Paired Clicks Research Articles

Effects of Breast Cancer Treatment on Neural Noise: a Longitudinal Design.

Cognitive dysfunction has been observed consistently in a subset of breast cancer survivors. Yet the precise neurophysiological origins of cancer-related cognitive decline remain unknown. The current study assessed neural noise (1/f activity in electroencephalogram [EEG]) in breast cancer survivors as a potential contributor to observed cognitive dysfunction from pre- to post-treatment. We measured EEG in a longitudinal design during performance of the paired-click task and the revised Attention Network Test (ANT-R) to investigate pre- versus post-treatment effects of neural noise in breast cancer patients (n = 20 in paired click; n = 19 in ANT-R) compared with healthy controls (n = 32 in paired click; n = 29 in ANT-R). In both paradigms, one sensory (paired click) and one cognitive (ANT-R), we found that neural noise was significantly elevated after treatment in patients, remaining constant from pretest to posttest in controls. In the ANT-R, patients responded more slowly than controls on invalid cuing trials. Increased neural noise was associated with poorer alerting and poorer inhibitory control of attention (as measured by behavioral network scores), particularly for patients after treatment. The current study is the first to show a deleterious effect of breast cancer and/or cancer treatment on neural noise, pointing to alterations in the relative balance of excitatory and inhibitory synaptic inputs, while also suggesting promising approaches for cognitive rehabilitation.

Bio-orthogonally Activatable Fluorescent Probe for Specific Imaging of Myeloid Cell Leukemia 1 Protein.

The antiapoptotic protein myeloid cell leukemia 1 (Mcl-1) has been increasingly identified as a promising potential therapeutic target attributed to its critical regulation effect in diverse cellar physiopathological events. Current fluorescence imaging strategies tend to be susceptible to the cellular microenvironment, and straightforward mapping of Mcl-1's level variation remains challenging. In this paper, an activatable "off-on" fluorescence strategy for Mcl-1 specific labeling was presented based on bio-orthogonal chemistry by introducing tetrazine-functionalized borondipyrromethene (TB) as a fluorescent reporter and trans-cyclooctyne-derived indole-2-carboxylic acid (TI) as an Mcl-1 targeting moiety. With the click pair of TB and TI, the Mcl-1 expression level in vitro and in vivo was successfully mapped straightforward. Also, the level changes of Mcl-1 upon drug challenge were demonstrated. This work provides a robust fluorescence strategy for Mcl-1 in situ imaging, and the results would further facilitate the comprehensive revelation of the Mcl-1 biological effect.

Alterations of auditory sensory gating in mice with noise-induced tinnitus treated with nicotine and cannabis extract.

Tinnitus is a phantom sound perception affecting both auditory and limbic structures. The mechanisms of tinnitus remain unclear and it is debatable whether tinnitus alters attention to sound and the ability to inhibit repetitive sounds, a phenomenon also known as auditory gating. Here we investigate if noise exposure interferes with auditory gating and whether natural extracts of cannabis or nicotine could improve auditory pre-attentional processing in noise-exposed mice. We used 22 male C57BL/6J mice divided into noise-exposed (exposed to a 9-11 kHz narrow band noise for 1 h) and sham (no sound during noise exposure) groups. Hearing thresholds were measured using auditory brainstem responses, and tinnitus-like behavior was assessed using Gap prepulse inhibition of acoustic startle. After noise exposure, mice were implanted with multi-electrodes in the dorsal hippocampus to assess auditory event-related potentials in response to paired clicks. The results showed that mice with tinnitus-like behavior displayed auditory gating of repetitive clicks, but with larger amplitudes and longer latencies of the N40 component of the aERP waveform. The combination of cannabis extract and nicotine improved the auditory gating ratio in noise-exposed mice without permanent hearing threshold shifts. Lastly, the longer latency of the N40 component appears due to an increased sensitivity to cannabis extract in noise-exposed mice compared to sham mice. The study suggests that the altered central plasticity in tinnitus is more sensitive to the combined actions on the cholinergic and the endocannabinoid systems. Overall, the findings contribute to a better understanding of pharmacological modulation of auditory sensory gating.

