Auditory Paired-click Paradigm 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, N100, and P200 Auditory Sensory Gating Deficits in Schizophrenia Patients.

BackgroundSensory gating describes neurological processes of filtering out redundant or unnecessary stimuli during information processing, and sensory gating deficits may contribute to the symptoms of schizophrenia. Among the three components of auditory event-related potentials reflecting sensory gating, P50 implies pre-attentional filtering of sensory information and N100/P200 reflects attention triggering and allocation processes. Although diminished P50 gating has been extensively documented in patients with schizophrenia, previous studies on N100 were inconclusive, and P200 has been rarely examined. This study aimed to investigate whether patients with schizophrenia have P50, N100, and P200 gating deficits compared with control subjects.MethodsControl subjects and clinically stable schizophrenia patients were recruited. The mid-latency auditory evoked responses, comprising P50, N100, and P200, were measured using the auditory-paired click paradigm without manipulation of attention. Sensory gating parameters included S1 amplitude, S2 amplitude, amplitude difference (S1-S2), and gating ratio (S2/S1). We also evaluated schizophrenia patients with PANSS to be correlated with sensory gating indices.ResultsOne hundred four patients and 102 control subjects were examined. Compared to the control group, schizophrenia patients had significant sensory gating deficits in P50, N100, and P200, reflected by larger gating ratios and smaller amplitude differences. Further analysis revealed that the S2 amplitude of P50 was larger, while the S1 amplitude of N100/P200 was smaller, in schizophrenia patients than in the controls. We found no correlations between sensory gating indices and schizophrenia positive or negative symptom clusters. However, we found a negative correlation between the P200 S2 amplitude and Bell’s emotional discomfort factor/Wallwork’s depressed factor.ConclusionTill date, this study has the largest sample size to analyze P50, N100, and P200 collectively by adopting the passive auditory paired-click paradigm without distractors. With covariates controlled for possible confounds, such as age, education, smoking amount and retained pairs, we found that schizophrenia patients had significant sensory gating deficits in P50-N100-P200. The schizophrenia patients had demonstrated a unique pattern of sensory gating deficits, including repetition suppression deficits in P50 and stimulus registration deficits in N100/200. These results suggest that sensory gating is a pervasive cognitive abnormality in schizophrenia patients that is not limited to the pre-attentive phase of information processing. Since P200 exhibited a large effect size and did not require additional time during recruitment, future studies of P50-N100-P200 collectively are highly recommended.

Prenatal Nicotine Exposure Disrupts Infant Neural Markers of Orienting.

Prenatal nicotine exposure (PNE) from maternal cigarette smoking is linked to developmental deficits, including impaired auditory processing, language, generalized intelligence, attention, and sleep. Fetal brain undergoes massive growth, organization, and connectivity during gestation, making it particularly vulnerable to neurotoxic insult. Nicotine binds to nicotinic acetylcholine receptors, which are extensively involved in growth, connectivity, and function of developing neural circuitry and neurotransmitter systems. Thus, PNE may have long-term impact on neurobehavioral development. The purpose of this study was to compare the auditory K-complex, an event-related potential reflective of auditory gating, sleep preservation and memory consolidation during sleep, in infants with and without PNE and to relate these neural correlates to neurobehavioral development. We compared brain responses to an auditory paired-click paradigm in 3- to 5-month-old infants during Stage 2 sleep, when the K-complex is best observed. We measured component amplitude and delta activity during the K-complex. Infants with PNE demonstrated significantly smaller amplitude of the N550 component and reduced delta-band power within elicited K-complexes compared to nonexposed infants and also were less likely to orient with a head turn to a novel auditory stimulus (bell ring) when awake. PNE may impair auditory sensory gating, which may contribute to disrupted sleep and to reduced auditory discrimination and learning, attention re-orienting, and/or arousal during wakefulness reported in other studies. Links between PNE and reduced K-complex amplitude and delta power may represent altered cholinergic and GABAergic synaptic programming and possibly reflect early neural bases for PNE-linked disruptions in sleep quality and auditory processing. These may pose significant disadvantage for language acquisition, attention, and social interaction necessary for academic and social success.

Modulation of mGlu2 Receptors, but Not PDE10A Inhibition Normalizes Pharmacologically-Induced Deviance in Auditory Evoked Potentials and Oscillations in Conscious Rats.

