinear differential equations for the beam width parameter of the prepulse and guided pulse are derived by moment theory approach. The effect of the guided pulse and prepulse intensities on the propagation of the guided laser pulse through the plasma channel formed by the prepulse is studied. Laser guidance up to several Rayleigh lengths is observed.

Hippocampal serotonin depletion facilitates the enhancement of prepulse inhibition by risperidone: Possible role of 5-HT2C receptors in the dorsal hippocampus

Abnormalities in both the hippocampal region and in serotonergic transmission are evident in patients with schizophrenia. We previously found that rats with serotonergic lesions targeting the dorsal hippocampus show altered psychotropic drug-induced hyperlocomotion and prepulse inhibition (PPI), behavioural paradigms relevant to aspects of schizophrenia. The present study explored the effect of serotonin depletion (>70%) along the dorsoventral axis of the hippocampus, or of partial serotonin depletion (∼50%) in the ventral hippocampus, on PPI modulation by acute antipsychotic drug treatment. We also used receptor binding autoradiography to investigate the neurochemical basis of behavioural effects. Following micro-injection of 5,7-dihydroxytryptamine, neither hippocampal serotonin depletion or partial serotonin depletion in the ventral hippocampus altered baseline PPI, startle magnitude or startle habituation. Acute treatment with clozapine or haloperidol had minimal effects on PPI in these lesioned rats or sham-operated controls. In contrast, risperidone treatment increased PPI to a significantly greater extent in rats with hippocampal serotonin depletion, an effect which was most prominent at low prepulse intensities. Partial serotonin depletion in the ventral hippocampus did not alter PPI modulation by risperidone. Neither type of serotonergic lesion altered the densities of 5-HT1A or 5-HT2A receptors in the hippocampus; serotonin transporters or 5-HT1A autoreceptors on raphe cell bodies; or dopamine transporters, D1 or D2 receptors in forebrain regions efferent to the hippocampus and implicated in schizophrenia, such as the nucleus accumbens. However, levels of [3H]mesulergine binding to 5-HT2C receptors were increased by approximately 70% in the dorsal hippocampus of rats with serotonin depletion in this region, while those in the ventral hippocampus were unaffected. Therefore, despite intact baseline PPI, abnormal PPI regulation in rats with >70% serotonin depletion in the hippocampus was unmasked by acute risperidone treatment. Selective upregulation of 5-HT2C receptors in the dorsal, but not ventral, hippocampus of these lesioned rats suggests that hippocampal 5-HT2C receptors vary in their adaptability to changes in serotonergic tone along the dorsoventral axis. These findings suggest that 5-HT2C receptors in the dorsal hippocampus may contribute to risperidone-induced enhancement of PPI.This article is part of a Special Issue entitled ‘Serotonin’.

Dysfunctional play and dopamine physiology in the Fischer 344 rat

Juvenile Fischer 344 rats are known to be less playful than other inbred strains, although the neurobiological substrate(s) responsible for this phenotype is uncertain. In the present study, Fischer 344 rats were compared to the commonly used outbred Sprague-Dawley strain on several behavioral and physiological parameters in order to ascertain whether the lack of play may be related to compromised activity of brain dopamine (DA) systems. As expected, Fischer 344 rats were far less playful than Sprague-Dawley rats, with Fischer 344 rats less likely to initiate playful contacts with a playful partner and less likely to respond playfully to these contacts. We also found that Fischer 344 rats showed less of a startle response and greater pre-pulse inhibition (PPI), especially at higher pre-pulse intensities. The increase in PPI seen in the Fischer 344 rat could be due to reduced DA modulation of sensorimotor gating and neurochemical measures were consistent with Fischer 344 rats releasing less DA than Sprague-Dawley rats. Fast scan cyclic voltammetry (FSCV) revealed Fischer 344 rats had less evoked DA release in dorsal and ventral striatal brain slices and high-performance liquid chromatography revealed Fischer 344 rats to have less DA turnover in the striatum and prefrontal cortex. We also found DA-dependent forms of cortical plasticity were deficient in the striatum and prefrontal cortex of the Fischer 344 rat. Taken together, these data indicate that deficits in play and enhanced PPI of Fischer 344 rats may be due to reduced DA modulation of corticostriatal and mesolimbic/mesocortical circuits critical to the execution of these behaviors.

