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Biomedical subjects

Kenneth B Campbell

Publications and source records attributed to Kenneth B Campbell.

17 recordsLinked to original sources
PubMed2006

Hypothyroidism leads to increased collagen-based stiffness and re-expression of large cardiac titin isoforms with high compliance.

Because long-term hypothyroidism results in diastolic dysfunction, we investigated myocardial passive stiffness in hypothyroidism and focused on the possible role of titin, an important determinant of diastolic stiffness. A rat model of hypothyroidism was used, obtained by administering propylthiouracil (PTU) for times that varied from 1 month (short-term) to 4 months (long-term). Titin expression was determined by transcript analysis, gel electrophoresis and immunoelectron microscopy. Diastolic function was measured at the isolated heart, skinned muscle, and cardiac myocyte levels. We found that hypothyroidism resulted in expression of a large titin isoform, the abundance of which gradually increased with time to become the most dominant isoform in long-term hypothyroid rats. This isoform co-migrates on high-resolution gels with fetal cardiac titin. Transcript analysis on myocardium of long-term PTU rats, provided evidence for expression of additional PEVK and Ig domain exons, similar to what has been described in fetal myocardium. Consistent with the expression of a large titin isoform, titin-based restoring and passive forces were significantly reduced in single cardiac myocytes and muscle strips of long-term hypothyroid rats. Overall muscle stiffness and LV diastolic wall stiffness were increased, however, due to increased collagen-based stiffness. We conclude that long term hypothyroidism triggers expression of a large cardiac titin isoform and that the ensuing reduction in titin-based passive stiffness functions as a compensatory mechanism to reduce LV wall stiffness.

Animals↗
PubMed2006

Effect of diastolic pressure on MLC2v phosphorylation in the rat left ventricle.

The effect of passive muscle stretch on the extent of MLC2v phosphorylation was investigated. We used an isolated rat heart preparation and controlled the passive pressure of the left ventricle (LV) at 0 or 15 mmHg. The hearts were flash frozen and the LV free wall was split into epicardial and the endocardial halves. The samples were solubilized using a novel method that minimizes changes in the phosphate content of MLC2v under non-denaturing conditions. The proteins were separated by urea glycerol PAGE and identified by mass spectrometry and Western blots. At 0 mmHg passive pressure, the extent of MLC2v phosphorylation of the epicardium (34.1+/-1.7%) was the same as that of the endocardium (35.3+/-3.4%). At 15 mmHg passive pressure, we found a significant increase in MLC2v phosphorylation in the epicardium (to 41.5+/-2.0%) and a significant reduction in the endocardium (to 24.2+/-1.2%), giving rise to a gradient in the extent of MLC2v phosphorylation from epicardium (high) to endocardium (low). These changes in MLC2v phosphorylation that take place in response to increased diastolic pressure are likely to impact on the calcium sensitivity of actomyosin interaction (with an increased sensitivity towards the epicardium) and may play a role in the Frank-Starling mechanism of the heart.

Animals↗
PubMed2006

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.

Acoustic Stimulation↗
PubMed2006

Troponin T modulates sarcomere length-dependent recruitment of cross-bridges in cardiac muscle.

The heterogenic nature of troponin T (TnT) isoforms in fast skeletal and cardiac muscle suggests important functional differences. Dynamic features of rat cardiac TnT (cTnT) and rat fast skeletal TnT (fsTnT) reconstituted cardiac muscle preparations were captured by fitting the force response of small amplitude (0.5%) muscle length changes to the recruitment-distortion model. The recruitment of force-bearing cross-bridges (XBs) by increases in muscle length was favored by cTnT. The recruitment magnitude was approximately 1.5 times greater for cTnT- than for fsTnT-reconstituted muscle fibers. The speed of length-mediated XB recruitment (b) in cTnT-reconstituted muscle fiber was 0.50-0.57 times as fast as fsTnT-reconstituted muscle fibers (3.05 vs. 5.32 s(-1) at sarcomere length, SL, of 1.9 microm and 4.16 vs. 8.36 s(-1) at SL of 2.2 microm). Due to slowing of b in cTnT-reconstituted muscle fibers, the frequency of minimum stiffness (f(min)) was shifted to lower frequencies of muscle length changes (at SL of 1.9 microm, 0.64 Hz, and 1.16 Hz for cTnT- and fsTnT-reconstituted muscle fibers, respectively; at SL of 2.2 microm, 0.79 Hz, and 1.11 Hz for cTnT- and fsTnT-reconstituted muscle fibers, respectively). Our model simulation of the data implicates TnT as a participant in the process by which SL- and XB-regulatory unit cooperative interactions activate thin filaments. Our data suggest that the amino-acid sequence differences in cTnT may confer a heart-specific regulatory role. cTnT may participate in tuning the heart muscle by decreasing the speed of XB recruitment so that the heart beats at a rate commensurate with f(min).

