Sensory Gating Deficits In Schizophrenia Research Articles

LEDA-Localized-EEG Dynamics Analyzer: a MATLAB-Based Innovative Toolbox for Analysis of EEG Source Dynamics

Establishing conclusive cortical activity dynamics from neuroimages and high dimensional neuronal data post-processing, such as scalp-EEG/ERP or its localized source data, is always challenging. For addressing this, we introduce LEDA, localized-EEG dynamics analyzer, offering our novel techniques, namely (1)the localized source activity to duration (LSAD) ratio that elegantly combines voxel activation with temporal information enabling a spatiotemporal condition comparison, (2)cortical region’s activation-duration summary generation, (3)anatomical dominance calculator, and (4)voxel activations’ GIF animation extraction feature. They effectively explore and quantify physiological spatiotemporal dynamics and provide insights more intuitive than EEG/ERP biomarkers. To demonstrate, we chose to study sensory gating deficits in schizophrenia for which the P50 wave biomarker is widely discussed. EEG response (64 channels@1 kHz) to auditory paired-click paradigm from 9 patients and 9 controls was processed to ERP. Source localization was achieved by using sLORETA, a widely-used source reconstruction algorithm. LSAD ratio of patients significantly differed from that of controls for the auditory cortical regions (p value < 0.05). It revealed that inhibitory alpha activity pattern was prominent in parietal, temporal and occipital lobe for controls and not patients. Conversely, the frontal lobe, specifically the middle frontal gyrus, was temporally the most active analogously across all subjects. LEDA also extracted that swift alpha activity exists between 100 and 300 ms time period. These derived results match with existing fMRI studies, speak beyond P50 wave suppression biomarker and emphasize that our methods successfully uncovered meaningful brain mechanisms at high spatiotemporal resolution. They are provided as an open-source MATLAB based toolbox for applicability to other neuronal pathological investigations.

P50 inhibition defects with psychopathology and cognitive impairment in patients with first-episode drug naïve schizophrenia

BackgroundMany studies have announced that P50 inhibition defects represent sensory gating deficits in schizophrenia, but studies seldom have searched the correlation between P50 inhibition defects and the psychopathology or cognitive impairment of patients with first-episode, drug naïve (FEDN) of schizophrenia. In this study, we investigated the auditory sensory gating deficits in a large number of Han patients with FEDN schizophrenia and their correlation with clinical symptoms and cognitive impairment. MethodsA total of 130 patients with FEDN schizophrenia and 189 healthy controls were recruited in this study. Positive and Negative Syndrome Scale (PANSS) and its five-factor model were used to score the psychopathology of the patients, and P50 inhibition was recorded using the 64-channel electroencephalography (EEG) system. ResultsPatients exhibited significantly longer S1 and S2 latency, lower S1 and S2 amplitudes and lower P50 difference than healthy controls (all p < 0.05). Significant correlations existed between S1 latency and PANSS negative symptoms or cognitive factor, P50 ratio and general psychopathology, P50 ratio and PANSS total score, P50 difference and general psychopathology, and P50 difference and PANSS total score (all p < 0.05). Multiple regression analysis revealed that S1 latency, sex, age, and education were contributors to negative symptom score (all p < 0.05). S1 latency, S2 latency, sex, age, and smoking status were contributors to cognitive factor (all p < 0.05). ConclusionsOur results show that patients with FEDN schizophrenia have P50 inhibition defects, which may be related to their psychopathological symptoms and cognitive impairment.

Abnormal beta and gamma frequency neural oscillations mediate auditory sensory gating deficit in schizophrenia

