MgADP Promotes Myosin Head Movement toward Actin at Low [Ca2+] to Increase Force Production and Ca2+-Sensitivity of Contraction in Permeabilized Porcine Myocardial Strips.

Myosin cross-bridges dissociate from actin following Mg2+-adenosine triphosphate (MgATP) binding. Myosin hydrolyses MgATP into inorganic phosphate (Pi) and Mg2+-adenosine diphosphate (ADP), and release of these hydrolysis products drives chemo-mechanical energy transitions within the cross-bridge cycle to power muscle contraction. Some forms of heart disease are associated with metabolic or enzymatic dysregulation of the MgATP-MgADP nucleotide pool, resulting in elevated cytosolic [MgADP] and impaired muscle relaxation. We investigated the mechanical and structural effects of increasing [MgADP] in permeabilized myocardial strips from porcine left ventricle samples. Sarcomere length was set to 2.0 µm at 28 °C, and all solutions contained 3% dextran T-500 to compress myofilament lattice spacing to near-physiological values. Under relaxing low [Ca2+] conditions (pCa 8.0, where pCa = -log10[Ca2+]), tension increased as [MgADP] increased from 0-5 mM. Complementary small-angle X-ray diffraction measurements show that the equatorial intensity ratio, I1,1/I1,0, also increased as [MgADP] increased from 0 to 5 mM, indicating myosin head movement away from the thick-filament backbone towards the thin-filament. Ca2+-activated force-pCa measurements show that Ca2+-sensitivity of contraction increased with 5 mM MgADP, compared to 0 mM MgADP. These data show that MgADP augments tension at low [Ca2+] and Ca2+-sensitivity of contraction, suggesting that MgADP destabilizes the quasi-helically ordered myosin OFF state, thereby shifting the cross-bridge population towards the disordered myosin ON state. Together, these results indicate that MgADP enhances the probability of cross-bridge binding to actin due to enhancement of both thick and thin filament-based activation mechanisms.

Formation of the Mouse Internal Capsule and Cerebral Peduncle: A Pioneering Role for Striatonigral Axons as Revealed in Isl1 Conditional Mutants.

The projection neurons of the striatum, the principal nucleus of the basal ganglia, belong to one of the following two major pathways: the striatopallidal (indirect) pathway or the striatonigral (direct) pathway. Striatonigral axons project long distances and encounter ascending tracts (thalamocortical) while coursing alongside descending tracts (corticofugal) as they extend through the internal capsule and cerebral peduncle. These observations suggest that striatal circuitry may help to guide their trajectories. To investigate the developmental contributions of striatonigral axons to internal capsule formation, we have made use of Sox8-EGFP (striatal direct pathway) and Fezf2-TdTomato (corticofugal pathway) BAC transgenic reporter mice in combination with immunohistochemical markers to trace these axonal pathways throughout development. We show that striatonigral axons pioneer the internal capsule and cerebral peduncle and are temporally and spatially well positioned to provide guidance for corticofugal and thalamocortical axons. Using Isl1 conditional knock-out (cKO) mice, which exhibit disrupted striatonigral axon outgrowth, we observe both corticofugal and thalamocortical axon defects with either ventral forebrain- or telencephalon-specific Isl1 inactivation, despite Isl1 not being expressed in either cortical or thalamic projection neurons. Striatonigral axon defects can thus disrupt internal capsule formation. Our genome-wide transcriptomic analysis in Isl1 cKOs reveals changes in gene expression relevant to cell adhesion, growth cone dynamics, and extracellular matrix composition, suggesting potential mechanisms by which the striatonigral pathway exerts this guidance role. Together, our data support a novel pioneering role for the striatal direct pathway in the correct assembly of the ascending and descending axon tracts within the internal capsule and cerebral peduncle.SIGNIFICANCE STATEMENT The basal ganglia are a group of subcortical nuclei with established roles in the coordination of voluntary motor programs, aspects of cognition, and the selection of appropriate social behaviors. Hence, disruptions in basal ganglia connectivity have been implicated in the motor, cognitive, and social dysfunction characterizing common neurodevelopmental disorders such as attention-deficit/hyperactivity disorder, autism spectrum disorder, obsessive-compulsive disorder, and tic disorder. Here, we identified a novel role for the striatonigral (direct) pathway in pioneering the internal capsule and cerebral peduncle, and in guiding axons extending to and from the cortex. Our findings suggest that the abnormal development of basal ganglia circuits can drive secondary internal capsule defects and thereby may contribute to the pathology of these disorders.

