Frequency-following responses (FFRs) were recorded to two naturally produced vowels (/a/ and /i/) in normal hearing subjects. A digitally implemented Fourier analyzer was used to measure response amplitude at the fundamental frequency and at 23 higher harmonics. Response components related to the stimulus envelope (

OBJECTIVE: To investigate the temporal relationship between speech auditory brainstem responses and acoustic pattern of the phoneme /ba/. METHODS: Speech elicited auditory brainstem responses (Speech ABR) to /ba/ were recorded in 23 normal-hearing subjects. Effect of stimulus intensity was assessed on Speech ABR components latencies in 11 subjects. The effect of different transducers on electromagnetic leakage was also measured. RESULTS: Speech ABR showed a reproducible onset response (OR) 6ms after stimulus onset. The frequency following response (FFR) waveform mimicked the 500Hz low pass filtered temporal waveform of phoneme /ba/ with a latency shift of 14.6ms. In addition, the OR and FFR latencies decreased with increasing stimulus intensity, with a greater rate for FFR (-1.4ms/10dB) than for OR (-0.6ms/10dB). CONCLUSIONS: A close relationship was found between the pattern of the acoustic stimulus and the FFR temporal structure. Furthermore, differences in latency behaviour suggest different generation mechanisms for FFR and OR. SIGNIFICANCE: The results provided further insight into the temporal encoding of basic speech stimulus at the brainstem level in humans.

OBJECTIVE: Listeners with sensorineural hearing loss (SNHL) typically experience reduced speech perception, which is not completely restored with amplification. This likely occurs because cochlear damage, in addition to elevating audiometric thresholds, alters the neural representation of speech transmitted to higher centers along the auditory neuroaxis. While the deleterious effects of SNHL on speech perception in humans have been well-documented using behavioral paradigms, our understanding of the neural correlates underlying these perceptual deficits remains limited. Using the scalp-recorded frequency following response (FFR), the authors examine the effects of SNHL and aging on subcortical neural representation of acoustic features important for pitch and speech perception, namely the periodicity envelope (F0) and temporal fine structure (TFS; formant structure), as reflected in the phase-locked neural activity generating the FFR. DESIGN: FFRs were obtained from 10 listeners with normal hearing (NH) and 9 listeners with mild-moderate SNHL in response to a steady-state English back vowel /u/ presented at multiple intensity levels. Use of multiple presentation levels facilitated comparisons at equal sound pressure level (SPL) and equal sensation level. In a second follow-up experiment to address the effect of age on envelope and TFS representation, FFRs were obtained from 25 NH and 19 listeners with mild to moderately severe SNHL to the same vowel stimulus presented at 80 dB SPL. Temporal waveforms, Fast Fourier Transform and spectrograms were used to evaluate the magnitude of the phase-locked activity at F0 (periodicity envelope) and F1 (TFS). RESULTS: Neural representation of both envelope (F0) and TFS (F1) at equal SPLs was stronger in NH listeners compared with listeners with SNHL. Also, comparison of neural representation of F0 and F1 across stimulus levels expressed in SPL and sensation level (accounting for audibility) revealed that level-related changes in F0 and F1 magnitude were different for listeners with SNHL compared with listeners with NH. Furthermore, the degradation in subcortical neural representation was observed to persist in listeners with SNHL even when the effects of age were controlled for. CONCLUSIONS: Overall, our results suggest a relatively greater degradation in the neural representation of TFS compared with periodicity envelope in individuals with SNHL. This degraded neural representation of TFS in SNHL, as reflected in the brainstem FFR, may reflect a disruption in the temporal pattern of phase-locked neural activity arising from altered tonotopic maps and/or wider filters causing poor frequency selectivity in these listeners. Finally, while preliminary results indicate that the deleterious effects of SNHL may be greater than age-related degradation in subcortical neural representation, the lack of a balanced age-matched control group in this study does not permit us to completely rule out the effects of age on subcortical neural representation.

The startle response may interrupt information processing (interruption hypothesis), and prepulse inhibition of startle (PPI) may protect that processing from interruption (protection hypothesis). These hypotheses were tested by measuring startle eyeblinks during an Attention Network Test (ANT), a combined flanker and cue reaction time (RT) task that measures the efficiency of multiple attentional networks. ANT trials with and without startle stimuli presented in the interval between the visual cue (prepulse) and target were compared. Results showed that the startle stimulus served as an alerting stimulus, speeding RT in the ANT. However, this reaction time speeding was most pronounced on trials with no startle response (100% PPI). This suggests that the alerting effect of the startle stimulus was attenuated by the startle response, and that PPI decreased the degree of this interference, in support of the interruption and protection hypotheses.

Feedforward inhibition deficits have been consistently demonstrated in a range of neuropsychiatric conditions using prepulse inhibition (PPI) of the acoustic startle eye-blink reflex when assessing sensorimotor gating. While PPI can be recorded in acutely decerebrated rats, behavioural, pharmacological and psychophysiological studies suggest the involvement of a complex neural network extending from brainstem nuclei to higher order cortical areas. The current functional magnetic resonance imaging study investigated the neural network underlying PPI and its association with electromyographically (EMG) recorded PPI of the acoustic startle eye-blink reflex in 16 healthy volunteers. A sparse imaging design was employed to model signal changes in blood oxygenation level-dependent (BOLD) responses to acoustic startle probes that were preceded by a prepulse at 120 ms or 480 ms stimulus onset asynchrony or without prepulse. Sensorimotor gating was EMG confirmed for the 120-ms prepulse condition, while startle responses in the 480-ms prepulse condition did not differ from startle alone. Multiple regression analysis of BOLD contrasts identified activation in pons, thalamus, caudate nuclei, left angular gyrus and bilaterally in anterior cingulate, associated with EMG-recorded sensorimotor gating. Planned contrasts confirmed increased pons activation for startle alone vs 120-ms prepulse condition, while increased anterior superior frontal gyrus activation was confirmed for the reverse contrast. Our findings are consistent with a primary pontine circuitry of sensorimotor gating that interconnects with inferior parietal, superior temporal, frontal and prefrontal cortices via thalamus and striatum. PPI processes in the prefrontal, frontal and superior temporal cortex were functionally distinct from sensorimotor gating.