BackgroundSensory gating is a process in which the brain's response to irrelevant and repetitive stimuli is inhibited. The sensory gating deficit in schizophrenia (SZ) is typically measured by the ratio or difference score of the P50 event-related potential (ERP) amplitudes in response to a paired click paradigm. While the P50 gating effect has usually been measured in relation to the peak amplitude of the S1 and S2 P50 ERPs, there is increasing evidence that inhibitory processes may be reflected by evoked or induced oscillatory activity during the inter-click interval in the beta (20–30 Hz) and gamma (30–50 Hz) frequency bands. We therefore examined the relationship between frequency specific activity in the inter-click interval with gating effects in the time and frequency domains. MethodPaired-auditory stimuli were presented to 131 participants with schizophrenia and 196 healthy controls (HC). P50 ERP amplitudes to S1 and S2as well as averaged- and single-trial beta (20–30 Hz) and gamma (30–50 Hz) frequency power during the inter-click interval were measured from the CZ electrode site. ResultsIn the time domain, P50 gating deficits were apparent in both ratio and difference scores. This effect was mainly due to smaller S1 amplitudes in the patient group. SZ patients exhibited less evoked beta and gamma power, particularly at the 0–100 ms time point, in response to S1. Early (0–100 ms) evoked beta and gamma responses were critical in determining the S1 amplitude and extent of P50 gating across the delay interval for both HC and SZ. ConclusionOur findings support a disruption in initial sensory registration in those with SZ, and do not support an active mechanism throughout the delay interval. The degree of response to S1 and early beta and gamma frequency oscillations in the delay interval provides information about the mechanisms supporting auditory sensory gating, and may provide a framework for studying the mechanisms that support sensory inhibition.

Consistency of abnormal sensory gating in first-admission and chronic schizophrenia across quantification methods.

The auditory P50/M50 ERP/event-related field is subject to sensory gating, with partial suppression of the amplitude of the second of two (S1 and S2) clicks presented 500 ms apart. Schizophrenia patients have less gating, although quantification methods and associated effect sizes vary across studies using first-admission and/or using chronic patients. The present study evaluated the impact of several methods of quantifying gating in first-admission (FA) and chronic (CHR) schizophrenia patients and in healthy controls (HC). Magnetoencephalogram was measured in 35 FA, 58 CHR, and 28 HC during a paired-click protocol. Sensory gating was quantified on sensor and source levels as a ratio (S2/S1) and as a S1-minus-S2 difference, with M50 amplitude scored relative to baseline and relative to M100 and to M40. Independent of quantification method, patients showed less sensory gating than HC, with medium-to-large effect sizes, without differences between FA and CHR. Results indicate that the frequently reported sensory gating deficit in schizophrenia is robust to variations in quantification methods and stage of disorder.

Testing a decades’ old assumption: Are individuals with lower sensory gating indeed more easily distracted?

The sensory gating deficits in schizophrenia have been theorized to associate with increased distractibility. We explore the potential associations between sensory and sensorimotor gating and subjective and objective indices of distraction in healthy subjects. Forty healthy males were assessed with the P50 suppression and pre-pulse inhibition of the startle reflex (PPI) paradigms. Additionally, a neurocognitive test battery was administered in a cross-over design: with/without auditory distraction. Significant effects of distraction were found in response inhibition, and verbal working memory and attention. Parameters from the PPI and P50 suppression paradigms were significantly associated with the distractor effects on strategy formation, cognitive inhibition and flexibility, visual short-term memory, and the level of subjective distraction. Subjectively reported distraction was significantly associated with verbal working memory and attention as well as executive and supervisory processes. Sensory and sensorimotor gating efficiency do not reflect the effect of distraction across executive and attention functions i.e. we did not observe a generalized distractor effect. Gating only related to the effect of distraction on strategy formation, cognitive inhibition and flexibility, as well as visual short term memory. Future studies should investigate if gating deficits affect the distractibility of the same specific cognitive functions in patients with schizophrenia.

Upregulation of adenosine A2A receptors induced by atypical antipsychotics and its correlation with sensory gating in schizophrenia patients

Sensory gating deficits have been found in patients with schizophrenia and their unaffected relatives. However, the underlying neurobiological mechanism of this deficit remains unclear. Pre-clinical studies have implicated adenosine in sensory gating deficits in schizophrenia. Therefore, the current study investigated a possible relationship between peripheral adenosine A2A receptor (ADORA2A) and sensory gating indices (P50 measures) in medication-free schizophrenia (n=31) and healthy (n=21) groups. The effects of six-week antipsychotic treatment were examined. At baseline, schizophrenia patients showed impaired sensory gating compared to healthy controls. However, there was no significant difference in ADORA2A gene expression among groups. In addition, ADORA2A expression was not correlated with sensory gating at any time point. Following treatment, we found a significant upregulation of ADORA2A expression. Intriguingly, we observed a significant positive association between ADORA2A upregulation and baseline P50 amplitudes in the schizophrenia group. A main finding of the current pilot study is the upregulation of ADORA2A expression following treatment with antipsychotics. In addition, this upregulation was predicted by baseline P50 amplitude, an observation that awaits replication in an expanded sample.