The effects of sleep on objective measures of gap detection using a time-efficient multi-deviant paradigm.

Auditory temporal resolution, measured through gap detection, is critical for the perception of speech. A time-efficient multi-deviant paradigm has previously been developed for gap detection. The purpose of the present study was to determine if this multi-deviant paradigm could be used for gap detection during NREM sleep. ERPs were recorded in 10 young adults while awake and during the first two hours of NREM sleep. A multi-deviant paradigm was employed with six different deviants varying in gap duration, ranging from 2 to 40 ms. During waking, a DRN was observed for the 10, 20, 30 and 40 ms gaps. The DRN was absent during sleep. A P2 was present in NREM for the 20, 30 and 40 ms gaps followed by a P3a to the 30 and 40 ms gaps. An N350 was observed following the 10, 20, 30 and 40 ms gaps. Previous studies have reported significant ERPs to gaps having shorter durations than the present study. The multi-deviant paradigm may not be suitable for the determination of gap threshold during sleep. Nevertheless, it provides an exquisite means to determine perceptibility and the extent of processing of longer duration, supra-threshold gaps during sleep.

Event-related potential evidence that very slowly presented auditory stimuli are passively processed differently in younger and older adults.

The occurrence of a very infrequent and unattended auditory stimulus is highly salient and may result in an interruption of the frontoparietal network controlling processing priorities. Research has suggested that older adults may be unable to compute the level of salience of unattended stimulus inputs. A multi-channel EEG was recorded in 20 younger adults and 20 older adults. In different conditions, a single 80 dB SPL auditory stimulus was presented relatively rapidly, every 1.5 s or very slowly, every 12.0 s. Participants ignored the auditory stimuli while watching a silent video. When the stimuli were presented rapidly, group differences were not observed for the amplitudes of N1 and P2, which peaked at 100 and 180 ms respectively. When stimuli were presented very slowly, their amplitudes were much enhanced for younger adults, but did not increase for older adults. The failure to observe a large increase in the amplitude of N1 and P2 in older adults for very slowly presented auditory stimuli provides strong evidence of a dysfunction of the salience network in this group.

Event-related potentials following gaps in noise: The effects of the intensity of preceding noise.

Auditory temporal resolution is critical for the perception of speech. It is often studied using gap detection methods in which a silent period (or "gap") is inserted in a long duration auditory stimulus. When the gap is inserted in a frequently occurring standard stimulus, it elicits a negative-going event-related potential, called the deviant-related negativity (DRN). A time-efficient multi-deviant paradigm was employed in which a standard 200 ms noise burst was presented on 50% of trials and a deviant stimulus, containing a gap, on the remaining 50% of trials. Seven different deviants were constructed by inserting a gap in the centre of the standard. The duration of the seven gaps ranged from 2 to 40 ms. In different conditions, the intensity of the noise burst was either 60 or 80 dB SPL. Ten adults watched a silent video while ignoring the auditory sequence. As expected, the amplitude of the DRN increased as gap duration became longer, regardless of the intensity of the noise in which the gap occurred. The intensity of the noise burst also affected the DRN measured peak-to-peak (DRN-to-following positivity). This was reduced when the gap occurred in the lower intensity noise burst. The time efficient multi-deviant paradigm can thus be employed to determine the effects of factors known to affect gap detection: the duration of the gap, and the intensity of the sound in which the gap is inserted.

Sleep deprivation moderates neural processes associated with passive auditory capture.

Sleep loss has a major effect on cognitive tasks that are dependent on the maintenance of active sustained attention. This study examines the effects of sleep deprivation on automatic information processing, more specifically, its effect on processes leading to involuntary auditory attention capture by task-irrelevant auditory events. Two experiments were run. In the first, 13 participants were totally sleep-deprived (TSD); in the second, 16 participants were partially sleep-deprived (PSD), sleeping only four hours. Event-related potentials were recorded while participants discriminated the duration of equiprobable short and long auditory tones. At rare times, a small change to the pitch of these stimuli occurred. This deviant was however irrelevant to the duration detection task. As expected, TSD had a significant effect on the attention-dependent duration detection task; performance was worse and the P3b, associated with ease of detection, was attenuated. PSD had a similar, but reduced effect. Critically, the small pitch deviant resulted in less behavioural distraction following TSD compared to normal sleep.Consistent with this, the P3a, associated with the attention capture process, was significantly reduced following both TSD and PSD. Processes related to the passive switching of attention to potentially critical, but unattended, stimulus events are moderated by sleep deprivation.