Adenosine Triphosphatases↗
PubMed2005

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.

Acoustic Stimulation↗
PubMed2005

"...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.

Acoustic Stimulation↗
PubMed2005

Is the failure to detect stimulus deviance during sleep due to a rapid fading of sensory memory or a degradation of stimulus encoding?

The mismatch negativity (MMN) is thought to reflect the outcome of a system responsible for the detection of change in an otherwise repetitive, homogenous acoustic environment. This process depends on the storage and maintenance of a sensory representation of the frequently presented stimulus to which the deviant stimulus is compared. Few studies have been able to record the MMN in non-rapid eye movement (NREM) sleep. This pattern of results might be explained by either a rapid fading of sensory memory or an inhibition of stimulus input prior to entry into the cortical MMN generator site. The present study used a very rapid rate of presentation in an attempt to capture mismatch-related negativity prior to the fading of sensory memory. Auditory event-related potentials were recorded from 12 subjects during a single sleep period. A 1000 Hz standard stimulus was presented every 150 ms. At random, on 6.6% of the trials, the standard was changed to either a large 2000 Hz or a small 1100 Hz deviant. In wakefulness, the large deviant elicited an extended negativity that was reduced in amplitude following the presentation of the small deviant. This negativity was also apparent during REM sleep following the presentation of the large deviant. These deviant-related negativities (DRNs) were probably a composite of N1 and MMN activity. During NREM sleep (stage 2 and slow-wave sleep), only the large deviant continued to elicit a DRN. However this DRN might be overlapped by the initial activity of a component that is unique to sleep, the N350. There was little evidence of the DRN or the MMN during sleep following the presentation of the small deviant. A rapid rate of presentation, therefore, does not preserve the MMN following small deviance within sleep. It is possible that inhibition of sensory input occurs before entry into the MMN generating system in the temporal cortex.

Adolescent↗
PubMed2004

Cellular and molecular mechanisms of systolic and diastolic dysfunction in an avian model of dilated cardiomyopathy.

We investigated the cellular and molecular mechanisms of systolic and diastolic dysfunction in a furazolidone (Fz)-induced model of dilated cardiomyopathy (DCM) in turkey poults. Serial echocardiograms disclosed marked systolic dysfunction in the Fz-treated poults, and ventricular weight and left ventricular (LV)/body weight ratio were significantly increased. Isolated heart experiments were performed to determine LV pressure-volume (P-V) relationships. In addition, LV sarcomere lengths (SLs) were measured after hearts had been fixed, and wall stress (sigma)-SL relationships were determined. When compared to control hearts, LV chamber volume in DCM hearts was approximately 3-fold increased, the active or developed LV P-V relationship was markedly depressed, the passive or diastolic P-V relationship was steeper, and SLs were significantly shorter. However, the developed sigma-SL relationships of DCM and control hearts were not different indicating that intrinsic myocardial capacity to generate active force is unaffected in this model of DCM. In contrast, passive sigma, and passive tension in trabecular muscle preparations increased much more steeply with SL in DCM than normal hearts. Trabecular muscle experiments disclosed that the increase in passive myocardial stiffness was primarily collagen based. Titin, the giant sarcomeric molecule, which is an important determinant of passive myocyte properties in normal myocardium, did not contribute significantly to increased passive myocardial stiffness in DCM. We conclude that increased collagen-based passive myocardial stiffness is the major cause of the steeper passive or diastolic P-V relationship in DCM. Further, altered passive myocardial properties and ventricular geometry in DCM play a critical role to reduce ventricular systolic function by limiting SL extension during diastole, thereby limiting the use of the myocardial length-tension relationship.

Animals↗
PubMed2004

Interpreting cardiac muscle force-length dynamics using a novel functional model.