The moderating role of the dopamine transporter 1 gene on P50 sensory gating and its modulation by nicotine

Although schizophrenia has been considered primarily a disease of dopaminergic neurotransmission, the role of dopamine in auditory sensory gating deficits in this disorder and their amelioration by smoking/nicotine is unclear. Hypothesizing that individual differences in striatal dopamine levels may moderate auditory gating and its modulation by nicotine, this preliminary study used the mid-latency (P50) auditory event-related potential (ERP) to examine the single dose (6 mg) effects of nicotine (vs. placebo) gum on sensory gating in 24 healthy nonsmokers varying in the genetic expression of the dopamine transporter (DAT). Consistent with an inverted-U relationship between dopamine level and the drug effects, individuals carrying the 9R (lower gene expression) allele, which is related to greater striatal dopamine levels, tended to evidence increased baseline gating compared to 10R (higher gene expression) allele carriers and showed a reduction in gating with acute nicotine. The present results may help to understand the link between excessive smoking and sensory gating deficits in schizophrenia and to explain the potential functional implications of genetic disposition on nicotinic treatment in schizophrenia.

Differential sensory gating functions between smokers and non-smokers among drug-naive first episode schizophrenic patients

Although an acute effect of cigarette smoking and nicotine on sensory gating of schizophrenias has been investigated in published papers, the chronic effect of cigarette smoking on this phenomenon has not yet been reported. We report the effects of chronic cigarette smoking, without new acute exposure before testing, on sensory gating using the P50 auditory evoked potential in a group of drug-naive first episode schizophrenic smokers and healthy smokers. Sensory gating was evaluated using auditory P50 suppression elicited using the conditioning (S1)–testing (S2) paradigm. Fifty six male drug-naive first episode schizophrenic patients were compared to 41 healthy male controls. Patients were classified into subgroups of current smokers (n=18) and non-smokers (n=38) to explore the effects of smoking on sensory gating. All subjects did not smoke a cigarette for at least 1h prior to testing. Schizophrenic patients showed an increased S2 amplitude and a poorer sensory gating as measured by both S2/S1 ratio and S1–S2 difference of P50 amplitude, as compared to healthy controls. However, smokers showed an increased S1 amplitude and better sensory gating than did non-smokers both in schizophrenia patients and healthy controls. Our findings support a sensory gating deficit among first episode schizophrenic patients. However, it was less pronounced among schizophrenic patients who were current cigarette smokers, suggesting a positive effect of chronic cigarette smoking on ameliorating this sensory gating deficit in schizophrenia. Our findings of the present study present new evidence supporting the self-medication hypothesis of self-medication by cigarette smoking in schizophrenia to possibly ameliorate pre-existing functional deficits.

Increased hemodynamic response in the hippocampus, thalamus and prefrontal cortex during abnormal sensory gating in schizophrenia

Objective Deficits in sensory gating are a common feature of schizophrenia. Failure of inhibitory gating mechanisms, shown by poor suppression of evoked responses to repeated auditory stimuli, has been previously studied using EEG methods. These methods yield information about the temporal characteristics of sensory gating deficits, but do not identify brain regions involved in the process. Hence, the neuroanatomical substrates of poor sensory gating in schizophrenia remain largely unknown. This study used functional magnetic resonance imaging (fMRI) to investigate the functional neuroanatomy of sensory gating deficits in schizophrenia. Methods Twelve patients with schizophrenia and 12 healthy comparison subjects were scanned at 3 Tesla while performing a sensory gating task developed for fMRI. P50 EEG evoked potential recordings from a paired-stimulus conditioning-test paradigm were obtained from the same subjects. Results Compared to healthy comparison subjects, patients with schizophrenia exhibited greater activation in the hippocampus, thalamus, and dorsolateral prefrontal cortex (DLPFC) during the fMRI sensory gating task. No group difference was observed in the superior temporal gyrus. Schizophrenia subjects also showed decreased P50 suppression as measured with EEG. Hemodynamic response in the fMRI measure was positively correlated with test/conditioning ratios from the EEG sensory gating measure. Conclusions Poor sensory gating in schizophrenia is associated with dysfunction of an apparent network of brain regions, including the hippocampus, thalamus and DLPFC. Greater activation of these regions is consistent with evidence for diminished inhibitory function in schizophrenia.