Disentangling specific inhibitory versus general decision-making processes during sleep deprivation using a Go/NoGo ERP paradigm.

This study used a Go/NoGo ERP paradigm in which Go and NoGo stimuli occurred rarely and equally often in an attempt to determine if sleep deprivation has a general effect on decision-making or a more specific effect on inhibition. A Go/NoGo task was administered six times to eleven participants during 36 h of sleep deprivation and once again post recovery sleep. In the Go condition, the participant was asked to respond to the rare stimulus. In the separate NoGo condition, the participant was asked to withhold the response to the rare stimulus. ERPs were recorded to the rare stimuli. The NoGo P3 should be attenuated if sleep loss mainly affects inhibitory processes. Both Go and NoGo P3 should be attenuated if sleep loss affects general detection processes. During sleep loss, accuracy decreased for both tasks. RT also gradually increased for the Go task. Performance during the NoGo task was more complex and was better accounted by a speed-accuracy trade-off. Overall, findings indicate that sleep deprivation did not have specific effects on inhibition. However, the amplitude of the Go P3 occurred as early as 12 h after waking and might reflect an effect of task repetition rather than true sleep deprivation. In contrast, the NoGo P3 amplitude was not significantly reduced until after 24 and 36 h of wakefulness, suggesting a true sleep deprivation effect. Both Go and NoGo P3 post recovery sleep did not return to baseline levels, possibly due to residual sleep inertia.

A time-efficient multi-deviant paradigm to determine the effects of gap duration on the mismatch negativity.

The insertion of a silent period (or gap) in a frequently occurring standard stimulus elicits a negative-going event-related potential (ERP), called the Deviant-Related Negativity (DRN). This is often studied using a single-deviant paradigm. To study the effects of gaps with multiple durations, a different sequence would be required for each gap. A more time-efficient multi-deviant paradigm has been developed in which stimuli of various gap widths are included in a single sequence. In the present study, 14 young adults watched a silent video while ignoring an auditory sequence. A single run of a multi-deviant sequence was presented in which 6 different rare deviants alternated with a standard stimulus. The standard was a 200-ms white noise burst. The deviants were constructed by inserting a gap in the standard. The duration of the 6 gaps ranged from 2 to 40 ms. Participants were also presented with multiple runs of single-deviant sequences. Each of the 3 deviants was run in a separate sequence. The amplitude of the DRN elicited by the deviant increased as gap duration became longer, although it did plateau for the longer duration gaps. The amplitudes of the DRNs were larger in the single-deviant paradigm than in the multi-deviant paradigm. However, the difference was only significant when the mastoid reference was used. Behavioural data showed a mean d' of 2.1 for the 5-ms gap. None of the participants were able to detect the 2-ms gap. There was no correlation between d' and the DRN amplitude. Still, the effects of gap duration on the amplitude of the DRN were similar between the single and multi-deviant sequences. This makes the multi-deviant paradigm a possible time-saving alternative to the single-deviant paradigm.

Can an auditory multi-feature optimal paradigm be used for the study of processes associated with attention capture in passive listeners?

OBJECTIVE: A rarely occurring and highly relevant auditory stimulus occurring outside of the current focus of attention can cause a switching of attention. Such attention capture is often studied in oddball paradigms consisting of a frequently occurring "standard" stimulus which is changed at odd times to form a "deviant". The deviant may result in the capturing of attention. An auditory ERP, the P3a, is often associated with this process. To collect a sufficient amount of data is however very time-consuming. A more multi-feature "optimal" paradigm has been proposed but it is not known if it is appropriate for the study of attention capture. METHODS: An optimal paradigm was run in which 6 different rare deviants (p=.08) were separated by a standard stimulus (p=.50) and compared to results when 4 oddball paradigms were also run. RESULTS: A large P3a was elicited by some of the deviants in the optimal paradigm but not by others. However, very similar results were observed when separate oddball paradigms were run. CONCLUSIONS & SIGNIFICANCE: The present study indicates that the optimal paradigm provides a very time-saving method to study attention capture and the P3a.