Lesions of the dorsomedial striatum disrupt prepulse inhibition

Prepulse inhibition (PPI) of startle is an experimentally tractable measure of sensorimotor gating that can be readily evaluated in mice, rats, monkeys, and humans. PPI is the inhibitory effect of a low-intensity stimulus, the prepulse, on the startle response to a subsequent high-intensity stimulus. PPI has garnered great interest as a marker of clinically relevant information processing abnormalities, because it is impaired in such neuropsychiatric conditions as schizophrenia, Tourette syndrome, and obsessive compulsive disorder (OCD). Pathology of the basal ganglia has been described in all three of these disorders, and it is therefore of great interest to determine the role of the basal ganglia in PPI. Previous work in rats described a PPI deficit after excitotoxic ventral striatal lesions and a more subtle attenuation after caudodorsal lesion, but no effect of other large lateral dorsal lesions. However, previous studies have not specifically investigated the role of the dorsomedial striatum in PPI. We investigated this issue using excitotoxic lesions in mice. We describe a marked reduction in PPI, at a variety of prepulse intensities, after bilateral lesions of dorsomedial striatum. There was no effect of lesion on baseline startle or habituation. In contrast, comparably sized lesions of the central dorsal striatum had no effect on PPI. These results reveal a role for the dorsomedial striatum in prepulse inhibition, which may have relevance for the abnormalities observed in this region in such disorders as Tourette syndrome and OCD.

Noise exposure during early development influences the acoustic startle reflex in adult rats

Noise exposure during the critical period of postnatal development in rats results in anomalous processing of acoustic stimuli in the adult auditory system. In the present study, the behavioral consequences of an acute acoustic trauma in the critical period are assessed in adult rats using the acoustic startle reflex (ASR) and prepulse inhibition (PPI) of ASR. Rat pups (strain Long-Evans) were exposed to broad-band noise of 125 dB SPL for 8 min on postnatal day 14; at the age of 3-5 months, ASR and PPI of ASR were examined and compared with those obtained in age-matched controls. In addition, hearing thresholds were measured in all animals by means of auditory brainstem responses. The results show that although the hearing thresholds in both groups of animals were not different, a reduced strength of the startle reflex was observed in exposed rats compared with controls. The efficacy of PPI in exposed and control rats was also markedly different. In contrast to control rats, in which an increase in prepulse intensity was accompanied by a consistent increase in the efficacy of PPI, the PPI function in the exposed animals was characterized by a steep increase in inhibitory efficacy at low prepulse intensities of 20-30 dB SPL. A further increase of prepulse intensity up to 60-70 dB SPL caused only a small and insignificant change of PPI. Our findings demonstrate that brief noise exposure in rat pups results in altered behavioral responses to sounds in adulthood, indicating anomalies in intensity coding and loudness perception.

Preplasma conditions for collisional Mo soft x-ray lasers with the grazing incidence pumping scheme

By comparing soft x-ray spectra from experiments with numerical calculation results, the preformed plasma medium was characterized for Mo 18.9nm x-ray lasers with the grazing incidence pumping scheme. The effects of prepulse intensities and durations on the charge state distributions as well as other parameters of preformed plasmas were investigated for previously demonstrated soft x-ray lasers. Experiments with small total energy were conducted to check the understanding of reasons why Mo 18.9nm soft x-ray lasers were realized on laser facility platforms with parameters varying so much.

Pharmacological characterizations of memantine-induced disruption of prepulse inhibition of the acoustic startle response in mice: Involvement of dopamine D2 and 5-HT2A receptors

It has recently been reported that psychotic symptoms in patients such as those with Parkinson's disease dementia (PDD) and Lewy body dementia (LBD) may worsen following treatment with memantine, a non-competitive NMDA receptor antagonist. Prepulse inhibition (PPI) of the acoustic startle response (ASR) is used as a measure for sensorimotor gating and it has been reported that PPI is disrupted by memantine. However, the mechanism of memantine-induced PPI disruption remains unclear. In the present study, we investigated the effects of memantine on PPI of the ASR in mice. Memantine (1.25–20mg/kg, intraperitoneally) increased the ASR and dose-dependently decreased PPI for all prepulse intensities tested. This effect of memantine on PPI was attenuated by pretreatment with the antipsychotics clozapine (3 and 6mg/kg), risperidone (0.3mg/kg) and haloperidol (0.5mg/kg), the selective D2 antagonist sulpiride (40mg/kg) and 5-HT2A/2C antagonist ketanserin (2 and 4mg/kg) but not with the selective D1 antagonist SCH23390 (0.05 and 0.1mg/kg). Clozapine (6mg/kg) and risperidone (0.3mg/kg) significantly attenuated the increased startle amplitude in the memantine-treated groups. These results suggest that involvement of dopaminergic and/or serotonergic neurotransmission may play a crucial role in memantine-induced PPI disruption, and additionally, indicate that blockade of either the D2 or 5-HT2A receptor may prevent disruption of PPI induced by memantine in mice. Conceivably, memantine may exacerbate psychotic symptoms in patients with PDD and LBD.

