Characterization of secophalloidin-induced force loss in cardiac myofibrils.

Secophalloidin (SPH) is known to cause in cardiac myofibrils force without Ca(2+) (half-maximal effect approximately 2 mM) followed by irreversible loss of Ca(2+)-activated force. At maximal Ca(2+) activation, SPH increases force (half-maximal effect < 0.1 mM). We found that SPH at low concentration (0.5 mM) did not cause either force activation or force loss at pCa 8.7, but both of these effects did occur when force was activated by Ca(2+). The force loss was prevented when SPH was applied during rigor or in the presence of 2,3-butanedione monoxime (85 mM). Furthermore, studying muscle in which the force was previously reduced by SPH (up to 50%) did not reveal significant changes in Ca(2+) sensitivity and cooperativity of Ca(2+) activation or qualitative alterations in SPH-induced changes in Ca(2+)-activated contraction. Data suggest that the force loss is mediated by cycling cross-bridges, and might reflect a reduction in force generated by individual cross-bridges.

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.

Dynamic left ventricular elastance: a model for integrating cardiac muscle contraction into ventricular pressure-volume relationships.

To integrate myocardial contractile processes into left ventricular (LV) function, a mathematical model was built. Muscle fiber force was set equal to the product of stiffness and elastic distortion of stiffness elements, i.e., force-bearing cross bridges (XB). Stiffness dynamics arose from recruitment of XB according to the kinetics of myofilament activation and fiber-length changes. Elastic distortion dynamics arose from XB cycling and the rate-of-change of fiber length. Muscle fiber stiffness and distortion dynamics were transformed into LV chamber elastance and volumetric distortion dynamics. LV pressure equaled the product of chamber elastance and volumetric distortion, just as muscle-fiber force equaled the product of muscle-fiber stiffness and lineal elastic distortion. Model validation was in terms of its ability to reproduce cycle-time-dependent LV pressure response, DeltaP(t), to incremental step-like volume changes, DeltaV, in the isolated rat heart. All DeltaP(t), regardless of the time in the cycle at which DeltaP(t) was elicited, consisted of three phases: phase 1, concurrent with the leading edge of DeltaV; phase 2, a brief transient recovery from phase 1; and phase 3, sustained for the duration of systole. Each phase varied with the time in the cycle at which DeltaP(t) was elicited. When the model was fit to the data, cooperative activation was required to sustain systole for longer periods than was possible with Ca(2+) activation alone. The model successfully reproduced all major features of the measured DeltaP(t) responses, and thus serves as a credible indicator of the role of underlying contractile processes in LV function.

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.

The use of evoked potentials in sleep research.

Averaged event-related potentials (ERPs) represent sensory and cognitive processing of stimuli during wakefulness independent of behavioral responses, and reflect the underlying state of the CNS (central nervous system) during sleep. Components measured during wakefulness which are reflective of arousal state or the automatic switching of attention are sensitive to prior sleep disruption. Components reflecting active attentional influences during the waking state appear to be preserved in a rudimentary form during REM sleep, but in a way that highlights the differences in the neurochemical environment between wakefulness and REM sleep. Certain ERP components only appear within sleep. These begin to emerge at NREM sleep onset and may reflect inhibition of information processing and thus have utility as markers of the functional status of sleep preparatory mechanisms. These large amplitude NREM components represent synchronized burst firing of large number of cortical cells and are a reflection of the nervous system's capacity to generate delta frequency EEG activity. As such they are useful in assessing the overall integrity of the nervous system in populations not showing substantial amounts of SWS as measured using traditional criteria. While requiring care in their interpretation, ERPs nonetheless provide a rich tool to investigators interested in probing the nervous system to evaluate daytime functioning in the face of sleep disruption, the ability of the sleeping nervous system to monitor the external environment, and the ability of the nervous system to respond to stimuli in a manner consistent with the initiation or maintenance of sleep.

The effect of visual task difficulty and attentional direction on the detection of acoustic change as indexed by the Mismatch Negativity.