Event-related potential measures of gap detection threshold during natural sleep.

OBJECTIVE: The minimum time interval between two stimuli that can be reliably detected is called the gap detection threshold. The present study examines whether an unconscious state, natural sleep affects the gap detection threshold. METHODS: Event-related potentials were recorded in 10 young adults while awake and during all-night sleep to provide an objective estimate of this threshold. These subjects were presented with 2, 4, 8 or 16ms gaps occurring in 1.5 duration white noise. RESULTS: During wakefulness, a significant N1 was elicited for the 8 and 16ms gaps. N1 was difficult to observe during stage N2 sleep, even for the longest gap. A large P2 was however elicited and was significant for the 8 and 16ms gaps. Also, a later, very large N350 was elicited by the 16ms gap. An N1 and P2 was significant only for the 16ms gap during REM sleep. SIGNIFICANCE: ERPs to gaps occurring in noise segments can therefore be successfully elicited during natural sleep. The gap detection threshold is similar in the waking and sleeping states.

Effects of a violation of an expected increase or decrease in intensity on detection of change within an auditory pattern.

An infrequent physical increase in the intensity of an auditory stimulus relative to an already loud frequently occurring "standard" is processed differently than an equally perceptible physical decrease in intensity. This may be because a physical increment results in increased activation in two different systems, a transient and a change detector system (signalling detection of an increase in transient energy and a change from the past, respectively). By contrast, a decrease in intensity results in increased activation in only the change detector system. The major question asked by the present study was whether a psychological (rather than a physical) increment would continue to be processed differently than a psychological decrement when both stimuli activated only the change detector system. Participants were presented with a sequence of 1000 Hz tones that followed a standard rule-based alternating high-low intensity pattern (LHLHLH). They were asked to watch a silent video and thus ignore the auditory stimuli. A rare "deviant" was created by repeating one of the stimuli (e.g., LHLHLLLH. The repetition of the high intensity stimulus thus acted as a relative, psychological increment compared to what the rule would have predicted (the low intensity); the repetition of the low intensity stimulus acted as a relative, psychological decrement compared to what the rule would have predicted (the high intensity). In different conditions, the intensity difference between the low and high intensity tones was either 3, 9 or 27 dB. A large MMN was elicited only when the separation between the low and high intensities was 27dB. Importantly, this MMN peaked significantly earlier and its amplitude was significantly larger following presentation of the psychological increment. Thus, a deviant representing an increment in intensity relative to what would be predicted by the auditory past is processed differently than a deviant representing a decrement, even when activation of the transient detector system is controlled. The psychological increment did not however elicit a later positivity, the P3a, often thought to reflect the interruption of the central executive and a forced switching of attention.

The extent of processing of near-hearing threshold stimuli during natural sleep.

OBJECTIVES: Event-related potential (ERPs) provide an exquisite means to monitor the extent of processing of external stimulus input during sleep. The processing of relatively high intensity stimuli has been well documented. Sleep normally occurs in much less noisy environments. The present study therefore employed ERPs to examine the extent of processing of very low intensity (near-hearing threshold) stimuli. DESIGN: Brief duration 1000 Hz auditory tone bursts varying in intensity at random from -5 to +45 dB from normative hearing level (nHL) in 10 dB steps were presented every 1.5 to 2.5 s when the subject was awake and reading a book and again during all-night sleep. SUBJECTS: n = 10 healthy young adults. MEASUREMENTS AND RESULTS: In the waking state, the auditory stimuli elicited a negative-going deflection, N1, peaking at about 100 ms, followed by a smaller positivity, P2, peaking at about 180 ms. N1-P2 gradually decreased in amplitude with decreases in stimulus intensity and remained visible at near-hearing threshold levels. During NREM sleep, the amplitude of N1 was at baseline level and was reduced to only 15% to 20% of its waking amplitude during REM sleep. P2 was much larger in sleep than in wakefulness. Importantly, during sleep, P2 could be reliably elicited by the auditory stimuli to within 15 dB of threshold. During NREM, a large amplitude negativity peaking at about 350 ms was elicited by the higher intensity stimuli. This N350 was much reduced in amplitude during REM sleep. A significant N350 was not, however, elicited when stimuli intensity levels were below 25 dB nHL. CONCLUSIONS: Auditory stimuli that are only slightly above hearing threshold appear to be processed extensively during a 200 to 400 ms interval in both NREM and REM sleep. The nature of this processing is, however, very different compared to the waking state.

