Auditory Steady-state Response Research Articles

Hierarchical Pathways from Sensory Processing to Cognitive, Clinical, and Functional Impairments in Schizophrenia.

Cognitive impairment is a hallmark of schizophrenia and a robust predictor of functional outcomes. Impairments are found in all phases of the illness and are only moderately attenuated by currently approved therapeutics. Neurophysiological indices of sensory discrimination (ie, mismatch negativity (MMN) and P3a amplitudes) and gamma-band auditory steady-state response (ASSR; power and phase locking) are translational biomarkers widely used in the development of novel therapeutics for neuropsychiatric disorders. It is unclear whether laboratory-based EEG measures add explanatory power to well-established models that use only cognitive, clinical, and functional outcome measures. Moreover, it is unclear if measures of sensory discrimination and gamma-band ASSR uniquely contribute to putative causal pathways linking sensory discrimination, neurocognition, negative symptoms, and functional outcomes in schizophrenia. To answer these questions, hierarchical associations among sensory processing, neurocognition, clinical symptoms, and functional outcomes were assessed via structural equation modeling in a large sample of schizophrenia patients (n = 695) and healthy comparison subjects (n = 503). The results showed that the neurophysiologic indices of sensory discrimination and gamma-band ASSR both significantly contribute to and yield unique hierarchical, "bottom-up" effects on neurocognition, symptoms, and functioning. Measures of sensory discrimination showed direct effects on neurocognition and negative symptoms, while gamma-band ASSR had a direct effect on neurocognition in patients. Continued investigation of the neural mechanisms underlying abnormal networks of MMN/P3a and gamma-band ASSR is needed to clarify the pathophysiology of schizophrenia and the development of novel therapeutic interventions.

The effects of roflumilast, a phosphodiesterase type-4 inhibitor, on EEG biomarkers in schizophrenia: A randomised controlled trial.

Patients with schizophrenia have significant cognitive deficits, which may profoundly impair quality of life. These deficits are also evident at the neurophysiological level with patients demonstrating altered event-related potential in several stages of cognitive processing compared to healthy controls; within the auditory domain, for example, there are replicated alterations in Mismatch Negativity, P300 and Auditory Steady State Response. However, there are no approved pharmacological treatments for cognitive deficits in schizophrenia. Here we examine whether the phosphodiesterase-4 inhibitor, roflumilast, can improve neurophysiological deficits in schizophrenia. Using a randomised, double-blind, placebo-controlled, crossover design study in 18 patients with schizophrenia, the effect of the phosphodiesterase-4 inhibitor, roflumilast (100 µg and 250 µg) on auditory steady state response (early stage), mismatch negativity and theta (intermediate stage) and P300 (late stage) was examined using electroencephalogram. A total of 18 subjects were randomised and included in the analysis. Roflumilast 250 µg significantly enhanced the amplitude of both the mismatch negativity (p=0.04) and working memory-related theta oscillations (p=0.02) compared to placebo but not in the other (early- or late-stage) cognitive markers. The results suggest that phosphodiesterase-4 inhibition, with roflumilast, can improve electroencephalogram cognitive markers, which are impaired in schizophrenia, and that phosphodiesterase-4 inhibition acts at an intermediate rather than early or late cognitive processing stage. This study also underlines the use of neurophysiological measures as cognitive biomarkers in experimental medicine.

A distributed frontotemporal network underlies gamma-band synchronization impairments in schizophrenia patients.

Synaptic interactions between parvalbumin-positive γ-aminobutyric acid (GABA)-ergic interneurons and pyramidal neurons evoke cortical gamma oscillations, which are known to be abnormal in schizophrenia. These cortical gamma oscillations can be indexed by the gamma-band auditory steady-state response (ASSR), a robust electroencephalographic (EEG) biomarker that is increasingly used to advance the development of novel therapeutics for schizophrenia, and other related brain disorders. Despite promise of ASSR, the neural substrates of ASSR have not yet been characterized. This study investigated the sources underlying ASSR in healthy subjects and schizophrenia patients. In this study, a novel method for noninvasively characterizing source locations was developed and applied to EEG recordings obtained from 293 healthy subjects and 427 schizophrenia patients who underwent ASSR testing. Results revealed a distributed network of temporal and frontal sources in both healthy subjects and schizophrenia patients. In both groups, primary contributing ASSR sources were identified in the right superior temporal cortex and the orbitofrontal cortex. In conjunction with normal activity in these areas, schizophrenia patients showed significantly reduced source dipole density of gamma-band ASSR (ITC > 0.25) in the left superior temporal cortex, orbitofrontal cortex, and left superior frontal cortex. In conclusion, a distributed network of temporal and frontal brain regions supports gamma phase synchronization. We demonstrated that failure to mount a coherent physiologic response to simple 40-Hz stimulation reflects disorganized network function in schizophrenia patients. Future translational studies are needed to more fully understand the neural mechanisms underlying gamma-band ASSR network abnormalities in schizophrenia.