Clozapine treatment reverses dizocilpine-induced deficits of pre-pulse inhibition of tactile startle response

Pre-pulse inhibition (PPI) is a phenomenon of neurobehavioral plasticity in which the motor response to a startling sensory stimulus is inhibited by a preceding sensory stimulus of a lower intensity. The current experiment used tactile startle rather than acoustic startle to determine the generality of PPI across sensory modalities. PPI is easily modeled in experimental animals and serves as a useful method for determining the neural bases for sensorimotor plasticity, which can be disturbed in sensory modulation disorders. In the current study, female Sprague–Dawley rats were tested for tactile startle PPI after an auditory pre-pulse. The glutamate NMDA receptor antagonist dizocilpine (MK-801, 0.05 mg/kg) caused a nearly total blockade of the PPI effect ( p < 0.0005). The antipsychotic drug clozapine (1.25 mg/kg, p < 0.001 and 2.5 mg/kg p < 0.05) significantly attenuated the dizocilpine-induced PPI impairment. Interestingly, the lower clozapine dose did not by self enhance PPI and the higher clozapine dose when given alone caused a significant ( p < 0.05) PPI impairment relative to control. Nicotine (0.2 and 0.4 mg/kg) did not significantly interact with the other treatments, though the higher nicotine dose did show a trend toward attenuating the PPI impairment caused by the high clozapine dose. These effects were replicated in a second experiment of clozapine–dizocilpine interactions without nicotine treatment. This study shows that PPI of tactile startle is dramatically impaired by blocking NMDA activation and that the prototypic atypical antipsychotic drug clozapine can correct this deficit. This may be relevant to the action of clozapine in attenuating sensory gating deficits in schizophrenia and may point to new avenues of treatment for sensory modulation disorders in which there is excessive tactile response.

Lateralization of auditory sensory gating and neuropsychological dysfunction in schizophrenia.

Sensory gating assessed via EEG in a paired-click paradigm has often served as a neurophysiological metric of attentional function in schizophrenia. However, the standard EEG measure of sensory gating using the P50 component at electrode Cz does not foster differential assessment of left and right hemisphere contributions. Magnetoencephalography (MEG) is complementary to EEG, and its analogous M50 component may be better suited for localization and analysis of such lateralized cortical generators. The authors hypothesized that 1) auditory gating would be evident in M50 sources in superior temporal gyrus, demonstrating ratios similar to P50; 2) M50 would resemble P50 in distinguishing gating in comparison subjects and patients with schizophrenia, but M50 would show lateralization of the gating deficit; and 3) P50 and M50 sensory gating ratios would predict neuropsychological measures in patients and comparison subjects, with the MEG identification of left and right hemisphere sources allowing for the evaluation of lateralization in brain-behavior relationships. Event-related EEG and MEG recordings were simultaneously obtained from 20 patients with schizophrenia and 15 comparison subjects. P50 amplitudes, M50 dipole source strengths, and P50 and M50 gating ratios were compared and assessed with respect to scores on neuropsychological performance measures. M50 dipoles localizing to superior temporal gyrus demonstrated gating similar to that of P50. As expected, patients demonstrated less P50 gating than did comparison subjects. Left (but not right) hemisphere M50 gating 1) correlated with EEG gating, 2) differentiated patients and comparison subjects, and 3) correlated with neuropsychological measures of sustained attention and working memory. Converging evidence from EEG, MEG, and neuropsychological measures points to left hemisphere dysfunction as strongly related to the well-established sensory gating deficit in schizophrenia.

The genetics of sensory gating deficits in schizophrenia.