Behavioral and electrophysiological evidence for early and automatic detection of phonological equivalence in variable speech inputs.

Speech sounds are not always perceived in accordance with their acoustic-phonetic content. For example, an early and automatic process of perceptual repair, which ensures conformity of speech inputs to the listener's native language phonology, applies to individual input segments that do not exist in the native inventory or to sound sequences that are illicit according to the native phonotactic restrictions on sound co-occurrences. The present study with Russian and Canadian English speakers shows that listeners may perceive phonetically distinct and licit sound sequences as equivalent when the native language system provides robust evidence for mapping multiple phonetic forms onto a single phonological representation. In Russian, due to an optional but productive t-deletion process that affects /stn/ clusters, the surface forms [sn] and [stn] may be phonologically equivalent and map to a single phonological form /stn/. In contrast, [sn] and [stn] clusters are usually phonologically distinct in (Canadian) English. Behavioral data from identification and discrimination tasks indicated that [sn] and [stn] clusters were more confusable for Russian than for English speakers. The EEG experiment employed an oddball paradigm with nonwords [asna] and [astna] used as the standard and deviant stimuli. A reliable mismatch negativity response was elicited approximately 100 msec postchange in the English group but not in the Russian group. These findings point to a perceptual repair mechanism that is engaged automatically at a prelexical level to ensure immediate encoding of speech inputs in phonological terms, which in turn enables efficient access to the meaning of a spoken utterance.

Spatial and temporal requirements for sonic hedgehog in the regulation of thalamic interneuron identity.

In caudal regions of the diencephalon, sonic hedgehog (Shh) is expressed in the ventral midline of prosomeres 1-3 (p1-p3), which underlie the pretectum, thalamus and prethalamus, respectively. Shh is also expressed in the zona limitans intrathalamica (zli), a dorsally projecting spike that forms at the p2-p3 boundary. The presence of two Shh signaling centers in the thalamus has made it difficult to determine the specific roles of either one in regional patterning and neuronal fate specification. To investigate the requirement of Shh from a focal source of expression in the ventral midline of the diencephalon, we used a newly generated mouse line carrying a targeted deletion of the 525 bp intronic sequence mediating Shh brain enhancer-1 (SBE1) activity. In SBE1 mutant mice, Shh transcription was initiated but not maintained in the ventral midline of the rostral midbrain and caudal diencephalon, yet expression in the zli was unaffected. In the absence of ventral midline Shh, rostral thalamic progenitors (pTH-R) adopted the molecular profile of a more caudal thalamic subtype (pTH-C). Surprisingly, despite their early mis-specification, neurons derived from the pTH-R domain continued to migrate to their proper thalamic nucleus, extended axons along their normal trajectory and expressed some, but not all, of their terminal differentiation markers. Our results, and those of others, suggest a model whereby Shh signaling from distinct spatial and temporal domains in the diencephalon exhibits unique and overlapping functions in the development of discrete classes of thalamic interneurons.

The effects of attention and conscious state on the detection of gaps in long duration auditory stimuli.

OBJECTIVE: To determine the extent to which the detection of a gap occurring in a long duration stimulus is affected by attention and conscious state. METHODS: The first experiment manipulated the extent to which active processing was required for the detection of a 20 ms gap in a 1.4 s duration pure tone stimulus. In a second experiment carried out during all-night sleep, a gap was presented in a 1.5 s noise segment having an intensity of 60 or 80 dB SPL. RESULTS: The gap-elicited N1 did not significantly vary with the extent of active processing during wakefulness. N1 was not elicited by the gap during NREM sleep and was much reduced during REM sleep. A large P2 and later N350 was however observed, varying directly in amplitude with the intensity of the noise segment. CONCLUSIONS: The operations required for the detection of a physical gap function early in processing, at a pre-conscious level. SIGNIFICANCE: Attention had relatively little effect on the detection of a gap as indexed by the amplitude of N1. Detection of a gap also appears to be made during sleep, as indexed by a large amplitude P2.