Considerable progress has been made in our understanding of the remarkable fidelity with which the human auditory brainstem represents key acoustic features of the speech signal. The brainstem response to speech can be assessed noninvasively by examining scalp-recorded evoked potentials. Morphologically, two main components of the scalp-recorded brainstem response can be differentiated, a transient onset response and a sustained frequency-following response (FFR). Together, these two components are capable of conveying important segmental and suprasegmental information inherent in the typical speech syllable. Here we examine the putative neural sources of the scalp-recorded brainstem response and review recent evidence that demonstrates that the brainstem response to speech is dynamic in nature and malleable by experience. Finally, we propose a putative mechanism for experience-dependent plasticity at the level of the brainstem.

Crowding, the identification difficulty for a target in the presence of nearby flankers, is ubiquitous in spatial vision and is considered a bottleneck of object recognition and visual awareness. Despite its significance, the neural mechanisms of crowding are still unclear. Here, we performed event-related potential and fMRI experiments to measure the cortical interaction between the target and flankers in human subjects. We found that the magnitude of the crowding effect was closely associated with an early suppressive cortical interaction. The cortical suppression was reflected in the earliest event-related potential component (C1), which originated in V1, and in the BOLD signal in V1, but not other higher cortical areas. Intriguingly, spatial attention played a critical role in the manifestation of the suppression. These findings provide direct and converging evidence that attention-dependent V1 suppression contributes to crowding at a very early stage of visual processing.

The frequency-following response (FFR) is a measure of the brain's periodic sound encoding. It is of increasing importance for studying the human auditory nervous system due to numerous associations with auditory cognition and dysfunction. Although the FFR is widely interpreted as originating from brainstem nuclei, a recent study using MEG suggested that there is also a right-lateralized contribution from the auditory cortex at the fundamental frequency (Coffey et al., 2016b). Our objectives in the present work were to validate and better localize this result using a completely different neuroimaging modality and to document the relationships between the FFR, the onset response, and cortical activity. Using a combination of EEG, fMRI, and diffusion-weighted imaging, we show that activity in the right auditory cortex is related to individual differences in FFR-fundamental frequency (f0) strength, a finding that was replicated with two independent stimulus sets, with and without acoustic energy at the fundamental frequency. We demonstrate a dissociation between this FFR-f0-sensitive response in the right and an area in left auditory cortex that is sensitive to individual differences in the timing of initial response to sound onset. Relationships to timing and their lateralization are supported by parallels in the microstructure of the underlying white matter, implicating a mechanism involving neural conduction efficiency. These data confirm that the FFR has a cortical contribution and suggest ways in which auditory neuroscience may be advanced by connecting early sound representation to measures of higher-level sound processing and cognitive function. SIGNIFICANCE STATEMENT: The frequency-following response (FFR) is an EEG signal that is used to explore how the auditory system encodes temporal regularities in sound and is related to differences in auditory function between individuals. It is known that brainstem nuclei contribute to the FFR, but recent findings of an additional cortical source are more controversial. Here, we use fMRI to validate and extend the prediction from MEG data of a right auditory cortex contribution to the FFR. We also demonstrate a dissociation between FFR-related cortical activity from that related to the latency of the response to sound onset, which is found in left auditory cortex. The findings provide a clearer picture of cortical processes for analysis of sound features.

This article reviews the event-related potential (ERP) literature in relation to the P2 waveform of the human auditory evoked potential. Within the auditory evoked potential, a positive deflection at approximately 150-250 ms is a ubiquitous feature. Unlike other cognitive components such as N1 or the P300, remarkably little has been done to investigate the underlying neurological correlates or significance of this waveform. Indeed until recently, many researchers considered it to be an intrinsic part of the 'vertex potential' complex, involving it and the earlier N1. This review seeks to describe the evidence supportive of P2 being the result of independent processes and highlights several features, such as its persistence from wakefulness into sleep, the general consensus that unlike most other EEG phenomena it increases with age, and the fact that it can be generated using respiratory stimuli.

Despite advances in the treatment of schizophrenia spectrum disorders with atypical antipsychotics (AAPs), there is still need for compounds with improved efficacy/side-effect ratios. Evidence from challenge studies suggests that the assessment of gating functions in humans and rodents with naturally low-gating levels might be a useful model to screen for novel compounds with antipsychotic properties. To further evaluate and extend this translational approach, three AAPs were examined. Compounds without antipsychotic properties served as negative control treatments. In a placebo-controlled, within-subject design, healthy males received either single doses of aripiprazole and risperidone (n=28), amisulpride and lorazepam (n=30), or modafinil and valproate (n=30), and placebo. Prepulse inhibiton (PPI) and P50 suppression were assessed. Clinically associated symptoms were evaluated using the SCL-90-R. Aripiprazole, risperidone, and amisulpride increased P50 suppression in low P50 gaters. Lorazepam, modafinil, and valproate did not influence P50 suppression in low gaters. Furthermore, low P50 gaters scored significantly higher on the SCL-90-R than high P50 gaters. Aripiprazole increased PPI in low PPI gaters, whereas modafinil and lorazepam attenuated PPI in both groups. Risperidone, amisulpride, and valproate did not influence PPI. P50 suppression in low gaters appears to be an antipsychotic-sensitive neurophysiologic marker. This conclusion is supported by the association of low P50 suppression and higher clinically associated scores. Furthermore, PPI might be sensitive for atypical mechanisms of antipsychotic medication. The translational model investigating differential effects of AAPs on gating in healthy subjects with naturally low gating can be beneficial for phase II/III development plans by providing additional information for critical decision making.