Sensory gating abnormalities are an early clinical symptom of schizophrenia, and are characterized by a decrease in the brain's normal ability to inhibit the response to unimportant stimuli. Patients appear hypervigilant and have difficulty focusing their attention. A neurobiologic mechanism involved in these difficulties is nicotinic cholinergic modulation of inhibitory neuronal activity in the hippocampus. One measure of sensory gating abnormalities, diminished inhibition of the P50 evoked response to repeated auditory stimuli, has been linked to the chromosome 15q14 locus of the alpha-7-nicotinic receptor gene. This site is one of several that have shown evidence for linkage to schizophrenia, as well as to bipolar disorder, across several studies. Polymorphisms in the core promoter of the gene are associated with schizophrenia and also with diminished inhibition of the P50 response. These genetic data may identify a new pathophysiologic target for drug discovery.

The sleep state-dependent P50 auditory evoked potential in neuropsychiatric diseases

Certain neuropsychiatric diseases are characterized, or even presaged, by disturbances in sleep–wake control and arousal, functions of the reticular activating system (RAS). One measure of RAS function is the P50 midlatency auditory evoked potential, which (1) is sleep state-dependent, being present during waking and paradoxical sleep but absent in slow wave sleep, (2) undergoes rapid habituation at stimulation frequencies >2 Hz, and (3) is blocked by the cholinergic antagonist, scopolamine, i.e., is generated, at least in part, by cholinergic mesopontine cell groups. Using a paired stimulus paradigm, the amplitude of the first response is a measure of the initial responsiveness of the system, while the ratio of the two responses at short interstimulus intervals is a measure of sensory gating. Previous studies showed that there was a sensory gating deficit in Schizophrenia, and a reduction in P50 potential amplitude in Autism and Alzheimer's disease. Our studies found a decrease in the amplitude of the P50 potential, indicative of reduced arousal, in Narcolepsy. We also found a sensory gating deficit of the P50 potential in Posttraumatic Stress Disorder (PTSD), Parkinson's disease (PD), Huntington's disease (HD) and Depression, indicative of a disinhibition of the neurological substrates of the P50 potential.

Neural correlates of sensory gating in the rat: decreased Fos induction in the lateral septum

In the P 50 gating or conditioning-testing paradigm in the rat, two identical click stimuli are presented with an inter-click interval of 500 ms. The reaction towards the second click, as measured with evoked potentials, is reduced in respect to that towards the first click; this phenomenon is called sensory gating. In the present experiments, the inter-click interval was varied systematically and auditory evoked potentials were measured. Sensory gating was found to occur only at intervals between 500 and 1000 ms, but not at longer intervals. Fos immunohistochemistry was then performed using two groups of rats exposed to double clicks: the inter-click interval was 500 ms in the experimental group and 2500 ms in the control group. Fos induction was analyzed in selected brain structures. In the auditory pathways, Fos-immunoreactive neurons were found in both groups of rats in the inferior colliculus and medial geniculate body. Fos-immunoreactive cells were also examined in the septum and hippocampus. In the ventral part of the lateral septal nucleus, the labeled neurons were significantly fewer in the experimental animals compared to the control group. Smaller and non-significant quantitative differences of Fos-positive neurons were documented in the medial septum and hippocampal CA1 region. These data point out a selective decrease in the lateral septum of Fos induced by auditory sensory gating, and suggest an involvement of this structure, and possibly of other parts of the septo-hippocampal system, in sensory gating mechanisms. The results might be relevant for theories on sensory gating deficits in schizophrenia.

Nicotinic receptor desensitization and sensory gating deficits in schizophrenia

Background: Nicotinic receptor dysfunction is a possible mechanism of the abnormal sensory gating observed in schizophrenia with the P50 auditory event-related potential. Although nicotinic receptors normally desensitize after activation by acetylcholine or nicotine, pathologically increased desensitization might cause receptor dysfunction in schizophrenia. To examine this possibility, central cholinergic neuronal activity was diminished by allowing schizophrenic patients to sleep briefly, after which they experienced a transient period of normal P50 gating, consistent with receptor resensitization during the absence of cholinergic stimulation. A critical test of the mechanism is whether this resensitization is blocked by concurrent administration of nicotine, which would provide continuous receptor stimulation. Methods: Six schizophrenic patients repeated the sleep experiment during nicotine exposure from a dermal patch, in a double-blind, placebo-controlled design. Results: The normalization of P50 gating immediately postsleep was replicated in the placebo arm, but this effect was decreased in all six patients during exposure to nicotine. Conclusions: The results suggest that nicotinic receptor desensitization is responsible for the loss of P50 gating in schizophrenia.