Orally active glutamate carboxypeptidase II inhibitor 2-MPPA attenuates dizocilpine-induced prepulse inhibition deficits in mice

Glutamate carboxypeptidase II (GCP II) is a glial enzyme responsible for the hydrolysis of N-acetylaspartylglutamate (NAAG) into glutamate and N-acetylaspartate (NAA). Abnormalities in glutamate neurotransmission are implicated in the pathophysiology of schizophrenia. In this study, we examined the effects of a novel, orally active GCP II inhibitor, 2-(3-mercaptopropyl)pentanedioic acid (2-MPPA), on the prepulse inhibition (PPI) deficits after administration of the N-methyl-d-aspartate (NMDA) receptor antagonist dizocilpine. Oral administration of 2-MPPA (10, 30 or 100mg/kg) significantly attenuated dizocilpine (0.1mg/kg)-induced PPI deficits in mice, in a dose dependent manner. Furthermore, the efficacy of 2-MPPA on dizocilpine-induced PPI deficits was significantly antagonized by pretreatment with the selective group II metabotropic glutamate receptor (mGluR) antagonist LY341495 (1.0mg/kg). In the same model, however, the selective group II mGluR agonist LY354740 (3, 10 or 30mg/kg) significantly attenuated dizocilpine-induced PPI deficits at only one dose and prepulse intensity. Our findings suggest that GCP II inhibition may be useful therapeutic strategy for schizophrenia. From a mechanistic perspective, while increased NAAG and activation of group II mGluRs may contribute to the therapeutic efficacy of 2-MPPA, it is likely that additional pharmacological activities are also involved.

Effects of laser prepulse on proton generation

Prepulse is a major issue for laser generation of protons, often limiting the performances of laser sources. Here, we show the use of prepulse (<1013 W/cm2, ns duration) to actively manipulate the proton beam direction. Under oblique high-intensity irradiation (≈1019 W/cm2, ps duration) of the thin foil target, and for low prepulse intensities, the proton beam is directed away from the “unperturbed” target normal. Observations are discussed in terms of target normal sheath acceleration, in combination with a laser-controllable shock locally deforming the target surface.

Acoustic startle and disruption of prepulse inhibition by dizocilpine in selectively bred mice.

In this study we examined the relationship between genetically produced differences in the magnitude of prepulse inhibition (PPI) of the acoustic startle response (ASR) and stress induced swim analgesia in genetically different strains of mice. Prepulse inhibition of the ASR and its changes due to dizocilpine (MK-801) injection were studied in 180 mice. The animals used in this study were obtained from our colony of 54 generation, Swiss-Webster mice selectively bred for high and low magnitude of analgesia. Three month old male mice of the high analgesia (HA) and the low analgesia (LA) lines, in addition to randomly bred controls (C) were used in the experiment. Thirty minutes before the ASR session the mice were injected intraperitoneally with saline or with 0.15, 0.25, 0.5 mg÷kg of dizocilpine maleate. Prepulses suppressed the acoustic startle response in all lines in a prepulse intensity-dependent manner, but only the differences between the weakest and the strongest prepulses appeared significant. Two-way ANCOVA performed separately for each line revealed a significant effect of dizocilpine and prepulse intensity. Only in the HA line, however, the disruption of PPI from the injection of dizocilpine was evidenced by significant treatment by prepulse interaction. That means the prepulses decreased ASR significantly less in dizocilpine- treated animals than in saline-treated animals. The results confirmed that the mouse lines manifesting differential ASR magnitudes along with different degrees of PPI sensitivity to dizocilpine, might be suitable for pharmacogenetic studies on the glutaminergic mechanism of the startle response.

PPI deficit induced by amphetamine is attenuated by the histamine H1 antagonist pyrilamine, but is exacerbated by the serotonin 5-HT2 antagonist ketanserin

Prepulse inhibition (PPI) of the startle response is a classic model of sensorimotor gating. Robust PPI impairments can be induced by dopamine agonists such as the indirect agonist amphetamine. The antipsychotic clozapine can attenuate PPI impairment induced by dopamine agonists. Clozapine is a complex drug with antagonistic effects on a variety of receptors, including serotonin and histamine. The relative contribution of its component actions to its efficacy is still unclear. To better characterize the role of histamine and serotonin receptors in the modulation of PPI in rats, we studied the effects of the H(1) histamine antagonist pyrilamine (10, 20, and 40 mg/kg) on amphetamine-induced (1 mg/kg) PPI deficits (Experiment 1); and the interaction of pyrilamine (20 mg/kg) with the 5-HT(2) antagonist ketanserin (1 and 2 mg/kg) on the amphetamine-induced PPI disruption (Experiment 2). Tactile startle stimuli consisted of 30 PSI air-puffs. Three acoustic prepulse intensity levels were used: 68, 71, and 77 dB, presented on a 65-dB background noise. In both experiments, all animals received all drug doses and combinations with different counterbalanced orders. Pyrilamine (20 mg/kg) was effective in counteracting the PPI impairment caused by amphetamine administration, whereas ketanserin exacerbated the amphetamine-induced PPI deficit. Based on its ability to reverse amphetamine-induced PPI deficits, blockade of histamine H(1) receptors seems to contribute to the therapeutic effect of the antipsychotic clozapine. Serotonin 5-HT(2)-receptor blockade, though, does not appear to contribute to this effect, and may in fact detract from it.