Threshold Mismatches between Pure-Tone Audiometry and Auditory Steady State Response in Non-Auditory Neuropathy Adults

Background and Objectives To evaluate mismatches between pure-tone audiometry (PTA) and auditory steady-state response (ASSR) tests in non-auditory neuropathy adults and investigate brain lesions that may explain the mismatches, especially in cases where the ASSR threshold was worse than the estimated PTA threshold.Subjects and Method PTA, speech audiometry, auditory brainstem response, ASSR, and neuroimaging tests were carried out on individuals selected. Among them, medical records of 30 subjects (16 males, 14 females; mean age=54.4±13.2 years) with significant mismatches between PTA and estimated ASSR thresholds were analyzed retrospectively. All neuroimaging tests were reviewed to identify any neurologic abnormalities.Results Pathologic brain lesions were found in 19 cases (63.3%) in the study group, all of which showed significant mismatch in hearing threshold between PTA and ASSR. Seven case of ischemic brain lesions (23.3%), five tumorous lesions (16.6%), and four brain vessel anomalies (13.3%) were found. Brain hemorrhage due to trauma were found in two cases (6.6%) as well as one case (3.3%) of unruptured aneurysm. Central auditory pathway disorder was suspected in two cases. The 11 cases showing normal results in the imaging studies included one mental retardation, one brain concussion, and seven cases (23.3%) with no specific causes. Six tinnitus cases included two subjects showing discrepancies between frequency matching in the tinnitogram.Conclusion In adults with a mismatch between PTA thresholds and estimated ASSR thresholds, especially for those with moderate to profound hearing loss, additional neuroimaging tests and other audiologic tests may reveal other possible causes of hearing loss.

A Quantitative Approach for the Objective Assessment of Coupling Efficiency for an Active Middle Ear Implant by Recording Auditory Steady-state Responses.

The coupling efficiency of a semi-implantable active middle ear implant with an electromagnetically driven floating mass transducer coupled to a middle ear ossicle or the round window can only be quantified postoperatively in cooperative patients by measuring behavioral vibroplasty in situ thresholds in comparison with bone conduction thresholds. The objective of the study was to develop a method to objectively determine the vibroplasty in situ thresholds by determining calibration factors from the relation between the objective and behavioral vibroplasty in situ thresholds. Prospective experimental study. Fifteen patients, implanted with an active middle ear implant for at least 6 months. Diagnostic. Vibroplasty in situ thresholds measured objectively by auditory steady state responses (floating mass transducer [FMT]ASSR). Subjective vibroplasty in situ thresholds were measured in this experimental ASSR set-up (FMTsubj.) and behaviorally by pure-tone audiometry (vibrogram). All thresholds were obtained at 500, 1000, 2000, and 4000 Hz. Thresholds could be objectively measured by ASSR in all patients. Differences between the FMTASSR and FMTsubj. were statistically significant but small. A significant correlation was found between the FMTASSR and the vibrogram thresholds at 4000 Hz but not for the other test frequencies. The method is feasible to measure objective vibroplasty in situ thresholds in active middle ear implant users. Since calibration factors could not be determined for all frequencies, the method is only applicable to comparatively determine the coupling efficiency of the floating mass transducer.