Näätänen's model of auditory processing purports that attention does not affect the MMN. The present study investigates this claim through two different manipulations. First, the effect of visual task difficulty on the passively elicited MMN is assessed. Second, the MMNs elicited by stimuli under attended and ignored conditions are compared. In Experiment 1, subjects were presented with mixed sequences of equiprobable auditory and visual stimuli. The auditory stimuli consisted of standard (80 dB SPL 1000 Hz), frequency deviant (1050 Hz), and intensity deviant (70 dB SPL) tone pips. In a first instance, subjects were instructed to ignore the auditory stimulation and engage in an easy and difficult visual discrimination task (focused condition). Subsequently, they were asked to attend to both modalities and detect visual and auditory deviant stimuli (divided condition). The results indicate that the passively elicited MMN to frequency and intensity deviants did not significantly vary with visual task difficulty, in spite of the fact that the easy and difficult tasks showed a wide variation in performance. The manipulation of the attentional direction (focused vs. divided conditions) did result in a significant effect on the MMN elicited by the intensity, but not frequency, deviant. The intensity MMN was larger at frontal sites when subjects' attention was directed to both modalities as compared to only the visual modality. The attentional effect on the MMN to the intensity deviants only may be due to the specific deviant feature or the poorer perceptual discriminability of this deviant from the standard. Experiment 2 was designed to address this issue. The methods of Experiment 2 were identical to those of Experiment 1 with the exception that the intensity deviant (60 dB SPL) was made to be more perceptible than the frequency deviant (1016 Hz) when compared to the standard stimulus (80 dB SPL 1000 Hz). The results of Experiment 2 also demonstrated that the passively elicited MMN was not affected by large variations in visual task difficulty; this provides convincing evidence that the MMN is independent of visual task demands. Similarly to Experiment 1, the direction of attention again had a significant effect on the MMN. In Experiment 2, however, the frequency MMN (and not the intensity MMN) was larger at frontal sites during divided attention compared to focused visual attention. The most parsimonious explanation of these results is that attention enhances the discriminability of the deviant from the standard background stimulation. As such, small acoustic changes would benefit from attention whereas the discriminability of larger changes may not be significantly enhanced.

Waking levels of salivary biomarkers are altered following sleep in a lab with no further increase associated with simulated night-time noise exposure.

The goals of this study were twofold. First, we assessed if waking salivary hormone profiles are altered by nighttime noise exposure in a laboratory environment. Second, we evaluated the potential influence that sleeping in the lab in itself may have had on salivary biomarkers, by comparing results obtained following sleep at home. Twelve adults (7 males, 5 females) between 19-25 yrs slept at home and in a sleep laboratory. Subjects provided six saliva samples during waking hours on the day prior to sleep in the lab, on both days after sleeping in the lab and on the day following the resumption of sleep at home. Following one night of adaptation, subjects were exposed throughout the 2nd night to simulated backup alarms that consisted of trains of 5 consecutive 500 ms duration audible tones. The time between the onset of each tone was 1 s and the time between trains (offset to onset) was 15 to 20 s. When compared to home conditions, cortisol and melatonin levels were higher following sleep in the laboratory 30 minutes after awakening. However, no significant differences were noted for any salivary biomarker between the 1st and 2nd night in the sleep lab, suggesting that these endpoints were not influenced by exposure to noise on the 2nd night. Waking profiles of alpha-amylase were not influenced by where the subjects slept. Subjective reports of sleep disturbance following sleep in the lab were also obtained. For most of the day there was no apparent influence of the laboratory noise exposure. However, subjects did report more sleepiness during the evening (8 pm) following the 2nd night in the laboratory. In general, overall sleep quality was rated slightly higher upon awakening from sleep at home. Factors that might have contributed to the observations in this study are discussed, including those related to the potentially non-representative sample.

Total sleep deprivation and novelty processing: implications for frontal lobe functioning.

