The functional relationship between visual backward masking and prepulse inhibition.

Disrupted sensory gating in pathological gambling

Cochlear root neurons (CRNs) provide short-latency acoustic inputs to the caudal pontine reticular nucleus that elicit an acoustic startle reflex (ASR). Auditory prepulse inhibition (PPI) of the acoustic startle response is the reduction in ASR magnitude that is observed when a strong acoustic startling stimulus (pulse) is shortly preceded by a weak sound (prepulse). It has been suggested that a short descending auditory pathway conveys auditory prepulses to the level of the CRNs to mediate the inhibition of ASR. However, no electrophysiological data is available to confirm such inhibition. We here investigated the effects of auditory prepulses on the neuronal activity of CRNs using extracellular recordings in vivo from single CRNs. Our results show that CRN responses are strongly inhibited by auditory prepulses. As occurs in the behavioral paradigm, the inhibition of the CRN responses depended on parameters of the auditory prepulse, such as intensity and interstimulus interval, showing their strongest inhibition at high intensity level and short interstimulus intervals. Furthermore, we tested the auditory PPI on the activity of different neuron types in the ventral cochlear nucleus. Of all neuron types tested, only CRNs exhibited a strong attenuation of activity. Our results corroborate our previous hypothesis that CRNs might be involved in the neural circuit of the inhibition of the ASR and suggest that several neuronal pathways participate in that circuit.

FC19-06 - Visual backward masking - an excellent endophenotype for Schizophrenia ?

The joint effect of forward and backward visual masking appears to be more extended in time than that predicted from an algebraic summation of individual forward and backward masking effects. It is suggested that this apparent extension of the temporal range of masking arises from the summation of forward and backward masking effects which in themselves are insufficient to influence observed performance. Such latent masking effects are possible if it is not assumed that when stimulus identification reaches the 100% level the mask has no effect at all on the stimulus.

Auditory filtering disturbances, as measured in the sensory gating and prepulse inhibition (PPI) paradigms, have been linked to aberrant auditory information processing and sensory overload in schizophrenic patients. In both paradigms, the response to the second stimulus (S2) is attenuated by an inhibitory effect of the first stimulus (S1). Dopamine (DA) agonists have been found to reduce gating of auditory evoked potentials (AEPs) and PPI in healthy human subjects and in rats. These effects have been linked to DA hyperactivity in the mesolimbic system. A non-invasive approach in studying the role of the DA system in PPI and AEP gating is to compare rat genotypes that are marked by distinct DA systems. Several questions were asked in the present study. Are PPI and AEP gating disturbed in (a) rats that are marked by a relatively high DA reactivity of the mesolimbic system, namely apomorphine-susceptible (APO-SUS) and WAG/Rij rats or in (b) rats that are marked by a relatively high DA activity of the nigrostriatal system, namely apomorphine-unsusceptible (APO-UNSUS) and ACI rats? Moreover, is the particular DA balance (c) between the nigrostriatal and mesolimbic system related to deficits in PPI and AEP gating? For this purpose, the above-mentioned four rat genotypes (APO-SUS, APO-UNSUS, ACI and WAG/Rij) that vary in DA balance between both systems, were compared in the AEP gating paradigm. PPI was only measured in the ACI and WAG/Rij rats, since it has already been shown in a previous study that APO-SUS rats show diminished PPI as compared to rats of the APO-UNSUS genotype. AEP gating of the vertex N50 was significantly reduced in WAG/Rij rats as compared to the remaining three rat genotypes (APO-SUS, APO-UNSUS and ACI). No PPI deficits were found in the ACI and WAG/Rij rats, although ACI rats had a significantly higher basal startle amplitude. The PPI deficit in APO-SUS and not in the other genotypes, suggests that especially a relatively high DA reactivity of the mesolimbic system, together with a relatively low activity of the nigrostriatal system, contributes to this deficit. In contrast, the N50 gating deficit in WAG/Rij rats and not in the other genotypes suggests that a relatively high DA activity of the nigrostriatal system together with a relatively high DA reactivity of the mesolimbic system is necessary for the presence of a N50 gating deficit. On the basis of these results we have concluded that both auditory filtering processes are differently regulated by DA in the nigrostriatal and mesolimbic systems.