The processing of infrequently-presented low-intensity stimuli during natural sleep: an event-related potential study.

Event-related potentials (ERPs) provide an exquisite means to measure the extent of processing of external stimuli during the sleep period. This study examines ERPs elicited by stimuli with physical characteristics akin to environmental noise encountered during sleep. Brief duration 40, 60 or 80 dB sound pressure level (SPL) tones were presented either rapidly (on average every two seconds) or slowly (on average every 10 seconds). The rates of presentation and intensity of the stimuli were similar to those observed in environmental studies of noise. ERPs were recorded from nine young adults during sleep and wakefulness. During wakefulness, the amplitude of an early negative ERP, N1, systematically increased as intensity level increased. A later positivity, the P3a, was apparent following the loudest 80 dB stimulus regardless of the rate of stimulus presentation; it was also apparent following the 60 dB stimulus, when stimuli were presented slowly. The appearance of the N1-P3a deflections suggests that operations of the central executive controlling ongoing cognitive activity was interrupted, forcing subjects to become aware of the obtrusive task-irrelevant stimuli. The auditory stimuli elicited very different ERP patterns during sleep. During non-rapid eye movement (NREM) sleep, the ERP was characterized by an enhanced (relative to wakefulness) early positivity, P2, followed by a very prominent negativity, the N350. Both deflections systematically varied in amplitude with stimulus intensity level; in addition, N350 was much larger when stimuli were presented at slow rates. The N350, a sleep-specific ERP, is thought to reflect the inhibition of processing of potentially sleep-disrupting stimulus input. During rapid eye movement (REM) sleep, a small amplitude N1 was apparent in the ERP, but only for the loudest, 80 dB stimulus. A small (nonsignificant) P3a-like deflection was also visible following the 80 dB stimulus, but only when stimuli were presented slowly. The findings of the present study offer, on one hand, an explanation of the means by which consciousness is prevented during sleep but also, on the other hand, an explanation of how sleep can be disrupted and possibly reversed, leading to an awakening.

Event-related potentials as a measure of sleep disturbance: a tutorial review.

This article reviews event-related potentials (ERPs) the minute responses of the human brain that are elicited by external auditory stimuli and how the ERPs can be used to measure sleep disturbance. ERPs consist of a series of negative- and positive-going components. A negative component peaking at about 100 ms, N1, is thought to reflect the outcome of a transient detector system, activated by change in the transient energy in an acoustic stimulus. Its output and thus the amplitude of N1 increases as the intensity level of the stimulus is increased and when the rate of presentation is slowed. When the output reaches a certain critical level, operations of the central executive are interrupted and attention is switched to the auditory channel. This switching of attention is thought to be indexed by a later positivity, P3a, peaking between 250 and 300 ms. In order to sleep, consciousness for all but the most relevant of stimuli must be prevented. Thus, during sleep onset and definitive non-rapid eye movement (NREM) sleep, the amplitude of N1 diminishes to near-baseline level. The amplitude of P2, peaking from 180 to 200 ms, is however larger in NREM sleep than in wakefulness. P2 is thought to reflect an inhibitory process protecting sleep from irrelevant disturbance. As stimulus input becomes increasingly obtrusive, the amplitude of P2 also increases. With increasing obtrusiveness particularly when stimuli are presented slowly, a later large negativity, peaking at about 350 ms, N350, becomes apparent. N350 is unique to sleep, its amplitude also increasing as the stimulus becomes more obtrusive. Many authors postulate that when the N350 reaches a critical amplitude, a very large amplitude N550, a component of the K-Complex is elicited. The K-Complex can only be elicited during NREM sleep. The P2, N350 and N550 processes are thus conceived as sleep protective mechanisms, activated sequentially as the risk for disturbance increases. During REM sleep, the transient detector system again becomes somewhat activated, the amplitude of N1 reaching from 15 to 40% of its waking level. Very intense and/or very infrequently presented stimuli might elicit a P3-like deflection suggesting an intrusion into some aspect of consciousness. The types of experimental paradigms used in most ERP studies are quite different from those used in the study of noise and its effects on sleep. ERP studies will need to employ procedures that have greater ecological generalization; stimulus intensity needs to be lower, less abrupt, with much longer durations, and importantly, stimuli should be presented much less often.