Improvement of cognitive impairments represents a high medical need in the development of new antipsychotics. Aberrant EEG gamma oscillations and reductions in the P1/N1 complex peak amplitude of the auditory evoked potential (AEP) are neurophysiological biomarkers for schizophrenia that indicate disruption in sensory information processing. Inhibition of phosphodiesterase (i.e. PDE10A) and activation of metabotropic glutamate receptor (mGluR2) signaling are believed to provide antipsychotic efficacy in schizophrenia, but it is unclear whether this occurs with cognition-enhancing potential. The present study used the auditory paired click paradigm in passive awake Sprague Dawley rats to 1) model disruption of AEP waveforms and oscillations as observed in schizophrenia by peripheral administration of amphetamine and the N-methyl-D-aspartate (NMDA) antagonist phencyclidine (PCP); 2) confirm the potential of the antipsychotics risperidone and olanzapine to attenuate these disruptions; 3) evaluate the potential of mGluR2 agonist LY404039 and PDE10 inhibitor PQ-10 to improve AEP deficits in both the amphetamine and PCP models. PCP and amphetamine disrupted auditory information processing to the first click, associated with suppression of the P1/N1 complex peak amplitude, and increased cortical gamma oscillations. Risperidone and olanzapine normalized PCP and amphetamine-induced abnormalities in AEP waveforms and aberrant gamma/alpha oscillations, respectively. LY404039 increased P1/N1 complex peak amplitudes and potently attenuated the disruptive effects of both PCP and amphetamine on AEPs amplitudes and oscillations. However, PQ-10 failed to show such effect in either models. These outcomes indicate that modulation of the mGluR2 results in effective restoration of abnormalities in AEP components in two widely used animal models of psychosis, whereas PDE10A inhibition does not.

Early Attentional Modulation of the Neural Network Evoked with the Auditory Paired-click Paradigm: An MEG Study

Although numerous research studies have explored the functional attributes of the human duration perception, the spatio- temporal information on cortical networks underlying this process is still an open question. Moreover, the issue of possible differences in the nature of timing mechanisms responsible for perception of sub- and supra-second intervals requires the implementation of the functional brain imaging techniques with both high spatial and temporal resolution. Attention is very frequently used as a modulating factor for the perceived duration of a sensory stimulus. The non-attended stimuli appear to last shorter than the attended ones, increasing the perceived duration of a concurrent stimulus (Gorea, 2011). This study challenges the accepted model of early sensory responses, activated during the first 100ms after stimulus presentation, as preattentive, automatic processes which modulate the neural sensitivity to incoming stimuli (gating phenomena). We utilized Elekta Neuromag 306-channel whole-head system for magnetoencephalography (MEG) measurements and multi-dipole Calibrated Start Spatio Temporal (CSST) localization technique (Ranken et al., 2002) to investigate whether voluntary attention directed at the second tone of a pair in the standard paired-click paradigm could affect cortical networks underlying the gating out phenomenon. MEG recordings were obtained in a magnetically shielded room at the Biomagnetic Center in Jena, Germany. Two consecutive (ISI=500ms) identical short tonnes (S1 and S2; duration=20ms; f=1200Hz; ITI=8±1s) were used to evoke standard gating cortical responses in 19 healthy participants (21-38 years). In the second condition, the task was to direct attention toward the second tone and to respond to a rarely presented non-identical second tone of the pair (R=1300Hz, p(S1R)=0.3). MEG recordings showed transient early and middle latency responses with peak amplitudes over the temporo-parietal sensors followed by a peak of a sustained activity. Less prominent transient activity was recorded over the frontal sensors, accompanied with a more steady- state component from 100 until 400ms post-stimulus for both conditions. Preliminary results of the CSST spatio-temporal analyses revealed 4-6 brain regions activated during 20-500ms time interval including bilateral superior temporal gyrus (STG), bilateral and medial prefrontal (PF), bilateral parietal (PA) regions, and central motor cortex area. A cortical source underlying the steady-state component was identified in the left prefrontal region for S1 tone, and in central posterior regions (PA) for the repeated tone S2. During the standard paradigm the M50 gating suppression was observed only for bilateral STG sources while bilateral PF and PA sources did not show any reduction in the response during the first 100ms post-stimulus. Targeting the attention towards the second tone enhanced the M50 amplitude of the bilateral STG responses in respect to the repeated stimulus S2 and caused a change in the activated network evident by the emergence of a new generator in the medial PF area (orbitofrontal) instead of dorsolateral PF generators evoked in non-attended condition. These results demonstrate that voluntary attention can exert a topological and functional modulatory influence on the neural network even during early stages of auditory processing.