Is P50 suppression a measure of sensory gating in schizophrenia?

Background: Abnormal P50 response has been hypothesized to reflect the sensory gating deficit in schizophrenia. Despite the extensive literature concerning the sensory filtering or gating deficit in schizophrenia, no evidence has been provided to test the relationship of the P50 phenomenon with patients’ experiences of perceptual anomalies. Methods: Sixteen drug-free DSM-IV diagnosed schizophrenic patients who reported moderate to severe perceptual anomalies in the auditory or visual modality were examined as compared to 16 schizophrenic patients who did not report perceptual anomalies, and 16 normal subjects. Both control groups were age- and gender-matched with the study group. Results: Patients reporting perceptual anomalies exhibited P50 patterns that did not differ from normal subjects. In contrast, patients who did not report perceptual anomalies showed the abnormal P50 ratios previously found to be associated with schizophrenia. Conclusions: These paradoxical findings do not support the hypothetical relationship between the P50 and behavioral measures of sensory gating, suggesting that additional studies are needed to further explore the clinical correlates of the P50.

A structured clinical assessment of external sensory gating deficits in schizophrenia

A structured clinical assessment of external sensory gating deficits in schizophrenia

Sensory gating deviance in schizophrenia in the context of task related effects

To replicate the findings of a sensory gating deficit in schizophrenia, and to determine if normals and schizophrenics are equally affected by cognitively mediated task-relevant factors, 10 healthy and 10 schizophrenic young adults were tested in two experimental conditions. In the first condition a pair of identical auditory clicks (conditioning stimulus and testing stimulus) was administered at an inter-stimulus interval fixed at 500 msec. In the second condition, the second stimulus could have one of two possible frequencies, and subjects were required to count the presentations of one and ignore the other. Subjects also completed two matched blocks of single stimulus (i.e. testing only) presentations to provide a baseline for assessing the effect of the warning stimulus on the evoked response. We found, in disagreement with previous results, that in schizophrenics, passive exposure to the paired stimuli produced a suppression of P50 amplitude to the second stimulus, that did not differ from that found in normals. However, under paired presentation conditions, testing P50 amplitude in normals, but not in schizophrenics, was enhanced by the count/no-count task introduction. We suggest that both groups are equally susceptible to the task independent (possibly “hard-wired”) suppressing effect of a conditioning stimulus presentation. However, only normals seem to exhibit a task-dependent effect, whose action at the P50 range demands the presence of a warning (conditioning) stimulus. Inspection of the full epoch data showed an apparently lesser task-related, warning dependent modulation of early ERP activity in schizophrenics, and a normal (or even supernormal) modulation of late activity. We consider this to support a notion of an early processing deficit in schizophrenia.

Sensory gating deficits in schizophrenia: new results.

It has been widely hypothesized that sensory gating failures and sensory overload occur in schizophrenic patients compared to normal subjects. The authors of this study sought to confirm and extend results of earlier studies that showed specific sensory gating deficits in schizophrenic patients. Age- and sex-matched schizophrenic patients (N = 20) and normal subjects (N = 20) were tested using electrophysiologically recorded P50 event-related potentials to assess the overall competence of the subjects' central sensory inhibitory capacity by measuring sensory filtering or gating. P50 area responses to two 75-dB (conditioning and test) click stimuli of 0.04-msec duration, averaged over 60 trials, were recorded for each subject. Normally, the first (conditioning) click stimulus induces gating mechanisms that result in diminished or gated P50 event-related potentials in response to the second click stimulus. The schizophrenic subjects manifested a significant sensory gating deficit at frontal, central, and parietal electrode placement sites, with a nonsignificant tendency for the deficit to be most prominent in the frontal areas of the brain. These data reflect a regionally diffuse loss of normal sensory gating in schizophrenic patients.