Background: At least 14% of Parkinson disease (PD) patients develop impulse control disorders (ICDs). The pathophysiology behind these behaviors and the impact of deep brain stimulation in a real-life setting remain unclear. Objectives: We prospectively examined the impact of bilateral subthalamic nucleus deep brain stimulation (STN-DBS) on ICDs in PD patients, as well as the relationship between impaired sensorimotor gaiting and impulsivity. Methods: Patients undergoing bilateral STN-DBS were assessed for ICDs preoperatively and 1-year postoperatively using a validated questionnaire (QUIP-RS). A subset of patients completed the Balloon Analogue Risk Task (BART) and auditory prepulse inhibition (PPI) testing. Results: Analysis revealed 12 patients had an improvement in score assessing ICDs (‘good responders'; p = 0.006) while 4 had a worse or stable score (‘poor responders'; p > 0.05). Good responders further exemplified a significant decrease in hypersexual behavior (p = 0.005) and binge eating (p = 0.01). Impaired PPI responses also significantly correlated with impulsivity in BART (r = -0.72, p = 0.044). Discussion: Following bilateral STN-DBS, 75% of our cohort had a reduction in ICDs, thus suggesting deep brain stimulation effectively manages ICDs in PD. The role of impaired PPI in predisposition to ICDs in PD warrants further investigation.

Backward masking in bipolar affective disorder

The identification of a briefly presented test stimulus is impaired when the test stimulus is followed by a masking stimulus consisting of random contours. Two theories have been proposed to account for this effect (backward masking by visual noise). According to interruption theory, the time which is available for test stimulus processing is limited by the onset of the masking stimulus. According to integration theory, test stimulus and masking stimulus are combined in a single percept where the test stimulus is degraded by the contours of the masking stimulus. A review of the methods used to decide between the two theories permits the conclusion that backward masking by visual noise requires a two-factor theory: integration for “short” (less than about 100 msec) and interruption for “long” test stimulus-masking stimulus asynchronies. It is shown that evidence for interruption can only be obtained when processing load is used as a converging operation. Finally, some approaches to the measurement of processing rate under backward masking are discussed.

Long-term neurological complications, termed sequelae, can result from viral encephalitis, which are not well understood. In human survivors, alphavirus encephalitis can cause severe neurobehavioral changes, in the most extreme cases, a schizophrenic-like syndrome. In the present study, we aimed to adapt an animal model of alphavirus infection survival to study the development of these long-term neurological complications. Upon low-dose infection of wild-type C57B/6 mice, asymptomatic and symptomatic groups were established and compared to mock-infected mice to measure general health and baseline neurological function, including the acoustic startle response and prepulse inhibition paradigm. Prepulse inhibition is a robust operational measure of sensorimotor gating, a fundamental form of information processing. Deficits in prepulse inhibition manifest as the inability to filter out extraneous sensory stimuli. Sensory gating is disrupted in schizophrenia and other mental disorders, as well as neurodegenerative diseases. Symptomatic mice developed deficits in prepulse inhibition that lasted through 6 months post infection; these deficits were absent in asymptomatic or mock-infected groups. Accompanying prepulse inhibition deficits, symptomatic animals exhibited thalamus damage as visualized with H&E staining, as well as increased GFAP expression in the posterior complex of the thalamus and dentate gyrus of the hippocampus. These histological changes and increased GFAP expression were absent in the asymptomatic and mock-infected animals, indicating that glial scarring could have contributed to the prepulse inhibition phenotype observed in the symptomatic animals. This model provides a tool to test mechanisms of and treatments for the neurological sequelae of viral encephalitis and begins to delineate potential explanations for the development of such sequelae post infection.

