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Department of Physiological Sciences, University of Florida Gainesville, Florida
Submitted 31 October 2006 ; accepted in final form 7 September 2007
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ABSTRACT |
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R50) of resistive (R) loads is a function of the total background resistance (R0). Increased R0 increases the R50, but the ratio R50/R0 remains constant. The respiratory-related evoked potential (RREP) is elicited only by R loads greater than the cognitive detection threshold, R50. We hypothesized that the RREP Nf, P1, and N1 peaks will be elicited only when the added load R/R0 is greater than the normal detection threshold, R50/R0 = 0.30. We also hypothesized that when the R0 is increased by adding extrinsic R, the RREP will not be elicited if the R/R0 is less than the 0.30 ratio. RREPs were recorded with healthy volunteers (n = 20) respiring through a non-rebreathing valve. Three inspiratory R loads that spanned the R50/R0 = 0.30 detection threshold were presented in two conditions: 1) no added R0 (R1 < 0.30, R2 > 0.30, R3 > 0.30); and 2) increased R0 = 13.3 cmH2O·l–1·s (R1 < 0.30, R2 < 0.30, R3 > 0.30). For the control R0, P1, Nf, and N1 peaks of the RREP were elicited by both R2 and R3, and not present with R1. The increased R0 decreased R2/R0 > 1.5 to R2/R0 < 0.15. With increased R0, the R1 and R2 loads did not elicit the RREP, but the Nf, P1, and N1 peaks were present for R3. These results demonstrate that the RREP is present if the R is above the cognitive detection threshold, and the RREP is absent if the load is below the detection threshold. When the R0 is increased to make the R/R0 less than the detection threshold, the R no longer elicits the RREP. load detection threshold; respiratory sensation; evoked potentials
R magnitude), and the RREP peak amplitude is correlated with the cognitive magnitude estimation of the load. Control breathing and R loads that are below the cognitive detection threshold do not elicit the RREP (2, 9, 13, 14, 18, 19). There is a direct relationship between the threshold for eliciting the P1, Nf, and N1 peaks of the RREP and the detection threshold of added loads (1, 9, 17). The fundamental question raised by these results is that the RREP is not elicited with loads below the detection threshold, yet the RREP is elicited by loads that exceed the R detection threshold; thus, can a change in the background R equivalent to the R that changes the R load cognitive threshold cause a corresponding change in the R load threshold for eliciting the RREP? Further, can increasing the background R eliminate and/or modulate the R load elicited RREP?
Inspiratory resistive load detection is a complex chain of neural events that requires the central neural cognitive processing of afferent information from mechanoreceptors in the respiratory system. There is a threshold for eliciting both the neural and perceptual events mediating cognitive load detection (1, 9, 17, 20, 21, 23, 26). The cognitive detection threshold for R loads is dependent on the background resistance (R0) of the subject's airways and the breathing apparatus. The detection threshold is defined as the added load that can be detected for 50% of its presentations (R50). Addition of an increased background resistance is known to increase the R50 (20). Wiley and Zechman (20) were the first to report variable R50 thresholds, but the detection threshold was a constant ratio with the background resistance, R50/R0 
0.3. This relationship was constant in the presence of elevated intrinsic and extrinsic background resistance (20). This means with low background R0 a R can be detected, but the load is no longer detected if the R0 is increased to make the R/R0 less than the detection threshold ratio of about 0.3. The threshold for cognitive load detection modulated by the background mechanical status of the subject suggests that the background load modulates the underlying sensory neural systems mediating resistive load detection (17). Based on the questions raised by these previous studies, if the RREP is only elicited with R loads above the detection threshold, then we reasoned that increased R0 would have a similar effect on the R eliciting the RREP; i.e., if the increased R0 abolished load detection, the increased R0 would also abolish the RREP. We therefore hypothesized that a detectable R (R50/R0 > 0.3) in the absence of an increased extrinsic background R will elicit the RREP; however, if the extrinsic background R is increased to make this R below the detection threshold (R50/R0 < 0.3), the RREP will not be elicited.
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METHODS |
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Pulmonary function testing. All subjects performed pulmonary function testing in the sitting position. Standard instructions according to American Thoracic Society Standards for spirometry testing were given to each subject. All subjects performed a forced vital capacity maneuver. Each test was repeated 2–4 times with at least a 1-min rest between each repetition. All subjects had a forced vital capacity and forced expired volume in 1 s greater than 80% predicted. Background resistance was measured using the forced oscillation method (Jaeger Toennies, Medizintechnikmit System, version 4.5). The test was repeated at least three times for each subject with a 1-min rest between repetitions. The average of three measures was used as the subject's intrinsic resistance.
Protocol. The subjects were seated comfortably in a lounge chair in a sound-isolated chamber, separated from the experimenter and experimental apparatus. A standard set of instructions were presented to the subjects to inform them of their task. The subjects respired through a mouthpiece and nonrebreathing valve (Hans Rudolph, 2600 series, Kansas City, MO) connected to a loading manifold. The loading manifold was hidden from the subject's view and connected to a pneumotachograph (Hans Rudolph, model 4813) by reinforced tubing connected to the inspiratory port of the nonrebreathing valve. The resistive loads were sintered bronze disks placed in series in the loading manifold (13) and separated by stoppered ports. Mouth pressure (Pm) was recorded from a port in the center of the nonrebreathing valve. The Pm was displayed on an oscilloscope in front of the experimenter for timing the load applications.