A good deal is now known about the neural circuitry involved in how conditioned fear can augment a simple reflex (fear-potentiated startle). This involves visual or auditory as well as shock pathways that project via the thalamus and perirhinal or insular cortex to the basolateral amygdala (BLA). The BLA projects to the central (CeA) and medial (MeA) nuclei of the amygdala, which project indirectly to a particular part of the acoustic startle pathway in the brainstem. N-methyl-D-aspartate (NMDA) receptors, as well as various intracellular cascades in the amygdala, are critical for fear learning, which is then mediated by glutamate acting in the CeA. Less predictable stimuli, such as a long-duration bright light or a fearful context, activate the BLA, which projects to the bed nucleus of the stria terminalis (BNST), which projects to the startle pathway much as the CeA does. The anxiogenic peptide corticotropin-releasing hormone increases startle by acting directly in the BNST. CeA-mediated behaviors may represent stimulus-specific fear, whereas BNST-mediated behaviors are more akin to anxiety. NMDA receptors are also involved in extinction of conditioned fear, and both extinction in rats and exposure-based psychotherapy in humans are facilitated by an NMDA-partial agonist called D-cycloserine. ((c) 2006 APA, all rights reserved).

The startle reflex (SR) elicited by abrupt stimuli can be modified by attention to nonstartling stimuli that shortly precede the startle-eliciting stimulus. The present study of 15 recent-onset, relatively asymptomatic schizophrenic outpatients and 14 demographically matched normal control subjects demonstrated that attentional modulation of SR is impaired in schizophrenic patients. Specifically, the control group exhibited greater startle eye-blink modification following to-be-attended prestimuli than following to-be-ignored prestimuli, whereas the patients failed to show the attentional modulation effect. These results suggest traitlike attentional deficits in schizophrenia because the patients were relatively asymptomatic. The measurement of attentional modulation of SR may provide a nonverbal, reflexive, state-independent marker of the vulnerability to schizophrenia.

Schizophrenia patients have been shown to have a defective sensorimotor gating process as indexed by impaired prepulse inhibition of the startle eyeblink reflex. Moreover, we have previously reported that schizophrenia patients have dysfunctional attentional modulation of prepulse inhibition. The present experiment combined our previous sample of 14 schizophrenia outpatients and 12 demographically matched control subjects with a new sample of 10 outpatients and 6 control subjects. All participants performed a tone-length judgement task that involved attending to one pitch of tone (the attended prepulse) and ignoring another pitch of tone (the ignored prepulse). During this task the acoustic startle eyeblink reflex was electromyographically recorded from the orbicularis oculi muscle. The results replicated the finding of impaired attentional modulation of prepulse inhibition in the new sample of schizophrenia outpatients compared to demographically matched control subjects. Specifically, the new control group exhibited greater startle modification during the attended prepulse, whereas the new patient group failed to show this differential effect. In addition, impaired prepulse inhibition following the attended prepulse was significantly correlated with heightened delusions, conceptual disorganization, and suspiciousness as measured with the expanded Brief Psychiatric Rating Scale. These correlations were significant with prepulse inhibition to the attended prepulse but not with prepulse inhibition to the ignored prepulse. Impaired prepulse inhibition was not correlated with negative symptoms. All in all, the results support the hypothesis that impaired attentional modulation of startle prepulse inhibition reflects basic neurocognitive processes related to thought disorder in schizophrenia.

The primate visual brain is classically portrayed as a large number of separate 'maps', each dedicated to the processing of specific visual cues, such as colour, motion or faces and their many features. In order to understand this fractionated architecture, the concept of cortical 'pathways' or 'streams' was introduced. In the currently prevailing view, the different maps are organised hierarchically into two major pathways, one involved in recognition and memory (the ventral stream or 'what' pathway) and the other in the programming of action (the dorsal stream or 'where' pathway). In this review, we question this heuristically influential but potentially misleading linear hierarchical pathway model and argue instead for a 'patchwork' or network model.

The most critical attribute of human language is its unbounded combinatorial nature: smaller elements can be combined into larger structures on the basis of a grammatical system, resulting in a hierarchy of linguistic units, such as words, phrases and sentences. Mentally parsing and representing such structures, however, poses challenges for speech comprehension. In speech, hierarchical linguistic structures do not have boundaries that are clearly defined by acoustic cues and must therefore be internally and incrementally constructed during comprehension. We found that, during listening to connected speech, cortical activity of different timescales concurrently tracked the time course of abstract linguistic structures at different hierarchical levels, such as words, phrases and sentences. Notably, the neural tracking of hierarchical linguistic structures was dissociated from the encoding of acoustic cues and from the predictability of incoming words. Our results indicate that a hierarchy of neural processing timescales underlies grammar-based internal construction of hierarchical linguistic structure.

Speech and music have structured rhythms. Here we discuss a major acoustic correlate of spoken and musical rhythms, the slow (0.25-32Hz) temporal modulations in sound intensity and compare the modulation properties of speech and music. We analyze these modulations using over 25h of speech and over 39h of recordings of Western music. We show that the speech modulation spectrum is highly consistent across 9 languages (including languages with typologically different rhythmic characteristics). A different, but similarly consistent modulation spectrum is observed for music, including classical music played by single instruments of different types, symphonic, jazz, and rock. The temporal modulations of speech and music show broad but well-separated peaks around 5 and 2Hz, respectively. These acoustically dominant time scales may be intrinsic features of speech and music, a possibility which should be investigated using more culturally diverse samples in each domain. Distinct modulation timescales for speech and music could facilitate their perceptual analysis and its neural processing.