To describe the dynamics of constantly activated cardiac muscle, we propose that length affects force via both recruitment and distortion of myosin cross bridges. This hypothesis was quantitatively tested for descriptive and explanative validity. Skinned cardiac muscle fibers from animals expressing primarily alpha-myosin heavy chain (MHC) (mouse, rat) or beta-MHC (rabbit, ferret) were activated with solutions from pCa 6.1 to 4.3. Activated fibers were subjected to small-amplitude length perturbations [deltaL(t)] rich in frequency content between 0.1 and 40 Hz. In descriptive validation tests, the model was fit to the ensuing force response [deltaF(t)] in the time domain. In fits to 118 records, the model successfully accounted for most of the measured variation in deltaF(t) (R(2) range, 0.997-0.736; median, 0.981). When some residual variations in deltaF(t) were not accounted for by the model (as at low activation), there was very little coherence (<0.5) between these residual force variations and the applied deltaL(t) input function, indicating that something other than deltaL(t) was causing the measured variation in deltaF(t). With one exception, model parameters were estimated with standard errors on the order of 1% or less. Thus parameters of the recruitment component of the model could be uniquely separated from parameters of the distortion component of the model and parameters estimated from any given fiber could be considered unique to that fiber. In explanative validation tests, we found that recruitment and distortion parameters were positively correlated with independent assessments of the physiological entity they were assumed to represent. The recruitment distortion model was judged to be valid from both descriptive and explanative perspectives and is, therefore, a useful construct for describing and explaining dynamic force-length relationships in constantly activated cardiac muscle.

Actin Cytoskeleton↗
PubMed2003

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.

Acoustic Stimulation↗
PubMed2002

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.

Adolescent↗
PubMed2002

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.

Actins↗
PubMed2002

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.

Animals↗
PubMed2002

Changes in the scalp topography of event-related potentials and behavioral responses during the sleep onset period.

Event-related potentials (ERPs) and behavioral responsiveness were investigated during the transition from wakefulness to sleep. Ten participants were presented with an auditory oddball task during repeated sleep onset periods. The EEG was recorded from 29 different scalp sites. A 1500-Hz tone pip was presented infrequently (p = .04) within a series of lower pitch 1000-Hz "standard" stimuli (p = .96). Participants were required to button press upon detection of the rare "target" stimulus. During wakefulness, almost all targets were detected. A large amplitude P300 was observed to these detected targets. This P300 was maximum over parietal areas of the scalp. During stage 1 sleep, subjects continued to respond on 47% of trials. The parietal P300 amplitude remained large to these detected targets. It was, however, much attenuated at frontal sites. When the participant failed to detect the target in either stage 1 or 2, no P300 was visible. P300 is thus associated with behavioral detection of the target stimulus, whether in wakefulness or stage 1 "sleep." Trials were also sorted by reaction time (RT), in which bins 1-3 represented increasingly long RT. In the waking state, P300 amplitude did not significantly vary across the different bins. Although mean RT latency varied by 512 ms from bin 1 to bin 3, P300 latency varied by only 25 ms. Differences in RT are thus probably due to response-related processes rather than stimulus classification time.

Acoustic Stimulation↗
PubMed2002

The effects of digital filtering on mismatch negativity in wakefulness and slow-wave sleep.

The mismatch negativity (MMN) is a response to a deviant auditory stimulus that occurs infrequently in a sequence of otherwise repetitive, homogeneous standard auditory stimuli. The MMN is presumed automatic and independent of conscious awareness. Recording of the MMN during unconscious states may be problematic. The frequency content of the long-lasting MMN may overlap and summate with other event-related slow potentials and low-frequency background electroencephalogram (EEG) activity. The purpose of this study is to determine the optimal filter settings for recording the MMN during unconscious states. Auditory event-related potentials (ERPs) were recorded from eight subjects in an oddball paradigm during wakefulness and Stages 3 and 4 of sleep [slow-wave sleep (SWS)] using a 0.16-35 Hz analogue bandpass. Deviant probability was 0.033. Stimulus-onset asynchrony was 150 ms. The EEG data were subsequently digitally filtered in the frequency domain. The low-pass filter was set at either 24, 12 or 6 Hz, and the high-pass filter at either 1, 2, 3 or 4 Hz. Applying a low-pass filter down to 12 Hz had a minimal impact on the waking or sleeping MMN amplitude. On the other hand, increasing the high-pass setting from 2 to 3 Hz permitted the visualization of the MMN recorded during sleep. The 4 Hz filter showed a similar trend but also markedly attenuated the amplitude of the waking MMN. A high-pass setting of 3 Hz provides a reasonable compromise. It has only a slight effect on the MMN when the subject is conscious, but still attenuates most of the unwanted slow potential activity when the subject enters SWS.

Acoustic Stimulation↗