Aberrant Auditory Steady-State Response of Awake Mice After Single Application of the NMDA Receptor Antagonist MK-801 Into the Medial Geniculate Body

BackgroundSystemic administration of noncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonists such as MK-801 is widely used to model psychosis of schizophrenia (SZ). Acute systemic MK-801 in rodents caused an increase of the auditory steady-state responses (ASSRs), the oscillatory neural responses to periodic auditory stimulation, while most studies in patients with SZ reported a decrease of ASSRs. This inconsistency may be attributable to the comprehensive effects of systemic administration of MK-801. Here, we examined how the ASSR is affected by selectively blocking NMDAR in the thalamus.MethodsWe implanted multiple electrodes in the auditory cortex (AC) and prefrontal cortex to simultaneously record the local field potential and spike activity (SA) of multiple sites from awake mice. Click-trains at a 40-Hz repetition rate were used to evoke the ASSR. We compared the mean trial power and phase-locking factor and the firing rate of SA before and after microinjection of MK-801 (1.5 µg) into the medial geniculate body (MGB).ResultsWe found that both the AC and prefrontal cortex showed a transient local field potential response at the onset of click-train stimulus, which was less affected by the application of MK-801 in the MGB. Following the onset response, the AC also showed a response continuing throughout the stimulus period, corresponding to the ASSR, which was suppressed by the application of MK-801.ConclusionOur data suggest that the MGB is one of the generators of ASSR, and NMDAR hypofunction in the thalamocortical projection may account for the ASSR deficits in SZ.

Haploinsufficiency of Cyfip2 Causes Lithium-Responsive Prefrontal Dysfunction.

Genetic variants of the cytoplasmic FMR1-interacting protein 2 (CYFIP2) encoding an actin-regulatory protein are associated with brain disorders, including intellectual disability and epilepsy. However, specific in vivo neuronal defects and potential treatments for CYFIP2-associated brain disorders remain largely unknown. Here, we characterized Cyfip2 heterozygous (Cyfip2+/- ) mice to understand their neurobehavioral phenotypes and the underlying pathological mechanisms. Furthermore, we examined a potential treatment for such phenotypes of the Cyfip2+/- mice and specified a neuronal function mediating its efficacy. We performed behavioral analyses of Cyfip2+/- mice. We combined molecular, ultrastructural, and in vitro and in vivo electrophysiological analyses of Cyfip2+/- prefrontal neurons. We also selectively reduced CYFIP2 in the prefrontal cortex (PFC) of mice with virus injections. Adult Cyfip2+/- mice exhibited lithium-responsive abnormal behaviors. We found increased filamentous actin, enlarged dendritic spines, and enhanced excitatory synaptic transmission and excitability in the adult Cyfip2+/- PFC that was restricted to layer 5 (L5) neurons. Consistently, adult Cyfip2+/- mice showed increased seizure susceptibility and auditory steady-state responses from the cortical electroencephalographic recordings. Among the identified prefrontal defects, lithium selectively normalized the hyperexcitability of Cyfip2+/- L5 neurons. RNA sequencing revealed reduced expression of potassium channel genes in the adult Cyfip2+/- PFC. Virus-mediated reduction of CYFIP2 in the PFC was sufficient to induce L5 hyperexcitability and lithium-responsive abnormal behavior. These results suggest that L5-specific prefrontal dysfunction, especially hyperexcitability, underlies both the pathophysiology and the lithium-mediated amelioration of neurobehavioral phenotypes in adult Cyfip2+/- mice, which can be implicated in CYFIP2-associated brain disorders. ANN NEUROL 2020;88:526-543.

Effects of (+)-bicuculline, a GABAa receptor antagonist, on auditory steady state response in free-moving rats.

Auditory steady-state responses (ASSRs) are states in which the electrical activity of the brain reacts steadily to repeated auditory stimuli. They are known to be useful for testing the functional integrity of neural circuits in the cortex, as well as for their capacity to generate synchronous activity in both human and animal models. Furthermore, abnormal gamma oscillations on ASSR are typically observed in patients with schizophrenia (SZ). Changes in neural synchrony may reflect aberrations in cortical gamma-aminobutyric acid (GABA) neurotransmission. However, GABA’s impact and effects related to ASSR are still unclear. Here, we examined the effect of a GABAa receptor antagonist, (+)-bicuculline, on ASSR in free-moving rats. (+)-Bicuculline (1, 2 and 4 mg/kg, sc) markedly and dose-dependently reduced ASSR signals, consistent with current hypotheses. In particular, (+)-bicuculline significantly reduced event-related spectral perturbations (ERSPs) at 2 and 4 mg/kg between 10 and 30 minutes post-dose. Further, bicuculline (2 and 4 mg/kg) significantly and dose-dependently increased baseline gamma power. Furthermore, the occurrence of convulsions was consistent with the drug’s pharmacokinetics. For example, high doses of (+)-bicuculline such as those greater than 880 ng/g in the brain induced convulsion. Additionally, time-dependent changes in ERSP with (+)-bicuculline were observed in accordance with drug concentration. This study partially unraveled the contribution of GABAa receptor signals to the generation of ASSR.