Prepulse inhibition (PPI) is the suppression of the startle reflex, when a weaker non-startling sensory stimulus (the prepulse) precedes the intense startling stimulus. Although the basic PPI neural circuitry resides in the brainstem, PPI can be enhanced by selective attention to the prepulse, indicating that this sensorimotor-gating process is influenced by higher-order perceptual/cognitive processes. Along with the auditory cortex, the brain structures involved in attentional modulations of PPI include both the lateral nucleus of the amygdala (LA), which contributes to the fear-conditioning modulation, and the posterior parietal cortex (PPC), which contributes to the spatially attentional modulation. The deeper layers of the superior colliculus (DpSC), which has been suggested as a midbrain component in the PPI circuitry, receive descending axonal projections from some forebrain structures associated with auditory perception, emotional conditioning, or spatial attention. This study was to examine whether the DpSC are also involved in attentional modulations of PPI in rats. The results showed that both fear conditioning of a prepulse sound and precedence-effect-induced perceptual separation between the conditioned prepulse and a noise masker facilitated selective attention to the prepulse and consequently enhanced PPI. Reversibly blocking glutamate receptors in the DpSC with 2-mM kynurenic acid eliminated both the conditioning-induced and the perceptual-separation-induced PPI enhancements. However, the baseline magnitudes of startle and PPI were not affected. The results suggest that the DpSC play a role in mediating the attentional enhancements of PPI, probably through both receiving top-down signals from certain forebrain structures and modulating the midbrain representations of prepulse signals.

How do we recognize what one person is saying when others are speaking at the same time? The

Prepulse inhibition (PPI), the suppression of the startle reflex by a preceding sensory stimulus (prepulse), can be top-down modulated in both humans and rats. This study investigated whether emotional-learning-induced enhancement of PPI in rats is prepulse specific. The results show that in socially reared rats, PPI elicited by a narrowband-noise prepulse on the broadband-noise background (masker) was enhanced after the prepulse became fear conditioned. This fear-conditioning-modulated PPI was further enhanced by introducing a perceived spatial separation between the conditioned prepulse and the broadband-noise masker. However, these PPI enhancements disappeared if the conditioned prepulse was replaced by a different narrowband-noise prepulse that was not fear conditioned. In isolation-reared rats, who had both enhanced baseline startle and reduced PPI before conditioning, neither fear conditioning of the prepulse nor perceived spatial separation between the conditioned prepulse and noise masker could enhance PPI. Thus, the emotional-learning-induced enhancement of PPI in socially reared rats is prepulse specific, indicating that auditory processing interacts with mnemonic signaling in the formation of top-down modulation of PPI. Since the deficiency of attentional modulation of PPI in schizophrenic patients is correlated with the symptom severity, the deficiency of top-down modulations of PPI in isolation-reared rats is useful for modeling schizophrenia.

Prepulse inhibition (PPI) of startle is the suppression of the startle reflex when a weaker sensory stimulus (the prepulse) shortly precedes the startling stimulus. PPI can be attentionally enhanced in both humans and laboratory animals. This study investigated whether the following three forebrain structures, which are critical for initial cortical processing of auditory signals, auditory fear conditioning/memories, and spatial attention, respectively, play a role in the top-down modulation of PPI in rats: the primary auditory cortex (A1), lateral nucleus of the amygdala (LA), and posterior parietal cortex (PPC). The results show that, under the noise-masking condition, PPI was enhanced by fear conditioning of the prepulse in a prepulse-specific manner, and the conditioning-induced PPI enhancement was further increased by perceptual separation between the conditioned prepulse and the noise masker. Reversibly blocking glutamate receptors in the A1 with 2 mm kynurenic acid eliminated both the conditioning-induced and perceptual separation-induced PPI enhancements. Blocking the LA eliminated the conditioning-induced but not the perceptual separation-induced PPI enhancement, and blocking the PPC specifically eliminated the perceptual separation-induced PPI enhancement. The two types of PPI enhancements were also eliminated by the extinction manipulation. Thus, the top-down modulation of PPI is differentially organized and depends on operations of various forebrain structures. Due to the fine-tuned modulation by higher-order cognitive processes, functions of PPI can be more flexible to complex environments. The top-down enhancements of PPI in rats are also useful for modeling some mental disorders, such as schizophrenia, attention deficit/hyperactivity disorder, and posttraumatic stress disorder.

The human startle eyeblink reflex is reliably modified by both cognitive and emotional processes. This review provides a comprehensive survey of the current literature on human startle modification and its psychological significance. Issues raised for short lead interval startle inhibition include its interpretation as a measure of protection of processing, sensorimotor gating and early attentional processing. For long lead interval effects, interpretations related to attentional and emotional processing are discussed. Also reviewed are clinical applications to information processing dysfunctions in the schizophrenia spectrum disorders, and to emotional processing disorders. Finally, an integrative summary that incorporates most of the cognitive findings is presented and directions for future research are identified regarding both cognitive and emotional modification of startle.

This study investigated how confusability between target and masking utterances affects the masking release achieved through spatial separation. Important distinguishing characteristics between competing voices were removed by processing speech with six-channel envelope vocoding, which simulates some aspects of listening with a cochlear implant. In the first experiment, vocoded target nonsense sentences were presented against two-talker vocoded maskers in conditions that provide different spatial impressions but not reliable cues that lead to traditional release from masking. Surprisingly, no benefit of spatial separation was found. The absence of spatial release was hypothesized to be the result of the highly positive target-to-masker ratios necessary to understand vocoded speech, which may have been sufficient to reduce confusability. In experiment 2, words excised from the vocoded nonsense sentences were presented against the same vocoded two-talker masker in a four-alternative forced-choice detection paradigm where threshold performance was achieved at negative target-to-masker ratios. Here, the spatial release from masking was more than 20 dB. The results suggest the importance of signal-to-noise ratio in the observation of

Some fifty years after the first physiological studies of auditory attention, the field is now ripening, with exciting recent insights into the psychophysics, psychology, and neural basis of auditory attention. Current research seeks to unravel the complex interactions of pre-attentive and attentive processing of the acoustic scene, the role of auditory attention in mediating receptive-field plasticity in both auditory spatial and auditory feature processing, the contrasts and parallels between auditory and visual attention pathways and mechanisms, the interplay of bottom-up and top-down attentional mechanisms, the influential role of attention, goals, and expectations in shaping auditory processing, and the orchestration of diverse attentional effects at multiple levels from the cochlea to the cortex.