Auditory event-related potential of subjects with suspected pre-psychotic state and first‐episode psychosis

BackgroundRecent schizophrenia research exploring the complicated pathogenesis of schizophrenia has focused on the subjects with at-risk mental states in order to exclude the influence of confounding factors. This study explores 3 sets of auditory-related event potentials in subjects with different risk levels of psychosis. MethodsSubjects were recruited from the SOPRES study in Taiwan. P50 and N100 using an auditory paired-click paradigm and duration MMN were assessed on 32 first-episode psychosis (FEP), 30 ultra-high risk (UHR), 37 E-BARS (early/broad at-risk mental states) participants and 56 controls. ResultsMMN was correlated with neither P50 nor N100, whereas many parameters of the latter two were intercorrelated with each other. Compared to healthy controls, MMNs were significantly lower in all 3 clinical groups (E-BARS, UHR and FEP). A gradient of sensory-gating deficits, manifested by increased P50 ratios (S2/S1) and decreased N100 differences, across different levels of clinical severity was suggested by a linear trend. For the UHR subjects, P50 gating ratio, N100 gating ratio, N100 difference, and N100S2 amplitude might be potential indicators to discriminate converters from non-converters. ConclusionsBy including subjects with E-BARS, our results provide new insight regarding pre-attentive auditory event-related potential in subjects across different risk levels of psychotic disorders. Impaired deviance detection shown by MMNs already exists in people at a pre-psychotic state regardless of clinical severity, while sensory‐gating deficits shown by P50/N100 varies depending on the risk levels in prodromal period. Further longitudinal research exploring the relationship between ERPs and subjects with a suspected pre-psychotic state is needed.

Sensory gating revisited: Relation between brain oscillations and auditory evoked potentials in schizophrenia

Disturbances of auditory information processing have repeatedly been shown in schizophrenia. To contribute to a better understanding of the neurophysiological underpinnings of habituation in auditory processing and its disturbance in schizophrenia we used three different approaches to analyze auditory evoked responses, namely phase-locking (PL) analyses, single trial amplitudes, and averaged event-related potentials (P50 and N100). Given that brain oscillations reflect the neuronal correlates of information processing we hypothesized that PL and amplitudes reflect even more essential parts of auditory processing than the averaged ERP responses. In 32 schizophrenia patients and 32 matched controls EEG was continuously recorded using an auditory paired click paradigm. PL of the lower frequency bands (alpha and theta) was significantly reduced in patients whereas no significant differences were present in higher frequencies (gamma and beta). Alpha and theta PL and amplitudes showed a marked increase after the first click and to a minor degree after the second one. This habituation was more prominent in controls whereas in schizophrenia patients the response to both clicks differed only slightly. N100 suppression was significantly reduced in schizophrenia patients whereas no group differences were present with respect to the P50. This corresponded to the finding that gamma mostly contributed to the prediction of the P50 response and theta mostly to the N100 response. Our data showed that analyzing phase and amplitude in single trials provides more information on auditory information processing and reflects differences between schizophrenia patients and controls better than analyzing the averaged ERP responses.

Generators of the intracranial P50 response in auditory sensory gating

Clarification of the cortical mechanisms underlying auditory sensory gating may advance our understanding of brain dysfunctions associated with schizophrenia. To this end, data from nine epilepsy patients who participated in an auditory paired-click paradigm during pre-surgical evaluation and had grids of electrodes covering temporal and frontal lobe were analyzed. A distributed source localization approach was applied to the intracranial P50 response and the Gating Difference Wave obtained by subtracting the response to the second stimuli from the response to the first stimuli.Source reconstruction of the P50 showed that the main generators of the response were localized in the temporal lobes. The analysis also suggested that the maximum neuronal activity contributing to the amplitude reduction in the P50 time range (phenomenon of auditory sensory gating) is localized at the frontal lobe.Present findings suggest that while the temporal lobe is the main generator of the P50 component, the frontal lobe seems to be a substantial contributor to the process of sensory gating as observed from scalp recordings.

Failure to Find P50 Suppression Deficits in Young First-Episode Patients With Schizophrenia and Clinically Unaffected Siblings

To evaluate whether the P50 gating deficit is present in young first-episode patients with schizophrenia and their healthy young siblings. An auditory paired-click paradigm was used to assess P50 gating in 53 patients, 27 unaffected siblings, and 28 healthy controls. P50 parameters were compared between patients, sibs, and unrelated controls by a mixed-effects regression model. P50 gating was not significantly impaired in patients with schizophrenia and healthy siblings as compared with controls. P50 gating was not found to be significantly impaired in young first-episode schizophrenia patients and in healthy young siblings. These results are in contrast with the existing literature. We suggest that P50 gating impairment may be developmentally or age dependent.