A pilot study: Auditory steady-state responses (ASSR) can be measured in human fetuses using fetal magnetoencephalography (fMEG).

BackgroundAuditory steady-state responses (ASSRs) are ongoing evoked brain responses to continuous auditory stimuli that play a role for auditory processing of complex sounds and speech perception. Transient auditory event-related responses (AERRs) have previously been recorded using fetal magnetoencephalography (fMEG) but involve different neurological pathways. Previous studies in children and adults demonstrated that the cortical components of the ASSR are significantly affected by state of consciousness and by maturational changes in neonates and young infants. To our knowledge, this is the first study to investigate ASSRs in human fetuses.Methods47 fMEG sessions were conducted with 24 healthy pregnant women in three gestational age groups (30–32 weeks, 33–35 weeks and 36–39 weeks). The stimulation consisted of amplitude-modulated (AM) tones with a duration of one second, a carrier frequency (CF) of 500 Hz and a modulation frequency (MF) of 27 Hz or 42 Hz. Both tones were presented in a random order with equal probability adding up to 80–100 repetitions per tone. The ASSR across trials was quantified by assessing phase synchrony in the cortical signals at the stimulation frequency.Results and conclusionTen out of 47 recordings were excluded due to technical problems or maternal movements. Analysis of the included 37 fetal recordings revealed a statistically significant response for the phase coherence between trials for the MF of 27 Hz but not for 42 Hz. An exploratory subgroup analysis moreover suggested an advantage in detectability for fetal behavioral state 2F (active asleep) compared to 1F (quiet asleep) detected using fetal heart rate. In conclusion, this pilot study is the first description of a method to detect human ASSRs in fetuses. The findings warrant further investigations of the developing fetal brain.

EEG based amplitude-modulated auditory steady-state response and auditory selective attention analysis

EEG based amplitude-modulated auditory steady-state response and auditory selective attention analysis

Analysis of selective attention processing on experienced simultaneous interpreters using EEG phase synchronization.

This study analyzed the selective attention processing related to cognitive load on simultaneous interpretation (SI). We tested simultaneous interpreter's brain function using EEG signals and calculated inter-trial coherence (ITC) extracted by the 40-Hz auditory steady-state response (ASSR). In this experiment, we set two conditions as Japanese-English translation and Japanese shadowing cognition. We also compared two subject groups: S rank with more than 15 years of SI experience (n=7) and C rank with less than one year experience (n=15). As a result, the ITCs for S rank in interpreting conditions were more significantly increased than C rank in the shadowing conditions (ITC: p<0.001). Our results demonstrate that 40-Hz ASSR might be a good indicator of selective attention and cognitive load during SI in ecologically valid environmental conditions. It can also be used to detect attention and cognitive control dysfunction in ADHD or schizophrenia.

Reduced auditory steady state responses in autism spectrum disorder

BackgroundAuditory steady state responses (ASSRs) are elicited by clicktrains or amplitude-modulated tones, which entrain auditory cortex at their specific modulation rate. Previous research has reported reductions in ASSRs at 40 Hz for autism spectrum disorder (ASD) participants and first-degree relatives of people diagnosed with ASD (Mol Autism. 2011;2:11, Biol Psychiatry. 2007;62:192–197).MethodsUsing a 1.5 s-long auditory clicktrain stimulus, designed to elicit an ASSR at 40 Hz, this study attempted to replicate and extend these findings. Magnetencephalography (MEG) data were collected from 18 adolescent ASD participants and 18 typically developing controls.ResultsThe ASSR localised to bilateral primary auditory regions. Regions of interest were thus defined in left and right primary auditory cortex (A1). While the transient gamma-band response (tGBR) from 0-0.1 s following presentation of the clicktrain stimulus was not different between groups, for either left or right A1, the ASD group had reduced oscillatory power at 40 Hz from 0.5 to 1.5 s post-stimulus onset, for both left and right A1. Additionally, the ASD group had reduced inter-trial coherence (phase consistency over trials) at 40 Hz from 0.64-0.82 s for right A1 and 1.04-1.22 s for left A1.LimitationsIn this study, we did not conduct a clinical autism assessment (e.g. the ADOS), and therefore, it remains unclear whether ASSR power and/or ITC are associated with the clinical symptoms of ASD.ConclusionOverall, our results support a specific reduction in ASSR oscillatory power and inter-trial coherence in ASD, rather than a generalised deficit in gamma-band responses. We argue that this could reflect a developmentally relevant reduction in non-linear neural processing.