Selective attention modifies long-latency cortical event-related potentials. Amplitudes are typically enhanced and/or latencies reduced when evoking stimuli are attended. However, there is controversy concerning the effects of selective attention on short-latency brain stem evoked potentials. The objective of the present study was to assess possible attention effects on the brain stem auditory frequency-following response (FFR) elicited by a periodic tone. Young adult subjects heard a repetitive auditory stimulus while detecting infrequent target stimuli in either an auditory or visual detection task. Five channels of high frequency electroencephalographic (EEG) activity were recorded along the scalp midline with the center electrode positioned at the vertex. The FFR was elicited by the repetitive tone during both tasks. There were significant individual differences in the electrode sites yielding maximum response amplitudes, but overall FFR amplitudes were significantly larger during the auditory attention task. These results suggest that selective attention in humans can modify signal processing in sensory (afferent) pathways at the level of the brain stem. This may reflect top-down perceptual preprocessing mediated by extensive descending (efferent) pathways that originate in the cortex. Overall, the FFR appears to be a robust indicator of early auditory neural processing and shows effects not seen in brain stem auditory evoked response studies employing transient (click) acoustic stimuli.

The frequency following response (FFR) in humans has been elicited by continuous tones as well as tone bursts. The responses were observable over a range of frequencies extending from 70 c/sec to greater than 1.5 kc/sec. The threshold for the continuous response has a mean of about 40 dB SL and is perhaps several dB lower for the burst response. The response threshold as a function of sound pressure level (SPL) increases rapidly at frequencies below 125 c/sec and above 1 kc/sec. These thresholds are particularly sharp at the lower frequencies. Narrow-band noise that just produces subjective tone masking also masks the FFR. The latency of the FFR is about 6 msec when the tone burst intensity is 30 dB over FFR threshold. Comparison with click response latencies indicates that the onset of the FFR corresponds with early waves IV and V.

Accumulating neuropsychological, electrophysiological and behavioural evidence suggests that the neural substrates of visual perception may be quite distinct from those underlying the visual control of actions. In other words, the set of object descriptions that permit identification and recognition may be computed independently of the set of descriptions that allow an observer to shape the hand appropriately to pick up an object. We propose that the ventral stream of projections from the striate cortex to the inferotemporal cortex plays the major role in the perceptual identification of objects, while the dorsal stream projecting from the striate cortex to the posterior parietal region mediates the required sensorimotor transformations for visually guided actions directed at such objects.

Recent evidence has shown top-down modulation of the brainstem frequency following response (FFR), generally in the form of signal enhancement from concurrent stimuli or from switching between attention-demanding task stimuli. However, it is also possible that the opposite may be true--the addition of a task, instead of a resting, passive state may suppress the FFR. Here we examined the influence of a subsequent task, and the relevance of the task modality, on signal clarity within the FFR. Participants performed visual and auditory discrimination tasks in the presence of an irrelevant background sound, as well as a baseline consisting of the same background stimuli in the absence of a task. FFR pitch strength and amplitude of the primary frequency response were assessed within non-task stimulus periods in order to examine influences due solely to general cognitive state, independent of stimulus-driven effects. Results show decreased signal clarity with the addition of a task, especially within the auditory modality. We additionally found consistent relationships between the extent of this suppressive effect and perceptual measures such as response time and proclivity towards one sensory modality. Together these results suggest that the current focus of attention can have a global, top-down effect on the quality of encoding early in the auditory pathway.

BACKGROUND: Prepulse inhibition (PPI) of the startle reflex reflects early stages of information processing and is modulated by selective attention. Animal models indicate medial frontal-thalamic circuitry is important in PPI modulation. We report data from the first functional magnetic resonance imaging (fMRI) study examining whether attending to or ignoring a prepulse differentially activates brain areas within this circuitry. METHODS: Ten healthy subjects received structural and functional MRI. During fMRI acquisition, subjects heard intermixed attended and ignored tones serving as prepulses to the startle stimulus. Regions of interest were traced on structural MRI and coregistered to fMRI images. RESULTS: Greater amplitude fMRI blood-oxygen-level-dependent response to attended than ignored PPI conditions occurred in the right thalamus, and bilaterally in the anterior and mediodorsal thalamic nuclei, whereas the startle-alone condition showed deactivation. In transitional medial cortex (Brodmann Area 32), which is involved in affective processing of noxious stimuli, the startle-alone condition elicited the greatest response, the attended-PPI condition showed the smallest response, and the ignored-PPI condition was intermediate. CONCLUSIONS: These findings extend animal models to humans by indicating thalamic involvement in the modulation of PPI. Further fMRI investigations may elucidate other key structures in the circuitry underlying normal and disordered modulation of PPI.

OBJECTIVE: Attentional deficits have been identified as an abnormality that individuals with schizotypal personality disorder share with schizophrenia patients. The purpose of this study was to examine automatic sensorimotor gating and controlled attentional modulation of the startle eye blink response in unmedicated subjects with schizotypal personality disorder. METHOD: Eighteen unmedicated patients with schizotypal personality disorder and 16 healthy individuals were assessed in an acoustic attention-to-prepulse paradigm. The participants performed a selective attention task involving the presentation of attended, ignored, and novel tones that served as prepulse tones. Acoustic startle probes were presented at short and long lead intervals after the onset of tones and occasionally during the intertone interval. RESULTS: The comparison subjects showed greater prepulse inhibition and prepulse facilitation during the attended than the ignored prepulses, demonstrating early and later attentional modulation of startle eye blink response. In contrast, the subjects with schizotypal personality disorder failed to show this pattern. CONCLUSIONS: Subjects with schizotypal personality disorder have deficits in controlled attentional processing, as indexed by modification of the startle eye blink response, that are similar to those observed in patients with schizophrenia.