Effect of Femtosecond Prepulse with Threshold Intensity for Optical Field Ionization on Electron Acceleration and Propagation of Intense Laser Pulse in Plasma

The effect of a prepulse with femtosecond duration, which precedes an intense laser pulse by 4 ns, on electron acceleration and propagation of an intense laser pulse in a plasma is investigated using a helium gas jet. When the prepulse intensity exceeds 1015 W/cm2, which is close to the threshold intensity for optical field ionization of helium, the maximum energy and number of accelerated electrons are significantly reduced. In addition, the amplitude of the plasma wave is relatively small, and the propagation length of the laser pulse is short. These results suggest that the preformed plasma produced by the femtosecond prepulse affects the electron acceleration and laser propagation. To investigate the effects of a preformed plasma, two-dimensional particle-in-cell simulations are carried out. The simulation results support the experimental results.

Effects of preformed plasma of CH foam on fast electron generation

In fast ignition, the intensity of an unavoidable pre-pulse of a heating laser is still high to generate plasmas even if the contrast ratio is high. So, a preformed plasma (pre-plasma) is created before a main pulse of the heating laser irradiates a target. The recent research suggests that coating an inner surface of the cone of the cone-guided target with the low-density foam enhances fast electron generation. But the pre-plasma and the foam structure, which consists of dense CH plasmas and voids, are ignored in that research. In this paper, effects of the pre-plasma and the foam structure on the fast electron generation are investigated with the use of an one-dimensional Particle-In-Cell code. It is found that effects of the pre-plasma on the fast electron generation are small and the foam structure weakens the generation of fast electrons with the moderate energy.

Lamotrigine blocks the initiation and expression of repeated high-dose methamphetamine-induced prepulse inhibition deficit in rats

Our group developed a new psychostimulant animal model reflecting some clinical aspects of schizophrenia better than the conventional model does. In this model, long-lasting prepulse inhibition (PPI) deficit at the basement state is induced via repeated administration of methamphetamine (METH, 2.5 mg/kg) without challenge injection of this psychostimulant. This study elucidates the effects of lamotrigine (LTG, 30 mg/kg) on the initiation and expression of a steady-state PPI deficit induced by the repeated METH administration. We assessed the effect of coadministration of LTG and METH on the initiation of PPI deficit. The LTG was injected 120 min after each METH injection for 5 times on every alternate day and for an additional 5 times every day, amounting to a total of 10 times. After 11–13 days of the withdrawal period, we measured PPI using the SR-LAB system. Using other animals after 20 min of LTG injection, we subsequently examined the effect of a single injection of LTG on the expression of PPI deficit caused by the repeated METH administration. The LTG blocked the initiation of PPI deficit induced by the repeated METH administration at 68 dB of prepulse intensity, but had no effect on the startle amplitude. The LTG prevented the initiation and expression of neuroplastic PPI deficit detected at the baseline state without any METH challenge injection, which was induced by the repeated administration of this psychostimulant. Results suggest that LTG is useful for blocking progressive deterioration of neurocognitive function and recovering the neurocognitive deficit in schizophrenia.

Laser-produced plasma helium-like titanium Kα x-ray source and its application to Rayleigh-Taylor instability study

Several experiments are performed on the ShenGuang-II laser facility to investigate an x-ray source and test radiography concepts. X-ray lines emitted from laser-produced plasmas are the most practical means of generating these high intensity sources. By using a time-integrated space-resolved keV spectroscope and pinhole camera, potential helium-like titanium Kα x-ray backlighting (radiography) line source is studied as a function of laser wavelength, ratio of pre-pulse intensity to main pulse intensity, and laser intensity (from 7.25 to ∼11.3 × 1015 W/cm2). One-dimensional radiography using a grid consisting of 5 μm Au wires on 16 μm period and the pinhole-assisted point projection is tested. The measurements show that the size of the helium-like titanium Kα source from a simple foil target is larger than 100 μm, and relative x-ray line emission conversion efficiency ξx from the incident laser light energy to heliumlike titanium K-shell spectrum increases significantly with pre-pulse intensity increasing, increases rapidly with laser wavelength decreasing, and increases moderately with main laser intensity increasing. It is also found that a gold gird foils can reach an imaging resolution better than 5-μm featured with high contrast. It is further demonstrated that the pinhole-assisted point projection at such a level will be a novel two-dimensional imaging diagnostic technique for inertial confinement fusion experiments.