Neuromodulation of Gamma-Range Auditory Steady-State Responses: A Scoping Review of Brain Stimulation Studies.

Neural oscillations represent a fundamental mechanism that enables coordinated action during normal brain functioning. Auditory steady-state responses (ASSRs) are used to test the ability to generate gamma-range activity. Different non-invasive brain stimulation (NIBS) techniques have the potential to modulate neural activation patterns that are aberrant in a variety of neuropsychiatric disorders. Here, we summarize the current state of knowledge on how different methods of NIBS (transcranial altering current stimulation—tACS, transcranial direct current stimulation—tDCS, transcranial random noise stimulation—tRNS, paired associative stimulation—PAS, repetitive transcranial magnetic stimulation—rTMS) affect the gamma-range ASSRs in both healthy and clinical populations. We show that the current research has been far from systematic and methodologically heterogeneous. Nevertheless, some brain stimulation techniques, especially tACS and rTMS show strong potential for further exploration. We outline the main findings and provide directions for further research into neuromodulation of ASSRs as a promising biomarker of different psychopathological conditions such as schizophrenia, bipolar disorder, attention deficit hyperactivity disorder (ADHD), autism.

An integrative approach for pediatric auditory neuropathy spectrum disorders: revisiting etiologies and exploring the prognostic utility of auditory steady-state response

Auditory neuropathy is an important entity in childhood sensorineural hearing loss. Due to diverse etiologies and clinical features, the management is often challenging. This study used an integrative patient-history, audiologic, genetic, and imaging-based approach to investigate the etiologies and audiologic features of 101 children with auditory neuropathy. Etiologically, 48 (47.5%), 16 (15.8%), 11 (10.9%), and 26 (25.7%) children were categorized as having acquired, genetic, cochlear nerve deficiency-related, and indefinite auditory neuropathy, respectively. The most common causes of acquired and genetic auditory neuropathy were prematurity and OTOF mutations, respectively. Patients with acquired auditory neuropathy presented hearing loss earlier (odds ratio, 10.2; 95% confidence interval, 2.2–47.4), whereas patients with genetic auditory neuropathy had higher presence rate of distortion product otoacoustic emissions (odds ratio, 10.7; 95% confidence interval, 1.3–85.4). In patients with different etiologies or pathological sites, moderate to strong correlations (Pearson’s r = 0.51–0.83) were observed between behavioral thresholds and auditory steady-state response thresholds. In conclusion, comprehensive assessments can provide etiological clues in ~75% of the children with auditory neuropathy. Different etiologies are associated with different audiologic features, and auditory steady-state responses might serve as an objective measure for estimating behavioral thresholds.

Wireless User-Generic Ear EEG.

In the past few years it has been demonstrated that electroencephalography (EEG) can be recorded from inside the ear (in-ear EEG). To open the door to low-profile earpieces as wearable brain-computer interfaces (BCIs), this work presents a practical in-ear EEG device based on multiple dry electrodes, a user-generic design, and a lightweight wireless interface for streaming data and device programming. The earpiece is designed for improved ear canal contact across a wide population of users and is fabricated in a low-cost and scalable manufacturing process based on standard techniques such as vacuum forming, plasma-treatment, and spray coating. A 2.5×2.5cm2 wireless recording module is designed to record and stream data wirelessly to a host computer. Performance was evaluated on three human subjects over three months and compared with clinical-grade wet scalp EEG recordings. Recordings of spontaneous and evoked physiological signals, eye-blinks, alpha rhythm, and the auditory steady-state response (ASSR), are presented. This is the first wireless in-ear EEG to our knowledge to incorporate a dry multielectrode, user-generic design. The user-generic ear EEG recorded a mean alpha modulation of 2.17, outperforming the state-of-the-art in dry electrode in-ear EEG systems.

Intact Auditory Cortical Cross-Frequency Coupling in Early and Chronic Schizophrenia.