Auditory brainstem response recovery from forward masking in insectivorous and frugivorous bats

Echolocating bats rely on precise temporal processing of sound, as echolocation calls may be emitted at rates as high as 150–200 sounds per second in the terminal “buzz” phase that precedes prey capture by insectivorous species. High call repetition rates could introduce forward masking effects that interfere with echo detection; however, echolocating bats may have evolved auditory specializations to prevent repetition suppression of auditory responses and facilitate detection of sounds separated by very brief time intervals. We assessed the time course of post-stimulus recovery of the auditory brainstem response (ABR) in two bat species that differ in the temporal characteristics of their sonar behaviors: the insectivorous Eptesicus fuscus, which uses high sonar call rates to capture prey and the frugivorous Carollia perspicillata, which uses lower call rates to forage. We recorded forward-masking ABRs to paired clicks at varied inter-stimulus intervals and measured recovery from prior stimulation as the ratio of response amplitudes and latencies evoked by the second stimulus relative to the first. We observed significant species-specific effects of forward masking on ABR responses in which E. fuscus maintained comparable responses to ISIs less than 4 ms compared to longer post-stimulus response recovery times (>6 ms) in C. perspicillata.

Examining the impact of schizotypal personality traits on event-related potential (ERP) indexes of sensory gating in a healthy population.

The aim of this study was to better understand the relation of schizotypy traits with sensory gating ability in a sample of community-dwelling individuals with high and low schizotypy traits. Sensory gating was assessed through the paired click paradigm and mid-latency evoked responses (i.e., P50, N100, P200), while schizotypy traits were assessed through the SPQ-BR which was used to classify participants into "high" and "low" schizotypy groups. Based on prior work, we hypothesized that those with the highest schizotypy scores would have reduced sensory gating ability. While this study does not show differences between relatively low and high schizotypy groups on sensory gating ability, it does suggest that our participants may have been experiencing deficits in attention allocation, a downstream cognitive processing measure. Scores on the SPQ-BR suggest that our sample was not close to the high end of the schizotypy traits which may help explain why no differences were found. This research shows the importance of including all levels of schizotypy ratings in clinical research as we can gain a clearer view of the impact of schizotypy on the brain and cognitive functioning in those with "high" levels of schizotypy. Additionally, this work highlights the importance of including measures of important factors such as impulsivity and sensation-seeking to better understand what aspects of schizotypy may be driving these sensory gating alterations reported in the literature.

Sensory Inhibition and Speech Perception-in-Noise Performance in Children With Normal Hearing.

This study investigated whether sensory inhibition in children may be associated with speech perception-in-noise performance. Additionally, gating networks associated with sensory inhibition were identified via standardized low-resolution brain electromagnetic tomography (sLORETA), and the detectability of the cortical auditory evoked potential (CAEP) N1 response was enhanced using a 4- to 30-Hz bandpass filter. CAEP gating responses, reflective of inhibition, were evoked via click pairs and recorded using high-density electroencephalography in neurotypical 5- to 8-year-olds and 22- to 24-year-olds. Amplitude gating indices were calculated and correlated with speech perception in noise. Gating generators were estimated using sLORETA. A 4- to 30-Hz filter was applied to detect the N1 gating component. Preliminary findings indicate children showed reduced gating, but there was a correlational trend between better speech perception and decreased N2 gating. Commensurate with decreased gating, children presented with incomplete compensatory gating networks. The 4- to 30-Hz filter identified the N1 response in a subset of children. There was a tenuous relationship between children's speech perception and sensory inhibition. This may suggest that sensory inhibition is only implicated in atypically poor speech perception. Finally, the 4- to 30-Hz filter settings are critical in N1 detectability. Gating may help evaluate reduced sensory inhibition in children with clinically poor speech perception using the appropriate methodology. Cortical gating generators in typically developing children are also newly identified.

Hearing, echolocation, and beam steering from day 0 in tongue-clicking bats.

Little is known about the ontogeny of lingual echolocation. We examined the echolocation development of Rousettus aegyptiacus, the Egyptian fruit bat, which uses rapid tongue movements to produce hyper-short clicks and steer the beam's direction. We recorded from day 0 to day 35 postbirth and assessed hearing and beam-steering abilities. On day 0, R. aegyptiacus pups emit isolation calls and hyper-short clicks in response to acoustic stimuli, demonstrating hearing. Auditory brainstem response recordings show that pups are sensitive to pure tones of the main hearing range of adult Rousettus and to brief clicks. Newborn pups produced clicks in the adult paired pattern and were able to use their tongues to steer the sonar beam. As they aged, pups produced click pairs faster, converging with adult intervals by age of first flights (7–8 weeks). In contrast with laryngeal bats, Rousettus echolocation frequency and duration are stable through to day 35, but shift by the time pups begin to fly, possibly owing to tongue-diet maturation effects. Furthermore, frequency and duration shift in the opposite direction of mammalian laryngeal vocalizations. Rousettus lingual echolocation thus appears to be a highly functional sensory system from birth and follows a different ontogeny from that of laryngeal bats.