An electrode cap with integral electrodes (NeuroScan) was used to record scalp EEG activity. The electrode positions were based on the International 10–20 System. The cap was placed on the subject's head, positioned, and secured with a strap. Scalp and electrode contact was made by the application of electroconducting paste administered through the center opening in the electrode. EEG activity was analyzed from F3, F4, CZ, C3', and C4'. The impedance levels for each electrode were checked and maintained below 5 k
. The electrode cap was then connected to an EEG system (model 12, Grass Instruments, Quincy, MA). The EEG activities were referenced to the joined earlobes. Two electrodes were placed over the lateral edge of the eye for recording vertical electrooculograms. Any load presentation that occurred with an eyeblink was discarded. The EEG signals were band-pass filtered (0.3 Hz–1 kHz), amplified, and sampled (2 kHz) for computer analysis. The EEG activities were led into a signal averaging computer system (Signal 2, Cambridge Electronic Design, model 1401).
The subjects wore a nose clip and breathed through a mouthpiece connected to the nonrebreathing valve and loading apparatus. All subjects were instructed to relax all postural and facial muscles. The subjects initially inspired through the minimum resistance port of the loading manifold (13). The occlusion valve was connected to the opening of this minimum resistance (Rmin) port. The Rmin of the apparatus was 1.6 cmH2O·l–1·s. When a resistance was presented, the stopper for that added resistance port was removed. The inspiratory load was presented by silently inflating the occlusion valve after the onset of the inspiratory airflow. Activation of the occlusion valve closed this Rmin port and channeled the inspired air through one of the three manifold resistance ports. The subjects inspired for 
500 ms through the increased resistance. The inspiratory resistive load was presented as an interruption of inspiration. The occlusion trigger control device provided an electrical output that was used to initiate data sample collection by the computer. Each load was separated by 2–6 unloaded breaths. Previous results (7, 9, 10, 20, 22, 24) reported that the R50 for resistive loads in healthy subjects with no background load is about 1–2 cmH2O·l–1·s, and the ratio of R50 to the background R0 is 0.3 (9, 20, 21). Based on this information and our previous results (9), one resistive load below the R50/R0 0.3 detection threshold ratio (R1 = 0.2 cmH2O·l–1·s, R1/R0 < 0.1) and two resistive loads that exceeded the detection threshold ratio were used for eliciting the evoked potentials (R2 = 3.8 cmH2O·l–1·s, R2/R0 > 1.5; R3 = 23.3 cmH2O·l–1·s, R3/R0 > 4.0).
There were two experimental trials: 1) control, without elevated background R0; and 2) with an elevated background R0 = 13.3 cmH2O·l–1·s. The order of the two experimental trials was randomized for each subject. Each experimental trial was divided into two sets of load presentations. Each set was separated by a rest period off the breathing apparatus. The order of the presentation of the three resistive loads was presented in a randomized block design to minimize temporal, order, and sequence effects similar to our previous studies (9, 13, 14). Each set consisted of 120 presentations. Each set of 120 presentations was divided into 24 blocks. Each block had five presentations of an individual load magnitude. Ordering of the different presentation blocks was randomized, with the restriction that each successive set of three blocks contained only one block of each resistive load magnitude. Over the set of 120 presentations, each load magnitude was presented in eight blocks, resulting in 40 total presentations of each load magnitude per set. For each trial, the two sets resulted in each load magnitude presented 80 times. The randomization was independently drawn for each set of 120 presentations and for each subject. For 5 of the 20 subjects, an additional experiment was performed with inspiratory occlusion replacing R3.
In the control, no background trial, the subject respired through the Rmin port, and the background resistance was the subject's intrinsic resistance plus the minimum resistance of the inspiratory circuit. For the experimental trial with increased background resistance (R0'), a 13.3 cmH2O·l–1·s resistance was placed in series with the inspiratory loading manifold and reinforced tubing. The background resistance was in the inspiratory circuit for all breaths. This background resistance decreased the R/R0' ratio, making the R1 and R2 loads below the R50/R0' 0.3 detection threshold ratio (R1 = 0.2 cmH2O·l–1·s, R1/R0' < 0.05; R2 = 3.8 cmH2O·l–1·s, R2/R0' < 0.15), while the R3 load remained above the detection threshold ratio (R3 = 23.3 cmH2O·l–1·s, R3/R0' > 1.0). The subject was allowed 5 min to respire with the increased background R0 before the first set of 120 resistive load presentations was administered as described above. The subject was then allowed 5 min rest off the breathing apparatus. The subject then returned to breathing against the increased R0', and the second set of 120 resistive load presentations was administered. The two experimental trials were presented in the same day for each subject.
Data analysis. The Pm and EEG activities for each load presentation were digitized and stored on the computer for subsequent signal averaging (Signal 2, Cambridge Electronics Design). Each resistive load magnitude was averaged separately as described previously (9, 13). The data analysis was performed for each load magnitude and the two trials.