BackgroundPrevious work has identified a hierarchical organization of neural oscillations that supports performance of complex cognitive and perceptual tasks, and can be indexed with phase-amplitude coupling (PAC) between low- and high-frequency oscillations. Our aim was to employ enhanced source localization afforded by magnetoencephalography (MEG) to expand on earlier reports of intact auditory cortical PAC in schizophrenia and to investigate how PAC may evolve over the early and chronic phases of the illness.MethodsIndividuals with early schizophrenia (n=12) (≤5 years of illness duration), chronic schizophrenia (n=16) (>5 years of illness duration) and healthy comparators (n = 17) performed the auditory steady state response (ASSR) to 40, 30, and 20 Hz stimuli during MEG recordings. We estimated amplitude and PAC on the MEG ASSR source localized to the auditory cortices.ResultsGamma amplitude during 40-Hz ASSR exhibited a significant group by hemisphere interaction, with both patient groups showing reduced right hemisphere amplitude and no overall lateralization in contrast to the right hemisphere lateralization demonstrated in controls. We found significant PAC in the right auditory cortex during the 40-Hz entrainment condition relative to baseline, however, PAC did not differ significantly between groups.ConclusionsIn the current study, we demonstrated an apparent sparing of ASSR-related PAC across phases of the illness, in contrast with impaired cortical gamma oscillation amplitudes. The distinction between our PAC and evoked ASSR findings supports the notion of separate but interacting circuits for the generation and maintenance of sensory gamma oscillations. The apparent sparing of PAC in both early and chronic schizophrenia patients could imply that the neuropathology of schizophrenia differentially affects these mechanisms across different stages of the disease. Future studies should investigate the distinction between PAC during passive tasks and more cognitively demanding task such as working memory so that we can begin to understand the influence of schizophrenia neuropathology on the larger framework for modulating neurocomputational capacity.

Translational neurophysiological biomarkers of N-methyl-d-aspartate receptor dysfunction in serine racemase knockout mice.

Alterations in glutamatergic function are well established in schizophrenia (Sz), but new treatment development is hampered by the lack of translational pathophysiological and target engagement biomarkers as well as by the lack of animal models that recapitulate the pathophysiological features of Sz. Here, we evaluated the rodent auditory steady state response (ASSR) and long-latency auditory event-related potential (aERP) as potential translational markers. These biomarkers were assessed for their sensitivity to both the N-methyl-d-aspartate receptor (NMDAR) antagonist phencyclidine (PCP) and to knock-out (KO) of Serine Racemase (SR), which is known to lead to Sz-like alterations in function of parvalbumin (PV)-type cortical interneurons. PCP led to significant increases of ASSR that were further increased in SRKO−/−, consistent with PV interneuron effects. Similar effects were observed in mice with selective NMDAR KO on PV interneurons. By contrast, PCP but not SRKO reduced the amplitude of the rodent analog of the human N1 potential. Overall, these findings support use of rodent ASSR and long-latency aERP, along with previously described measures such as mismatch negativity (MMN), as translational biomarkers, and support SRKO mice as a potential rodent model for PV interneuron dysfunction in Sz.

Protocol for Rapid, Accurate, Electrophysiologic, Auditory Assessment of Infants and Toddlers.

Audiologists often lack confidence in results produced by current protocols for diagnostic electrophysiologic testing of infants. This leads to repeat testing appointments and slow protocols which extend the time needed to complete the testing and consequently delay fitting of amplification. A recent publication (Sininger et al50) has shown how new technologies can be applied to electrophysiologic testing systems to improve confidence in results and allow faster test protocols. Average test times for complete audiogram predictions when using new technologies and protocols were found to be just over 32 minutes using auditory brainstem response (ABR) and just under 20 minutes using auditory steady-state response (ASSR) technology. The purpose of this manuscript is to provide details of expedited test protocols for infant and toddler diagnostic electrophysiologic testing. Several new technologies and their role in test speed and confidence are described including CE-Chirp stimuli, automated detection of ABRs using a technique called F MP, Bayesian weighting which is an alternative to standard artifact rejection and Next-Generation ASSR with improved response detection and chirp stimuli. The test protocol has the following features: (1) preliminary testing includes impedance measures and otoacoustic emissions, (2) starting test levels are based on Broad-Band CE-Chirp thresholds in each ear, (3) ABRs or ASSRs are considered present based on automated detection rather than on replication of responses, (4) number of test levels is minimized, (5) ASSR generally evaluates four frequencies in each ear simultaneously with flexibility to change all test levels independently. Combining new technologies with common-sense strategies has been shown to substantially reduce test times for predicting audiometric thresholds in infants and toddlers (Sininger et al50). Details and rationales for changing test strategies and protocols are given and case examples are used to illustrate.