Facile Generation of Potent Bispecific Fab via Sortase A and Click Chemistry for Cancer Immunotherapy.

Simple SummaryThe formats of bispecific antibody have been investigated for many years to enhance the stability of the structure and anti-tumor efficacy. One of the formats combining two Fabs at their C termini provides unmodified variable region and comparable activity to other fragment-based bispecific antibodies that are usually combined in a head-to-tail manner. However, the current strategy to produce the BiFab molecule is limited to a semisynthetic method that introduces unnatural amino acid to antibodies’ sequences during production. To improve the application of BiFab format in investigational biodrugs, we have applied sortase A-mediated “bio-click” chemistry to generate BiFab, for facile assembly of Fab molecules that have been expressed and stored as BiFab module candidates. The BiFabs made by our method stimulate T cell proliferation and activation with favorable in vitro and in vivo anti-tumor activit. Our results indicate that BiFab made by sortase A-mediated click chemistry could be used to efficiently generate various BiFabs with high potency, which further supports personalized tumor immunotherapy in the future.Bispecific antibodies (BsAbs) for T cell engagement have shown great promise in cancer immunotherapy, and their clinical applications have been proven in treating hematological malignance. Bispecific antibody binding fragment (BiFab) represents a promising platform for generating non-Fc bispecific antibodies. However, the generation of BiFab is still challenging, especially by means of chemical conjugation. More conjugation strategies, e.g., enzymatic conjugation and modular BiFab preparation, are needed to improve the robustness and flexibility of BiFab preparation. We successfully used chemo-enzymatic conjugation approach to generate bispecific antibody (i.e., BiFab) with Fabs from full-length antibodies. Paired click handles (e.g., N3 and DBCO) was introduced to the C-terminal LPETG tag of Fabs via sortase A mediated transpeptidation, followed by site-specific conjugation between two click handle-modified Fabs for BiFab generation. Both BiFabCD20/CD3 (EC50 = 0.26 ng/mL) and BiFabHer2/CD3 exhibited superior efficacy in mediating T cells, from either PBMC or ATC, to kill target tumor cell lines while spared antigen-negative tumor cells in vitro. The BiFabCD20/CD3 also efficiently inhibited CD20-positive tumor growth in mouse xenograft model. We have established a facile sortase A-mediated click handle installation to generate homogeneous and functional BiFabs. The exemplary BiFabs against different targets showed superior efficacy in redirecting and activating T cells to specifically kill target tumor cells, demonstrating the robustness of sortase A-mediated “bio-click” chemistry in generating various potent BiFabs. This approach also holds promise for further efficient construction of a Fab derivative library for personalized tumor immunotherapy in the future.

Oscillatory connectivity as a mechanism of auditory sensory gating and its disruption in schizophrenia.

Although innumerable studies using an auditory sensory gating paradigm have confirmed that individuals with schizophrenia (SZ) show less reduction in brain response to the second in a pair of clicks, this large literature has not yielded consensus on the circuit(s) responsible for gating nor for the gating difference in SZ. Clinically stable adult inpatients (N=157) and matched community participants (N=90) participated in a standard auditory sensory gating protocol. Responses to paired clicks were quantified as peak-to-peak amplitude from a response at approximately 50ms to a response at approximately 100ms in MEG-derived source waveforms. For bilateral sources in each of four regions near Heschl's gyrus, the gating ratio was computed as the response to the second stimulus divided by the response to the first stimulus. Spectrally resolved Granger causality quantified effective connectivity among regions manifested in alpha-band oscillatory coupling before and during stimulation. Poorer sensory gating localized to A1 in SZ than in controls confirmed previous results, here found in adjacent brain regions as well. Spontaneous, stimulus-independent effective connectivity within the hemisphere from angular gyrus to portions of the superior temporal gyrus was lower in SZ and correlated with gating ratio. Significant involvement of frontal and subcortical brain regions previously proposed as contributing to the auditory gating abnormality was not found. Findings point to endogenous connectivity evident in a sequence of activity from angular gyrus to portions of superior temporal gyrus as a mechanism contributing to normal and abnormal gating in SZ and potentially to sensory and cognitive symptoms.