Patients with schizophrenia-spectrum disorders show deficient prepulse inhibition (PPI) of the startle eyeblink reflex which is thought to reflect an early stage of information processing called automatic sensorimotor gating. They also exhibit deficient attentional modulation of PPI and prepulse facilitation (PPF) of startle which is thought to reflect deficient early and later controlled attentional processing. This is the first study to assess attentional modulation of PPI and PPF in a 3-group schizophrenia-spectrum sample of age- and sex-matched unmedicated schizotypal personality disorder (SPD) and schizophrenia patients, and healthy controls. Participants performed a tone-length judgment task involving attended, ignored, and novel tone prepulses while the acoustic startle eyeblink reflex was measured. Healthy controls showed greater PPI and PPF during the attended prepulses compared with the ignored prepulses. In contrast, both the SPD and schizophrenia patient groups failed to show this pattern, indicating deficient early and later controlled attentional processing. These findings suggest abnormal attentional modulation of PPI and PPF may be a trait-like feature found in patients with schizophrenia-spectrum disorders. Among the schizophrenia-spectrum sample, more deficient PPI during the attended prepulses was associated with greater symptom severity as measured by the total 18-item Brief Psychiatric Rating Scale score.

Schizophrenia is a complex neuropsychiatric disorder that is associated with persistent psychosocial disability in affected individuals. Although studies of schizophrenia have traditionally focused on deficits in higher-order processes such as working memory and executive function, there is an increasing realization that, in this disorder, deficits can be found throughout the cortex and are manifest even at the level of early sensory processing. These deficits are highly amenable to translational investigation and represent potential novel targets for clinical intervention. Deficits, moreover, have been linked to specific structural abnormalities in post-mortem auditory cortex tissue from individuals with schizophrenia, providing unique insights into underlying pathophysiological mechanisms.

Sensory gating is a neurophysiological measure of inhibition that is characterised by a reduction in the P50 event-related potential to a repeated identical stimulus. The objective of this work was to determine the cognitive mechanisms that relate to the neurological phenomenon of auditory sensory gating. Sixty participants underwent a battery of 10 cognitive tasks, including qualitatively different measures of attentional inhibition, working memory, and fluid intelligence. Participants additionally completed a paired-stimulus paradigm as a measure of auditory sensory gating. A correlational analysis revealed that several tasks correlated significantly with sensory gating. However once fluid intelligence and working memory were accounted for, only a measure of latent inhibition and accuracy scores on the continuous performance task showed significant sensitivity to sensory gating. We conclude that sensory gating reflects the identification of goal-irrelevant information at the encoding (input) stage and the subsequent ability to selectively attend to goal-relevant information based on that previous identification.

Auditory nerve single-unit population studies have demonstrated that phase-locking plays a dominant role in the neural encoding of both the spectrum and voice pitch of speech sounds. Phase-locked neural activity underlying the scalp-recorded human frequency-following response (FFR) has also been shown to encode certain spectral features of steady-state and time-variant speech sounds as well as pitch of several complex sounds that produce time-invariant pitch percepts. By extension, it was hypothesized that the human FFR may preserve pitch-relevant information for speech sounds that elicit time-variant as well as steady-state pitch percepts. FFRs were elicited in response to the four lexical tones of Mandarin Chinese as well as to a complex auditory stimulus which was spectrally different but equivalent in fundamental frequency (f0) contour to one of the Chinese tones. Autocorrelation-based pitch extraction measures revealed that the FFR does indeed preserve pitch-relevant information for all stimuli. Phase-locked interpeak intervals closely followed f0. Spectrally different stimuli that were equivalent in F0 similarly showed robust interpeak intervals that followed f0. These FFR findings support the viability of early, population-based 'predominant interval' representations of pitch in the auditory brainstem that are based on temporal patterns of phase-locked neural activity.

Selective attention is the mechanism that allows focusing one's attention on a particular stimulus while filtering out a range of other stimuli, for instance, on a single conversation in a noisy room. Attending to one sound source rather than another changes activity in the human auditory cortex, but it is unclear whether attention to different acoustic features, such as voice pitch and speaker location, modulates subcortical activity. Studies using a dichotic listening paradigm indicated that auditory brainstem processing may be modulated by the direction of attention. We investigated whether endogenous selective attention to one of two speech signals affects amplitude and phase locking in auditory brainstem responses when the signals were either discriminable by frequency content alone, or by frequency content and spatial location. Frequency-following responses to the speech sounds were significantly modulated in both conditions. The modulation was specific to the task-relevant frequency band. The effect was stronger when both frequency and spatial information were available. Patterns of response were variable between participants, and were correlated with psychophysical discriminability of the stimuli, suggesting that the modulation was biologically relevant. Our results demonstrate that auditory brainstem responses are susceptible to efferent modulation related to behavioral goals. Furthermore they suggest that mechanisms of selective attention actively shape activity at early subcortical processing stages according to task relevance and based on frequency and spatial cues.

Prepulse inhibition (PPI) is the suppression of the startle reflex when the startling stimulus is shortly preceded by a non-startling stimulus (the prepulse). Previous studies have shown that both fear conditioning of a prepulse and precedence-effect-induced perceptual separation between the conditioned prepulse and a noise masker facilitate selective attention to the prepulse and consequently enhance PPI with a remarkable prepulse-feature specificity. This study investigated whether the two types of attentional enhancements of PPI in rats also exhibit a prepulse-location specificity. The results showed that when a prepulse was delivered by each of the two spatially separated loudspeakers, fear conditioning of the prepulse at a particularly perceived location (left or right to the tested rat) enhanced PPI without exhibiting any perceived-location specificity. However, when a noise masker was presented, the precedence-effect-induced perceptual separation between the conditioned prepulse and the noise masker further enhanced PPI when the prepulse was perceived as coming from the location that was conditioned but not the location without being conditioned. Moreover, both conditioning-induced and perceptual separation-induced PPI enhancements were eliminated by extinction learning, whose effect could be blocked by systemic injection of the selective antagonist of metabotropic glutamate receptor subtype 5 (mGluR5), 2-methyl-6-(phenylethynyl)-pyridine (MPEP). Thus, fear conditioning of a prepulse perceived at a particular location not only facilitates selective attention to the conditioned prepulse but also induces a learning-based spatial gating effect on the spatial unmasking of the conditioned prepulse, leading to that the perceptual separation-induced PPI enhancement becomes perceived-location specific.