OBJECTIVE: Mounting evidence suggests that the frontal lobes are particularly vulnerable to total sleep deprivation (TSD). Detection of novelty involves the frontal lobes. The presentation of rare, novel stimuli elicits an event-related potential (novel P3), which maximizes over anterior regions of the scalp. We hypothesized that TSD would impair novelty detection, resulting in a smaller novel P3 over the frontal region, with a topographic shift toward posterior areas. METHODS: An auditory novelty oddball task was administered to a TSD group after 36 h of waking and again following recovery sleep, and to a control group after 12 h of waking. EEG was recorded from Fz, Cz and Pz. RESULTS: A large anterior P3 was elicited in the control group. In the TSD group, this novel P3 was smaller at Fz. A later novel positivity appeared in parietal areas. The novel P3 returned to baseline levels and the late novel P3 was difficult to observe following recovery sleep. CONCLUSIONS: TSD appears to compromise the usual automatic detection of novelty probably due to frontal deactivation. Participants may compensate by relying on posterior brain mechanisms involving active memory comparison. The late novel P3 component may also reflect a secondary effortful attempt to encode and to categorize novel stimuli. SIGNIFICANCE: This study suggests that TSD may compromise cognitive functioning in different regions of the brain. The detection of novelty, probably mediated by the frontal lobes, is particularly at risk.

"...and were instructed to read a self-selected book while ignoring the auditory stimuli": the effects of task demands on the mismatch negativity.

OBJECTIVE: The Mismatch Negativity (MMN) is commonly recorded while the subject is reading, and instructed to ignore the auditory stimuli. It is generally assumed that the demands of the diversion task will have no effect on the MMN. Several studies, however, have reported that a diversion task presumably requiring strong attentional focus is associated with a smaller MMN than that elicited during a less demanding task. This study examines the effect of variations in the classical reading paradigm on the MMN. METHODS: In Experiment 1, event-related potentials (ERP) were recorded while subjects were presented with standard (80 dB SPL 1000 Hz) and frequency deviant (1050 Hz) stimuli. Subjects were instructed to ignore the tone pips and, in separate conditions, engage in different tasks. They were asked to read a text or to sit passively. Subjects were informed that they would subsequently be queried or not about the content of the reading. In Experiment 2, the auditory sequence included the same standard (80 dB SPL 1000 Hz) but the deviant was changed to an intensity decrement (70 dB SPL). A different sample of subjects was again asked to ignore the auditory stimuli and engage in different reading tasks that would or not be followed by query. RESULTS: In all task conditions, MMN was elicited by the frequency and intensity change. The intensity MMN did not significantly vary with task. A significant effect of task was, however, found for the frequency MMN. Its amplitude was largest when subjects were later queried about their reading. CONCLUSIONS: This finding is counter-intuitive in light of previous research on the attentional modulation of the MMN. The pattern of frequency MMN results may relate to the differences in cortical excitability across tasks. SIGNIFICANCE: The present results indicate that the nature of the diversion task may affect the MMN. The choice of diversion task during MMN recording should thus be carefully considered.

Calcium-independent activation of skinned cardiac muscle by secophalloidin.

Thin filament regulation of muscle contraction is believed to be mediated by both Ca2+ and strongly bound myosin cross-bridges. We found that secophalloidin (SPH, 5-8 mM) activates cross-bridge cycling without Ca2+ causing isometric force comparable to that induced by Ca2+. At saturated [SPH], Ca2+ further increased force by 20%. SPH-induced force was reversible upon washing with a relaxing solution. However, there was more than 30% irreversible loss in subsequent Ca2+-activated force. We hypothesize that SPH activates muscle via strongly bound cross-bridges. SPH-activated contraction provides a new model for studying the role of Ca2+ and cross-bridges in muscle regulation.

Effects of sleep onset on the mismatch negativity (MMN) to frequency deviants using a rapid rate of presentation.