MMN elicitation during natural sleep to violations of an auditory pattern.

The mismatch negativity (MMN) ERP component is generally considered to reflect the outcome of a pre-conscious change detection mechanism. The manipulation of active task demands has typically demonstrated that the MMN operates relatively independently of inferred attention. It remains a possibility, however, that subjects are capable of covertly sampling, or "eavesdropping" on, the irrelevant auditory stimuli, even during the most demanding of diversion tasks. The presence of the MMN in an unconscious state, such as natural sleep, provides strong evidence that its operations take place at a pre-conscious level. There exists consistent evidence that the MMN can be elicited at least during REM sleep, but these MMNs were typically elicited using oddball paradigms in which the new physical properties of deviants may trigger fresh afferent activation. The current sleep study employed a standard pattern in which two pure tones alternated (e.g. ABABABAB). Deviants were repetitions (e.g., ABABBBAB), and therefore physically identical to the preceding standard. In different conditions, the tones of the pattern were separated by either 1 or 6 semitones. A clear MMN was elicited in the waking state in the 6 semitone condition. The MMN was also elicited in the 6 semitone condition during REM sleep. No MMN was apparent in REM sleep in the 1 semitone condition. The MMN was not apparent in either the 6 or 1 semitone condition during NREM sleep. These results confirm the operation of the MMN in REM sleep, and support the view that the MMN operates at a pre-conscious level of processing.

The extent of active processing of a long-duration stimulus modulates the scalp-recorded sustained potential.

A long-duration stimulus will elicit a negative sustained potential (SP) that is maximum in amplitude over fronto-central areas of the scalp. This study examines how the duration of active attentional processing of the stimulus might also elicit a nonsensory contingent negative variation (CNV) that overlaps and summates to the SP. Subjects were presented with either a low- or high-pitched 1.4s duration stimulus. In different conditions, a 20 ms gap occurred either 300 or 1300 ms after stimulus onset in half the stimuli. The subject's task was to button press upon detection of the gap in the low-pitched stimulus. The subject was not required to respond to the gap occurring in the high-pitched tone. In a separate Ignore condition, subjects ignored all stimuli and read a book. In the Ignore condition, a SP was apparent to the long-duration stimuli. In the Attend condition, a large amplitude slow wave, probably the CNV, overlapped and summated with the SP. The extent of the overlapping CNV was dependent on whether the gap occurred early or late. The CNV was not apparent following presentation of the high-pitched tone, when the gap did not need to be detected. Consistent with previous studies, a SP was thus elicited even when active processing of the stimulus was not required. The morphology of the scalp-recorded SP was, nevertheless, much modified by an overlapping and summating CNV, depending on the extent to which active processing of the long-duration stimulus was required.

The influence of strongly focused visual attention on the detection of change in an auditory pattern.

The mismatch negativity, an ERP that reflects the detection of change in the auditory environment, is considered to be a relatively automatic process. Its automaticity has by in large been studied using the oddball paradigm, in which a physical feature of a frequently presented standard stimulus is changed. In the present study, the automaticity of the MMN is tested using a MMN elicited by a violation of a more abstract auditory pattern. Fourteen subjects were presented with an alternating pattern of two tones (ABABAB) that was occasionally broken by deviant repetitions (e.g., ABABABBBAB). The alternating tones were separated by 1 or 6 semitones in different conditions. The subjects were engaged in a continuous multiple object tracking (MOT) task and thus ignored the auditory stimuli. Difficulty of the MOT task was manipulated by increasing the number of objects to be tracked. Subjects were also asked to read a text and ignore the auditory stimuli in another condition. A much larger MMN was elicited by pattern violations in the 6 than in the 1 semitone condition. The difficult visual task should have presumably required greater attentional focus than the easy task, and performance did deteriorate during the difficult MOT. The MMN, however, was not affected by the demands of the MOT task. This finding suggests that the MMN elicited by the violation of a pattern is not affected by the presumed attentional demands of a difficult continuous task such as multiple object tracking.