Zika virus (ZIKV) has recently caused a pandemic disease, and many cases of ZIKV infection in pregnant women resulted in abortion, stillbirth, deaths and congenital defects including microcephaly, which now has been proposed as ZIKV congenital syndrome. This study aimed to investigate the in situ immune response profile and mechanisms of neuronal cell damage in fatal Zika microcephaly cases. Brain tissue samples were collected from 15 cases, including 10 microcephalic ZIKV-positive neonates with fatal outcome and five neonatal control flavivirus-negative neonates that died due to other causes, but with preserved central nervous system (CNS) architecture. In microcephaly cases, the histopathological features of the tissue samples were characterized in three CNS areas (meninges, perivascular space, and parenchyma). The changes found were mainly calcification, necrosis, neuronophagy, gliosis, microglial nodules, and inflammatory infiltration of mononuclear cells. The in situ immune response against ZIKV in the CNS of newborns is complex. Despite the predominant expression of Th2 cytokines, other cytokines such as Th1, Th17, Treg, Th9, and Th22 are involved to a lesser extent, but are still likely to participate in the immunopathogenic mechanisms of neural disease in fatal cases of microcephaly caused by ZIKV.

Prepulse inhibition (PPI) is the attenuation of the startle reflex when the sudden intense startling stimulus is shortly preceded by a weaker, non-startling sensory stimulus (prepulse). PPI reflects a protective function of reducing disruptive influences to the processing of prepulse signals and is recognized as a model of sensorimotor gating. In humans, PPI is modulated by both attentional and emotional responses to prepulse, indicating that this early-stage gating is top-down modulated by higher-order cognitive processes. Recent studies have confirmed top-down modulation of PPI in animals, because PPI in rats is enhanced by auditory fear conditioning and perceived separation between fear-conditioned prepulse and masker. This review summarizes recent studies of top-down modulation of PPI conducted in humans and those in rats. Since both baseline PPI and attentional modulation of PPI in patients with schizophrenia are impaired, and both baseline PPI and conditional modulation of PPI in rats with isolation rearing are impaired, this review emphasizes that investigation of top-down modulation of PPI is critical for establishing new animal models for studying both cognitive features and neural bases of schizophrenia. Deficits in either baseline PPI or attentional modulation of PPI in either patients with attention-deficit/hyperactivity disorder (ADHD) or ADHD-modeling rats are also discussed.

Perceptual segregation of multiple sounds, which overlap in both time and spectra, into individual auditory streams is critical for hearing in natural environments. Some cues such as interaural time disparities (ITDs) play an important role in the segregation, especially when sounds are separated in space. In this study, we investigated the neural representation of two uncorrelated narrowband noises that shared the identical spectrum in the rat inferior colliculus (IC) using frequency-following-response (FFR) recordings, when the ITD for each noise stimulus was manipulated. The results of this study showed that recorded FFRs exhibited two distinctive components: the fast-varying temporal fine structure (TFS) component (FFRTFS) and the slow-varying envelope component (FFRENV). When a single narrowband noise was presented alone, the FFRTFS, but not the FFRENV, was sensitive to ITDs. When two narrowband noises were presented simultaneously, the FFRTFS took advantage of the ITD disparity that was associated with perceived spatial separation between the two concurrent sounds, and displayed a better linear synchronization to the sound with an ipsilateral-leading ITD. However, no effects of ITDs were found on the FFRENV. These results suggest that the FFRTFS and FFRENV represent two distinct types of signal processing in the auditory brainstem and contribute differentially to sound segregation based on spatial cues: the FFRTFS is more critical to spatial release from masking.

An electrical response which reproduces the waveform and frequency of the sound stimulus can be recorded from the central neural pathway for audition. Controversy has existed for some years over whether this frequency-following response (FFR) is neural or an artifact such as remote pickup of the cochlear microphonic or cross talk in the recording system. Two experiments resolve this issue by demonstrating that the frequency-following response depends upon functionally intact neural pathways. The frequency-following response, as well as auditory evoked potentials, is abolished by section of the eighth nerve; it is reversibly abolished by cooling of the cochlear nucleus.

The startle reflex, which interferes with on-going cognitive/behavioral activities, is of important protective function for humans and animals. Prepulse inhibition (PPI), as an operational measure of sensorimotor gating, is the suppression of the startle reflex in response to an intense startling stimulus (pulse) when this startling stimulus is shortly preceded by a weaker non-startling stimulus (prepulse). In both humans and laboratory animals, PPI can be enhanced by facilitating selective attention to the prepulse, suggesting that higher-order cognitive/perceptual processes modulate PPI. It has been well known that both the cholinergic system located in the basal forebrain and the deep layers of the superior colliculus in the PPI-mediating circuit are top-down modulated by the medial agranular cortex (AGm), which is a subdivision of the medial prefrontal cortex (PFC) and has wide axonal connections with both cortical regions (including the posterior parietal cortex) and subcortical structures critical for attention/orientation processes. This study investigated whether the AGm is involved in attentional modulation of PPI. The results showed that PPI was enhanced by fear conditioning of the prepulse, and then further enhanced by perceived spatial separation between the conditioned prepulse and a back-ground masking noise based on the auditory precedence effect. Bilateral injection of 2-mM kynurenic acid, a broad spectrum antagonist of glutamate receptors, into the AGm, but not the primary somatosensory cortex, eliminated these two types of attentional enhancement of PPI. Thus, the AGm plays a role in facilitating attention to the prepulse and is involved in the top-down modulation of PPI.

Musical training is known to modify cortical organization. Here, we show that such modifications extend to subcortical sensory structures and generalize to processing of speech. Musicians had earlier and larger brainstem responses than nonmusician controls to both speech and music stimuli presented in auditory and audiovisual conditions, evident as early as 10 ms after acoustic onset. Phase-locking to stimulus periodicity, which likely underlies perception of pitch, was enhanced in musicians and strongly correlated with length of musical practice. In addition, viewing videos of speech (lip-reading) and music (instrument being played) enhanced temporal and frequency encoding in the auditory brainstem, particularly in musicians. These findings demonstrate practice-related changes in the early sensory encoding of auditory and audiovisual information.