0158 Loss of Connexin 36 Elicits Abnormalities in Thalamocortical Network Activity Relevant to Neuropsychiatric Disorders

Abstract Introduction Neuronal gap-junctions are extensively expressed in mammalian forebrain and suggested to contribute to state-regulation and thalamocortical network activity. However, the physiological role of gap-junctions on these processes remains poorly understood. Connexin-36 (Cxn36) is highly expressed in the brain, representing a mechanism for electrical coupling of inhibitory neurons. We examined the effects of global Cnx36 deletion on sleep/wake and spontaneous and evoked EEG activity. Methods We recorded in vivo EEG/EMG in Cxn36KO mice and littermate controls. Electrodes were stereotaxically implanted above frontal cortices. We analyzed sleep/wake states and algorithmically detected sleep spindles over 24 hours. Mice underwent auditory stimulation paradigms including the auditory steady state response (ASSR; 1 second train 20-50Hz clicks, 100 reps., 85dB) and mismatch negativity (MMN; 2.5kHz standard 90%, 10kHz deviant 10%, 300ms ISI, 90dB). Social behavior and investigation-evoked EEG activity were also assessed via the social habituation task (repeated 5 min exposures to novel mouse). Results Cnx36KO mice exhibited limited sleep/wake abnormalities (n=7/group). Power spectra of EEG revealed significant impairments in spontaneous gamma-band activity (30-80Hz; All States, Light &amp; Dark Phases), and beta activity (15-25Hz; All States, Light Phase). Sigma activity (10-15Hz) was significantly decreased (NREM and REM, Light phase). This was particularly pronounced during NREM-REM transitions. Despite no changes in spindle density, both spindle amplitude and duration were significantly decreased in Cnx36KOs. Cxn36KOs exhibited a blunted gamma-band response to acute ketamine (15mg/kg; IP), impaired 30 &amp; 40Hz ASSR, and an abnormal response in the MMN task (decrease ERP peak amplitude &amp; gamma). Finally, Cxn36KO mice exhibit impaired social habituation and significantly decreased investigation evoked slow gamma-band activity (30 - 55Hz). Conclusion Our data suggest Cxn36 plays a critical role in regulating thalamocortical network activity. Further, impairments in Cnx36KO mice reflect abnormalities in neuropsychiatric disorders, including schizophrenia, implicating Cnx36 containing gap junctions as a novel therapeutic target. Support Research supported by VA CDA Award BX002130 (JMM), VA Merit Awards BX004500 (JMM), BX001404 (RB), and NIMH RO1 MH39683 (Ritchie E. Brown).

Using ASSR with narrow-band chirps to evaluate hearing in children and adults.

All studies concerning the reliability and threshold prediction of auditory steady-state responses (ASSR) focused on a particular group of patients. The present article evaluates the use of narrow-band, chirp-evoked ASSR for testing hearing in adults and children of all ages and with different types of hearing loss, as well as normal hearing. The aims are: to determine whether there are possible influencing factors, mainly the degree of hearing loss; and to validate the clinical value of using ASSR with chirp-stimuli. This is a retrospective study of 667 patients who had been diagnosed with and treated for hearing loss at our tertiary referral center. The following results were compared: ASSR to pure tone audiometry (PTA); click-ABRs to PTA; and click-ABRs to ASSR. We then calculated mean, median and standard deviation. A regression analysis was used to examine the correlation between: ASSR and click-ABRs; "estimated" audiogram and PTA; click-ABRs and PTA; and ASSR and PTA. We found significant correlations at all frequencies when comparing ASSR to click-ABRs, click-ABRs to PTA, and ASSR to PTA. Concerning the degree of hearing loss, there were significant differences between the patients with normal hearing and those with moderate-to-profound hearing loss. ASSR with narrow-band chirps are a reliable tool for estimating hearing thresholds in children and adults with all kinds of hearing loss. We have demonstrated that threshold differences between PTA and ASSR are negligible in the clinical routine. The "estimated" ASSR audiogram is a good approach for communicating ASSR results to the average user.