Auditory Brainstem Response to Paired Click Stimulation as an Indicator of Peripheral Synaptic Health in Noise-Induced Cochlear Synaptopathy.

IntroductionA defect in the cochlear afferent synapse between the inner hair cells and spiral ganglion neurons, after noise exposure, without changes in the hearing threshold has been reported. Animal studies on auditory evoked potentials demonstrated changes in the auditory brainstem response (ABR) measurements of peak I amplitude and the loss of synapses, which affect the temporal resolution of complex sounds. Human studies of auditory evoked potential have reported ambiguous results regarding the relationship between peak I amplitude and noise exposure. Paired click stimuli have been used to investigate the temporal processing abilities of humans and animals. In this study, we investigated the utility of measuring auditory evoked potentials in response to paired click stimuli to assess the temporal processing function of ribbon synapses in noise-induced cochlear synaptopathy.Materials and MethodsTwenty-two Sprague Dawley rats were used in this study, and synaptopathy was induced by narrow-band noise exposure (16 kHz with 1 kHz bandwidth, 105 dB sound pressure level for 2 h). ABRs to tone and paired click stimuli were measured before and 1, 3, 7, and 14 days after noise exposure. For histological analyses, hair cells and ribbon synapses were immunostained and the synapses quantified. The relationships among ABR peak I amplitude, number of synapses, and ABR to paired click stimuli were examined.ResultsOur results showed that ABR thresholds increase 1 day after noise exposure but fully recover to baseline levels after 14 days. Further, we demonstrated test frequency-dependent decreases in peak I amplitude and the number of synapses after noise exposure. These decreases were statistically significant at frequencies of 16 and 32 kHz. However, the ABR recovery threshold to paired click stimuli increased, which represent deterioration in the ability of temporal auditory processing. Our results indicate that the ABR recovery threshold is highly correlated with ABR peak I amplitude after noise exposure. We also established a direct correlation between the ABR recovery threshold and histological findings.ConclusionThe result from this study suggests that in animal studies, the ABR to paired click stimuli along with peak I amplitude has potential as an assessment tool for hidden hearing loss.

Classification of biosonar target echoes based on coarse and fine spectral features in the bottlenose dolphin (Tursiops truncatus)

Previous bottlenose dolphin studies suggest that the coarse envelope of an echo spectrum ("macrostructure") has hierarchical dominance over finer-scale spectral features ("microstructure") during synthetic echo discrimination tasks. In this study, two dolphins listened to and discriminated between underwater sound stimuli consisting of pairs of clicks with different micro- and macrostructures. After conditioning dolphins to reliably discriminate between two "anchor" stimuli with different micro- and macrostructures, probe stimuli, which contained a macrostructure identical to one of the anchor stimuli and the microstructure of the alternate anchor, were infrequently presented. Dolphins responded to probes in a manner consistent with macrostructure primacy.

A Novel Wearable Device for Motor Recovery of Hand Function in Chronic Stroke Survivors

Background. In monkey, reticulospinal connections to hand and forearm muscles are spontaneously strengthened following corticospinal lesions, likely contributing to recovery of function. In healthy humans, pairing auditory clicks with electrical stimulation of a muscle induces plastic changes in motor pathways (probably including the reticulospinal tract), with features reminiscent of spike-timing dependent plasticity. In this study, we tested whether pairing clicks with muscle stimulation could improve hand function in chronic stroke survivors. Methods. Clicks were delivered via a miniature earpiece; transcutaneous electrical stimuli at motor threshold targeted forearm extensor muscles. A wearable electronic device (WD) allowed patients to receive stimulation at home while performing normal daily activities. A total of 95 patients >6 months poststroke were randomized to 3 groups: WD with shock paired 12 ms before click; WD with clicks and shocks delivered independently; standard care. Those allocated to the device used it for at least 4 h/d, every day for 4 weeks. Upper-limb function was assessed at baseline and weeks 2, 4, and 8 using the Action Research Arm Test (ARAT), which has 4 subdomains (Grasp, Grip, Pinch, and Gross). Results. Severity across the 3 groups was comparable at baseline. Only the paired stimulation group showed significant improvement in total ARAT (median baseline: 7.5; week 8: 11.5; P = .019) and the Grasp subscore (median baseline: 1; week 8: 4; P = .004). Conclusion. A wearable device delivering paired clicks and shocks over 4 weeks can produce a small but significant improvement in upper-limb function in stroke survivors.

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.