This study examined the effects of sleep onset-the transition from a waking, conscious state to one of sleep and unconsciousness-on the mismatch negativity (MMN) following frequency deviants when a rapid rate of stimulus presentation is employed. The MMN is thought to reflect a brief-lasting sensory memory. Rapid rates of stimulus presentation should guard the sensory memory from fading. A 1,000 Hz standard stimulus was presented every 150 ms. At random, on 6.6% of the trials, the standard was changed to either a large 2,000 or a small 1,100 Hz deviant. During alert wakefulness (when subject ignored the stimuli and read a book), the large deviant elicited a larger deviant related negativity (DRN) than did the small deviant. This negativity may be a composite of both N1 and MMN activity while that following the small deviant is probably a 'true' MMN. The large deviant continued to elicit a DRN in relaxed wakefulness (eyes closed) and Stages 1 and 2 of sleep, although it was much reduced in amplitude. A significant MMN was recorded for the small deviant only in alert wakefulness. The failure to observe an MMN to small deviance and the attenuation of the DRN to large deviance at sleep onset therefore is probably not due to a decay of sensory memory. It is more likely that cortical encoding of both the standard and deviant is weakened during sleep onset because of prior thalamic inhibition of sensory input.

Event-related potentials reveal the effects of altering personal identity.

Subjects were presented with terminal words that identified a sentence to reflect their true selves or another irrelevant individual. Subjects were asked to push one button if the statement reflected their true identity and another if it did not. The ERP to the terminal word consisted of a double-peaked positivity. Both the initial P300 (peaking between 300-350 ms) and a later P550 (peaking between 550 and 575 ms) were significantly larger to words that reflected the subject's true identity. When subjects were asked to take on a new identity, the P300 became larger to new, false words but the later P550 was large to both the false and the true words. The P550 to true identity words became smaller over a period of 3 days as subjects rehearsed their new roles. However, the P550 remained large to the false identity words although it was now attenuated relative to the true identity words. The late positivities may reflect a complex decisional process involving at least two stages. The initial stage might the initial yes-no decision. The later positivity may reflect the personal relevance of the terminal word. In this case, one's own true identity only begins to lose its relevance after time, and enacting the false identity then increases the positivity to this new identity.

Event-related potential measures of the inhibition of information processing: II. The sleep onset period.

The loss of consciousness during the sleep onset period is associated with dramatic changes in information processing. Human event-related potentials (ERPs) reflect these changes. Short- and mid-latency ERPs are only minimally affected by sleep onset. On the other hand, long-latency ERPs are very much affected. A negative wave, N1, peaking at approximately 100 ms gradually decreases in amplitude until it reaches baseline level during definitive stage 2 sleep. The changes in N1 are especially apparent when the subject no longer signals awareness of the external stimulus or when stage 1 is dominated by theta activity in the EEG. The positive peaks, P1 and P2, peaking at approximately 50 and 180 ms, respectively, may appear to increase in amplitude (i.e. also be less negative). A long-lasting processing negativity (PN) may overlap and summate with these peaks during the waking state. During sleep onset, the PN dissipates, thus explaining the apparent positive baseline shift in the ERP waveform. In an oddball task, when an alert and awake subject detects a rare, relevant stimulus, a large positive wave, P300, maximum over parietal areas of the scalp, is observed. This P300 is, however, widely dispersed and can be observed over frontal areas of the scalp. When the subject no longer signals detection of this target stimulus, P300 can no longer be recorded. During stage 1, the parietal P300 remains large, providing the subject overtly detects the target. The amplitude of the frontal aspect of P300 is much reduced as response times slow. This may reflect deactivation of the frontal lobes during the sleep onset period. The infrequent change of an otherwise rapidly presented homogenous train of stimuli is associated with another long-lasting negativity, the mismatch negativity (MMN). The MMN also decreases in amplitude during the sleep onset period, reaching baseline level during definitive sleep. The vertex sharp wave (VSW) becomes apparent during the sleep onset period. Associated with the VSW is a late negative ERP, sometimes called the sleep N2 or the N350, peaking between 300 and 350 ms. It is unique to the sleep onset and sleep periods, becoming very large during stage 1-theta or when the subject no longer shows signs of awareness of the external stimulus.

Effects of band-pass spatial frequency filtering of face and object images on the amplitude of N170.