AbstractPrepulse inhibition (PPI) of the startle reflex occurs when a non-startling stimulus is presented shortly prior to the startling stimulus. PPI is an operational measure for sensorimotor gating. PPI in humans is enhanced by attention, but there is no evidence yet for attentional modulation of PPI in animals. We here combined PPI and conditioned inhibition paradigms in order to investigate attentional modulation of PPI in rats. PPI was assessed before and after training for conditioned inhibition of fear with the conditioned stimulus (auditory CS) and conditioned inhibitor (visual CI) as prepulses. The CI significantly enhanced PPI after training, whereas presentation of the CS had no effect on PPI. These data suggest attentional modulation of PPI in rats by biologically salient prestimuli. This new paradigm may be useful for examining attentional modulation of PPI in animals and to compare attentional modulation in humans and animals.]]>

OBJECTIVE: To establish reliable procedures and normative values to quantify brainstem encoding of speech sounds. METHODS: Auditory brainstem responses to speech syllables presented in quiet and in background noise were obtained from 38 normal children. Brainstem responses consist of transient and sustained, periodic components-much like the speech signal itself. Transient peak responses were analyzed with measures of latency, amplitude, area, and slope. Magnitude of sustained, periodic frequency-following responses was assessed with root mean square, fundamental frequency, and first formant amplitudes; timing was assessed by stimulus-to-response and quiet-to-noise inter-response correlations. RESULTS: Measures of transient and sustained components of the brainstem response to speech syllables were reliably obtained with high test-retest stability and low variability across subjects. All components of the brainstem response were robust in quiet. Background noise disrupted the transient responses whereas the sustained response was more resistant to the deleterious effects of noise. CONCLUSIONS: The speech-evoked brainstem response faithfully reflects many acoustic properties of the speech signal. Procedures to quantitatively describe it have been developed. SIGNIFICANCE: Accurate and precise manifestation of stimulus timing at the auditory brainstem is a hallmark of the normal perceptual system. The brainstem response to speech sounds provides a mechanism for understanding the neural bases of normal and deficient attention-independent auditory function.

By Fourier's theorem, signals can be decomposed into a sum of sinusoids of different frequencies. This is especially relevant for hearing, because the inner ear performs a form of mechanical Fourier transform by mapping frequencies along the length of the cochlear partition. An alternative signal decomposition, originated by Hilbert, is to factor a signal into the product of a slowly varying envelope and a rapidly varying fine time structure. Neurons in the auditory brainstem sensitive to these features have been found in mammalian physiological studies. To investigate the relative perceptual importance of envelope and fine structure, we synthesized stimuli that we call 'auditory chimaeras', which have the envelope of one sound and the fine structure of another. Here we show that the envelope is most important for speech reception, and the fine structure is most important for pitch perception and sound localization. When the two features are in conflict, the sound of speech is heard at a location determined by the fine structure, but the words are identified according to the envelope. This finding reveals a possible acoustic basis for the hypothesized 'what' and 'where' pathways in the auditory cortex.

INTRODUCTION: Under specific conditions, a weak lead stimulus, or

BACKGROUND: Individual with internet gaming disorder (IGD) often experience a high level of loneliness, and neuroimaging studies have demonstrated that amygdala function is associated with both IGD and loneliness. However, the neurobiological basis underlying these relationships remains unclear. METHODS: In the current study, Granger causal analysis was performed to investigate amygdalar subdivision-based resting-state effective connectivity differences between 111 IGD subjects and 120 matched participants with recreational game use (RGUs). We further correlated neuroimaging findings with clinical measures. Mediation analysis was conducted to explore whether amygdalar subdivision-based effective connectivity mediated the relationship between IGD severity and loneliness. RESULTS: Compared with RGUs, IGD subjects showed inhibitory effective connections from the left pregenual anterior cingulate cortex (pACC) to the left laterobasal amygdala (LBA) and from the right medial prefrontal cortex (mPFC) to the left LBA, as well as an excitatory effective connection from the left middle prefrontal gyrus (MFG) to the right superficial amygdala. Further analyses demonstrated that the left pACC-left LBA effective connection was negatively correlated with both Internet Addiction Test and UCLA Loneliness scores, and it mediated the relationship between the two. CONCLUSION: IGD subjects and RGUs showed different connectivity patterns involving amygdalar subdivisions. These findings support a neurobiological mechanism for the relationship between IGD and loneliness, and suggest targets for therapeutic approaches that could be used to treat IGD.

BACKGROUND: People with schizophrenia recognize speech poorly under multiple-people-talking (informational masking) conditions. In reverberant environments, direct-wave signals from a speech source are perceptually integrated with the source reflections (the precedence effect), forming perceived spatial separation (PSS) between different sources and consequently improving target-speech recognition against informational masking. However, the brain substrates underlying the schizophrenia-related vulnerability to informational masking and whether schizophrenia affects the unmasking effect of PSS are largely unknown. METHOD: Using psychoacoustic testing and functional magnetic resonance imaging, respectively, the speech recognition under either the PSS or perceived spatial co-location (PSC) condition and the underlying brain substrates were examined in 20 patients with schizophrenia and 16 healthy controls. RESULTS: Speech recognition was worse in patients than controls. Under the PSS (but not PSC) condition, speech recognition was correlated with activation of the superior parietal lobule (SPL), and target speech-induced activation of the SPL, precuneus, middle cingulate cortex and caudate significantly declined in patients. Moreover, the separation (PSS)-against-co-location (PSC) contrast revealed (1) activation of the SPL, precuneus and anterior cingulate cortex in controls, (2) suppression of the SPL and precuneus in patients, (3) activation of the pars triangularis of the inferior frontal gyrus and middle frontal gyrus in both controls and patients, (4) activation of the medial superior frontal gyrus in patients, and (5) impaired functional connectivity of the SPL in patients. CONCLUSIONS: Introducing the PSS listening condition efficiently reveals both the brain substrates underlying schizophrenia-related speech-recognition deficits against informational masking and the schizophrenia-related neural compensatory strategy for impaired SPL functions.