BackgroundThough cognitive remediation has shown modest benefits for schizophrenia, relatively few training programs for have targeted the visual processing deficits common in the illness. Residual visual processing deficits following cognitive remediation may explain why cognitive remediation has had limited effects on visual learning and memory compared to auditory learning and memory. We sought to test whether training early visual processing would improve visual memory and facial affect recognition by targeting a well-characterized visual deficit in schizophrenia: visual backward masking (VBM). The deficit is so common in schizophrenia, and in non-affected family members to a lesser degree, that it is viewed as an endophenotype. The VBM deficit, however, can normalize as we have previously shown. In our prior open-label pilot study, individuals with schizophrenia (Surti and Wexler, 2012) made substantial gains in VBM performance with rudimentary computerized VBM training. The VBM improvements were also accompanied by improvements in visual memory.To test the hypothesis that improved early sensory training could lead to other cognitive gains in the same domain, we conducted a randomized control study with a new, more sophisticated computerized VBM training program, and compared it to an active control condition. We expected that visual memory and facial affect recognition would improve with the novel visual training (VT), and that VBM would improve with the VT as well.Methods23 individuals with stable schizophrenia or schizoaffective disorder were randomized to receive 20 sessions of VT or an active control. The VT consisted of VBM training with multiple levels of difficulty, adaptive tracking, virtual rewards, and a variety of letters, numbers, and shapes to train different areas of the visual field. The active control condition was a commercially available computerized typing tutorial (TT) with animation, game narrative, and multiple typing activities. Participants were tested before and after training with: the Matrics Cognitive Consensus Battery (MCCB), including the Brief Visuospatial Memory Test-Revised (BVMT) as the study’s primary outcome; the Profile of Nonverbal Sensitivity (mini-PONS) to assess non-verbal social cues; standardized VBM tests; and typing assessments. Repeated measure ANOVAs were conducted in SPSS24 after checking for normality.Results22 of 23 individuals completed the study, and by participants’ reports, both interventions were well tolerated, equally enjoyable and equally motivating, though the VT was slightly more frustrating for participants. Even when co-varying for education, which was higher in the VT group, there were no condition by time interactions for the BVMT, the mini-PONS, overall MCCB, or typing ability. There was a significant condition by time interactions for VBM performance (F = 5.8, p =0.028), with a substantial improvement in the VT group (Cohen’s d = 0.54; p=0.004).DiscussionPatients with schizophrenia equally tolerated a computerized visual training designed in-house and an off-the shelf highly gamified control training, but only the visual training, specifically designed for individuals with schizophrenia, had effects on the trained task. The effects of the visual training did not generalize to visual memory, facial affect recognition, or global cognition, so further work is needed to facilitate generalization.

Deficits in prepulse inhibition may be a common feature in first-episode schizophrenia, bipolar disorder (BD) and major depressive disorder (MDD). We sought to explore the levels and viability of prepulse inhibition to differentiate first-episode schizophrenia, BD and MDD in patient populations. We tested patients with first-episode schizophrenia, BD or MDD and healthy controls using prepulse inhibition paradigms, namely perceived spatial co-location (PSC-PPI) and perceived spatial separation (PSS-PPI). We included 53 patients with first-episode schizophrenia, 30 with BD and 25 with MDD, as well as 82 healthy controls. The PSS-PPI indicated that the levels of prepulse inhibition were smallest to largest, respectively, in the first-episode schizophrenia, BD, MDD and control groups. Relative to the healthy controls, the prepulse inhibition deficits in the first-episode schizophrenia group were significant (p < 0.001), but the prepulse inhibitions were similar between patients with BD and healthy controls, and between patients with MDD and healthy controls. The receiver operating characteristic curve analysis showed that PSS-PPI (area under the curve [AUC] 0.73, p < 0.001) and latency (AUC 0.72, p < 0.001) were significant for differentiating patients with first-episode schizophrenia or BD from healthy controls. The demographics of the 4 groups were not ideally matched. We did not perform cognitive assessments. The possible confounding effect of medications on prepulse inhibition could not be eliminated. The level of prepulse inhibition among patients with first-episode schizophrenia was the lowest, with levels among patients with BD, patients with MDD and healthy controls increasingly higher. The PSS-PPI paradigm was more effective than PSC-PPI to recognize deficits in prepulse inhibition. These results provide a basis for further research on biological indicators that can assist differential diagnoses in psychosis.