Previous studies have suggested that physiological responses are greatest and face recognition performance is best when a band of middle relative spatial frequencies (SFs) is included in stimuli. Conversely, behavioural data suggest that object recognition performance shows comparatively little effect of SF variations. Here, we examine the effects of SF filtering on the amplitude of the N170 ERP component when participants are shown images of faces and objects. Our findings show that with face stimuli the amplitude of N170 exhibits a band-pass modulation function, with responses to middle SFs (around 11 cycles per face) being statistically indistinguishable from responses to full-band faces. In contrast to faces, object stimuli elicited a relatively flat function across much of the spectrum. However, for both faces and objects, middle spatial frequencies were sufficient to elicit the same N170 magnitude as full-band images. Our results with face stimuli are in accordance with previous work examining single-cell and MEG responses. Our results with objects are compatible with previous behavioural work showing a relative robustness of object recognition to SF manipulations. Our findings are novel in showing that the middle band elicits the same N170 as full-band images in both faces and objects.

Evidence that the mismatch negativity to pattern violations does not vary with deviant probability.

OBJECTIVE: To determine whether the classic inverse relationship between the amplitude of the mismatch negativity (MMN) and deviant probability can be demonstrated to violations of a concrete rule pattern. METHODS: In Experiment 1, oddball and patterned auditory sequences were presented with high (p = 0.16) and rare (p = 0.02) deviant probability. In Experiment 2, a slightly different pattern was presented with high, moderate (p = 0.08), low (p = 0.04), and rare deviant probability. In Experiment 3, deviants in the patterns from Experiments 1 and 2 were actively detected at high and rare probability. RESULTS: In Experiment 1, the amplitude of the MMN varied inversely with deviant probability in both conditions. In Experiment 2, no effect of probability was observed. Experiment 3 supported the hypothesis that high deviant probability causes instability in the memory representation of the standard in the pattern from Experiment 1. CONCLUSIONS: The amplitude of the MMN to concrete pattern violations does not vary with deviant probability. SIGNIFICANCE: The amplitude of the MMN may not vary with deviant probability. Once a stable memory representation is formed for the standard regularities in an auditory sequence, further examples may not strengthen that representation.

Event-related potential measures of processing during an Implicit Association Test.

This study recorded event-related potentials during the Implicit Association Test, a reaction time-based measure of implicit social attitudes. An N2, peaking at about 350 ms was larger in the incongruent condition, perhaps reflecting greater response monitoring. The latency to an initial late positive peak, P300, a measure of stimulus classification time, was not longer in the incongruent than the congruent condition. A later small amplitude positive peak was observed in the incongruent condition, but was not visible in the congruent condition. The additional positivity is consistent with the hypothesis that participants make an initial decision to determine whether a task set switch is required, and then make a subsequent decision about the correct response, perhaps resulting in delayed reaction times.

Model representation of the nonlinear step response in cardiac muscle.

Motivated by the need for an analytical tool that can be used routinely to analyze data collected from isolated, detergent-skinned cardiac muscle fibers, we developed a mathematical model for representing the force response to step changes in muscle length (i.e., quick stretch and release). Our proposed model is reasonably simple, consisting of only five parameters representing: (1) the rate constant by which length change-induced distortion of elastic elements is dissipated; (2) the stiffness of the muscle fiber; (3) the amplitude of length-mediated recruitment of stiffness elements; (4) the rate constant by which this length-mediated recruitment takes place; and (5) the magnitude of the nonlinear interaction term by which distortion of elastic elements affects the number of recruited stiffness elements. Fitting this model to a family of force recordings representing responses to eight amplitudes of step length change (+/-2.0% baseline muscle length in 0.5% increments) enabled four things: (1) reproduction of all the identifiable features seen in a family of force responses to both positive and negative length changes; (2) close fitting of all records from the whole family of these responses with very little residual error; (3) estimation of all five model parameters with a great degree of certainty; and (4) importantly, ready discrimination between cardiac muscle fibers with different contractile regulatory proteins but showing only subtly different contractile function. We recommend this mathematical model as an analytic tool for routine use in studies of cardiac muscle fiber contractile function. Such model-based analysis gives novel insight to the contractile behavior of cardiac muscle fibers, and it is useful for characterizing the mechanistic effects that alterations of cardiac contractile proteins have on cardiac contractile function.

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.