The Binaural Interaction Component of the Auditory Brainstem Response Under Precedence Effect Conditions.

The purpose of this study was to measure the binaural interaction component (BIC) derived from click-evoked auditory brainstem responses (ABRs) using stimuli configured to elicit the Precedence Effect. The hypothesis was that the contribution of binaural processing to echo suppression can be evidenced by a diminished or absent BIC associated with the echo. Ten normal-hearing young adults provided ABRs generated by sequences of click pairs. Results showed that BICs elicited by diotic clicks in isolation were obliterated when those diotic clicks were preceded by a click pair having an interaural time difference of 400 µs and where the interclick interval was 8.4 ms. The presence of the leading click pair increased the latency of the ABR generated by the lagging diotic click pair but did not decrease its amplitude. The results were interpreted as indicating a contribution of binaural processing at the level of the brainstem to echo suppression, at least for the conditions tested here.

Photobiomodulation using low-level 808 nm diode laser rescues cochlear synaptopathy after acoustic overexposure in rat.

A certain degree of noise can cause hearing problems without a permanent change in the hearing threshold, which is called hidden hearing loss and results from partial loss of auditory synapses. Photobiomodulation (PBM) enhances neural growth and connections in the peripheral nervous systems. In this study, we assessed whether PBM could rescue cochlear synaptopathy after acoustic overexposure in rat. PBM was performed for 7 days after noise exposure. The auditory brainstem responses (ABRs) were acquired before and after noise exposure using a tone and a paired-click stimulus. Auditory response to paired click sound with short time interval was performed to evaluate auditory temporal processing ability. In the result, hearing threshold recovered 2 weeks after noise exposure in both groups. Peak wave 1 amplitude of the ABR and ABR recovery threshold did not recover in the noise only group, whereas it fully recovered in the noise + PBM group. The number of synaptic ribbons was significantly different in the control and noise only groups, while there was no difference between the control and noise + PBM group. These results indicate that PBM rescued peak wave 1 amplitude and maintained the auditory temporal processing ability resulting from a loss of synaptic ribbons after acoustic overexposure.

Synthesis of stable azide and alkyne functionalized phosphoramidite nucleosides

The use of CuAAC chemistry to crosslink and stabilize oligonucleotides has been limited by the incompatibility of azides with the phosphoramidites used in automated oligonucleotide synthesis. Herein we report optimized reaction conditions to synthesize azide derivatives of thymidine and cytidine phosphoramidites. Investigation of the stability of the novel phosphoramidites using 31P NMR at room temperature showed less than 10% degradation after 6 h. The azide modified thymidine was successfully utilized as an internal modifier in the standard phosphoramidite synthesis of a DNA sequence. The synthesized azide and alkyne derivatives of pyrimidines will allow efficient incorporation of azide and alkyne click pairs into nucleic acids, thus widening the applicability of click chemistry in investigating the chemistry of nucleic acids.

Evoked Potentials Investigations of Deficit Versus Nondeficit Schizophrenia: EEG-MEG Preliminary Data.

Heterogeneity of schizophrenia is a major obstacle toward understanding the disorder. One likely subtype is the deficit syndrome (DS) where patients suffer from predominantly negative symptoms. This study investigated the evoked responses and the evoked magnetic fields to identify the neurophysiological deviations associated with the DS. Ten subjects were recruited for each group (Control, DS, and Nondeficit schizophrenia [NDS]). Subjects underwent magnetoencephalography (MEG) and electroencephalography (EEG) testing while listening to an oddball paradigm to generate the P300 as well as a paired click paradigm to generate the mid-latency auditory-evoked responses (MLAER) in a sensory gating paradigm. MEG-coherence source imaging (CSI) during P300 task revealed a significantly higher average coherence value in DS than NDS subjects in the gamma band (30-80 Hz), when listening to standard stimuli but only NDS subjects had a higher average coherence level in the gamma band than controls when listening to the novel sounds. P50, N100, and P3a ERP amplitudes (EEG analysis) were significantly decreased in NDS compared with DS subjects. The data suggest that the deviations in the 2 patient groups are qualitatively different. Deviances in NDS patients suggest difficulty in both early (as in the gating paradigm), as well as later top-down processes (P300 paradigm). The main deviation in the DS group was an exaggerated responsiveness to ongoing irrelevant stimuli detected by EEG whereas NDS subjects had an exaggerated response to novelty.