Attenuation of auditory startle and prepulse inhibition by unexpected changes in ambient illumination through dopaminergic mechanisms

Prepulse inhibition (PPI) of the startle response in mice is increasingly used as a paradigm of sensory gating with potential predictive and construct validity towards schizophrenia. Establishment of a mouse PPI paradigm in which typical and atypical antipsychotic drugs directly improve a low performance PPI. Three strains of mice--C57Bl/6J, 129S6/SvEvTac and DBA/2J--were tested in a startle paradigm with three prepulse intensities, 2, 4 and 8 dB above background. Under these conditions, risperidone (0, 0.25, 0.5 and 1 mg/kg i.p.) and clozapine (0, 1, 3 and 9 mg/kg i.p.) improved PPI in all three strains, with order of effect in DBA/2J > 129S6SvEvTac > C57Bl/6J. The DBA/2J strain showed larger PPI-enhancing effects, without disturbing the basal startle response. Two alpha7 nicotinic receptor agonists, GTS-21 (1-10 mg/kg i.p.) and AR-R17779 (1-10 mg/kg i.p.) were inactive in the PPI procedure in DBA/2J mice. DBA/2J mice were very sensitive to the antipsychotic-like effects of atypical (clozapine) and typical (risperidone) antipsychotics, and this strain is proposed as a model to directly measure sensory gating properties of drugs. Alpha7 Nicotinergic receptor agonists were ineffective in this PPI paradigm.

Prepulse inhibition (PPI), an operational measure of sensorimotor gating, is deficient in schizophrenia patients. PPI was compared among 4 strains of rats: Sprague-Dawley, Spontaneously Hypertensive, Wistar Kyoto (WKY), and Brown Norway (BN). PPI was dramatically lower in BN versus the other strains, especially WKY, for both acoustic and airpuff startle stimuli, whereas startle amplitude was similar between BN and WKY. Female BN also had lower PPI than did female WKY. Response to increasing prepulse intensities showed a right shift in the BN relative to the WKY. Visual prepulses also showed deficiencies in BN versus WKY. The absence of background noise did not negate strain differences. Auditory brainstem response to clicks and tone pips revealed no differences in auditory threshold between the 2 strains. These results are the first to demonstrate that BN have impaired sensorimotor gating compared with WKY, without impaired acoustic acuity.

Deficits in information processing appear to be core features in the pathogenesis of schizophrenia. Prepulse inhibition (PPI) and habituation of the startle reflex are operational measures of early information processing. Impaired PPI in schizophrenia has been replicated in many studies and is regarded as an endophenotype for schizophrenia. However, reports on the stability of PPI over a longer period of time are lacking, both for patients with schizophrenia and for healthy subjects. The current study examined 25 initially drug-naive, first-episode schizophrenia patients and 23 healthy matched controls. Three PPI measures [stimulus onset asynchrony (SOA) 30, 60, 120 ms] and habituation were assessed at baseline, and again after 6 yr. Sixteen patients and 17 healthy controls completed the study, and 13 patients and 17 healthy controls were included in the final analysis. The schizophrenia patients had PPI deficits compared to controls at baseline. After 6 yr, no significant group differences were found. PPI had increased significantly in the patients and had decreased significantly in controls. In addition, patients showed significantly less habituation than controls while habituation did not change in patients or controls. The present results show that PPI in drug-naive, first-episode schizophrenia patients can improve significantly over time. As PPI increased in patients over the same period that it decreased in controls, it is likely that the increase was caused by disease-related factors such as disease process, clinical state, or medication.