Forward masking recovery in bottlenose dolphins (Tursiops truncatus): Auditory brainstem responses to paired-click stimuli in high-pass masking noise

Adaptation is a fundamental process in the auditory system and underlies the automatic gain control system of echolocating bottlenose dolphins. As pulse-echo delay increases, auditory brainstem response (ABR) amplitudes to the echoes progressively increase. This study examined adaptation across cochlear frequency regions using a paired-click (i.e., forward masking) paradigm and high-pass masking noise. Bottlenose dolphins passively listened to paired click stimuli (20–160 kHz “pink” spectra). A “conditioning” click was followed by a “probe” click with equal amplitude and a time delay ranging from 125 to 750 μs. ABRs to click pairs were obtained with and without high-pass masking noise that precluded the basal turn of the cochlea from responding to the click stimuli. The ABR evoked by a single click (temporally aligned with the first click of the paired-click condition) was subtracted from the click-pair ABR to visualize the response evoked by the probe click. Probe ABR amplitudes recovered linearly with increasing delay relative to the conditioning click, and were approximately 70% of full response amplitude at 750-μs delay. Paired-click interval ABR amplitude recovery functions were similar for the unmasked and high-pass masked conditions. [Work sponsored by ONR.]

Temporal Ventriloquism Reveals Intact Audiovisual Temporal Integration in Amblyopia.

We have shown previously that amblyopia involves impaired detection of asynchrony between auditory and visual events. To distinguish whether this impairment represents a defect in temporal integration or nonintegrative multisensory processing (e.g., cross-modal matching), we used the temporal ventriloquism effect in which visual temporal order judgment (TOJ) is normally enhanced by a lagging auditory click. Participants with amblyopia (n = 9) and normally sighted controls (n = 9) performed a visual TOJ task. Pairs of clicks accompanied the two lights such that the first click preceded the first light, or second click lagged the second light by 100, 200, or 450 ms. Baseline audiovisual synchrony and visual-only conditions also were tested. Within both groups, just noticeable differences for the visual TOJ task were significantly reduced compared with baseline in the 100- and 200-ms click lag conditions. Within the amblyopia group, poorer stereo acuity and poorer visual acuity in the amblyopic eye were significantly associated with greater enhancement in visual TOJ performance in the 200-ms click lag condition. Audiovisual temporal integration is intact in amblyopia, as indicated by perceptual enhancement in the temporal ventriloquism effect. Furthermore, poorer stereo acuity and poorer visual acuity in the amblyopic eye are associated with a widened temporal binding window for the effect. These findings suggest that previously reported abnormalities in audiovisual multisensory processing may result from impaired cross-modal matching rather than a diminished capacity for temporal audiovisual integration.

Effects of GABA-B receptor positive modulator on ketamine-induced psychosis-relevant behaviors and hippocampal electrical activity in freely moving rats.

Decreased GABAB receptor function is proposed to mediate some symptoms of schizophrenia. In this study, we tested the effect of CGP7930, a GABAB receptor positive allosteric modulator, on ketamine-induced psychosis-relevant behaviors and hippocampal electrical activity in behaving rats. Electrodes were bilaterally implanted into the hippocampus, and cannulae were placed into the lateral ventricles of Long-Evans rats. CGP7930 or vehicle was injected intraperitoneally (i.p.) or intracerebroventricularly (i.c.v.), alone or 15min prior to ketamine (3mg/kg, subcutaneous) injection. Paired click auditory evoked potentials in the hippocampus (AEP), prepulse inhibition (PPI), and locomotor activity were recorded before and after drug injection. CGP7930 at doses of 1mg/kg (i.p.) prevented ketamine-induced deficit of PPI. CGP7930 (1mg/kg i.p.) also prevented the decrease in gating of hippocampal AEP and the increase in hippocampal gamma (65-100Hz) waves induced by ketamine. Unilateral i.c.v. infusion of CGP7930 (0.3mM/1μL) also prevented the decrease in gating of hippocampal AEP induced by ketamine. Ketamine-induced behavioral hyperlocomotion was suppressed by 5mg/kg i.p. CGP7930. CGP7930 alone, without ketamine, did not significantly affect integrated PPI, locomotion, gating of hippocampal AEP, or gamma waves. CGP7930 (1mg/kg i.p.) increased heterosynaptically mediated paired pulse depression in the hippocampus, a measure of GABAB receptor function in vivo. CGP7930 reduces the behavioral and electrophysiological disruptions induced by ketamine in animals, and the hippocampus may be one of the neural targets where CGP7930 exerts its actions.