Individual subject responses were used for RREP peak component identification, amplitude, and latency analyses (6, 9, 16). Baseline-to-peak amplitude values were determined separately for each peak. Peak amplitudes were correlated with the resistive load magnitudes. The Nf peak is the negative peak recorded over the frontal cortex (F3, F4), occurring within 25–40 ms. The P1 peak is the positive potential recorded over the somatosensory cortex (C3', C4'), occurring within a 40- to 70-ms time window. The N1 peak is the more broadly distributed negative potential recorded over the vertex (CZ) and surrounding electrode sites (C3' and C4'), occurring within 80–120 ms. The latencies and amplitudes of the RREP peaks (Nf, P1, and N1) were compared using one-way repeated-measures ANOVA. The repeated measures post hoc analysis was performed with orthogonal and Tukey contrasts for comparing RREP peak amplitudes and latencies for load magnitude within each R0 condition and between R0 conditions. The R3 was the only load magnitude that could be compared between R0 conditions because the R1 and R2 did not elicit a RREP with increased R0'. A P < 0.05 was considered statistically significant.
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RESULTS |
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N1 peak. The N1 peak of the RREP was elicited by R2 and R3 loads and recorded at the CZ, C3', and C4' electrode sites in all subjects during no background R breathing (Fig. 1B). The N1 peak amplitude for R3 was not significantly greater than for R2. There were no significant differences for the N1 peak latency between the R2 and R3 loads (Table 1). In the increased R0' condition, N1 peak of the RREP was elicited only by the R3 load (Fig. 1B) and inspiratory occlusion. The R3 N1 peak amplitude during increased R0' breathing was not significantly different than the R3 N1 peak amplitude with no background R. There were no significant differences for the N1 peak latency of the RREP with R3 load between the no background R and increased R0' (Table 1). Inspiratory occlusion elicited the N1 peak in both conditions, and there was no significant difference in N1 peak amplitude or latency (Table 1).
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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R50/R0 0.3 (9), and were not present with the subthreshold R1 load (9). For the increased R0' trials, the Nf, P1, and N1 peaks of the RREP were not elicited by R1 and R2 loads, which were below the R50/R0 0.3 detection threshold ratio (9, 20, 26). However, during increased R0' breathing the RREP was elicited by the R3 load and inspiratory occlusion, which remained above the R50/R0 0.3 detection threshold ratio. These results address the fundamental question on the relationship between the load magnitude required to elicit the RREP and modulation of the threshold for cognitive detection of added extrinsic R loads. The significance of these results is the demonstration that the RREP can be abolished if the background conditions inhibit load detection. The results further support the direct relationship between the Nf, P1, and N1 peaks of the RREP and the cognitive detectability of R loads. In addition, these results demonstrated that the threshold for detection is a function of background ventilatory state and is directly related to the threshold for the neural activity mediating cognitive awareness of the load. The detection of an inspiratory load as a function of the background resistance has been well established (9, 20, 22, 26). The relationship between the magnitude of an added stimulus required to produce a just-noticeable difference in sensation and the background level of the stimulus has been shown to be a constant fraction in normal subjects and patients (9, 20, 22, 26). If the background stimulus is increased, a greater added stimulus is required to produce a just-noticeable difference in sensation (detection). This means that a greater change in mechanical stimulation is required to elicit the sensory neural activity mediating load detection. Increasing the R0 changes the threshold for cognitive awareness of a transiently increased resistive load and suggests that this is due to the effect the increased R0 on load-related central neural afferent processing.
The ratio of the R0 for detection of R load 50% of the time, R50/R0, has been reported to be 0.3 (9, 20, 26). This means the R load magnitude of the detection threshold R50 is 30% of the total background resistance, R0. When an R load is less than 30% of R0, the load was seldom detected (9, 20, 26), and the RREP was not observed (1, 9). In the present study with no added background resistance, the R1 load was less than 30% of R0 for all subjects, therefore below the detection threshold (9). The R1 load did not elicit any of the peaks of the RREP, similar to our previous report (9). However, the R2 and R3 load magnitudes were greater than 30% of the R0 for these subjects, therefore above the detection threshold ratio. Consistent with our previous report (9), the RREP was observed with both these loads. In addition, with control background R0 there was a significant relationship between R load magnitude above the detection threshold ratio and RREP peak amplitudes, again consistent with previous reports on the relationship between RREP peak amplitude and R load magnitude (9, 13, 14, 19). The somatosensory P1 peak amplitude increased with increasing R load above the detection threshold (Fig. 2). The frontal Nf peak amplitude similarly increased with increasing detectable R load, as did the N1 peak. These results are consistent with previous studies that there is a R load threshold for eliciting the RREP, which suggests that the threshold of the RREP is correlated with the detection threshold (9), and when the load exceeds the detection threshold, there is a direct relationship between RREP peak amplitude and R load magnitude (9, 13, 14, 19).
Wiley and Zechman (20) originally reported that subjects with an elevated background R0' required a greater added R load for detection to occur. However, the ratio of the R50 to the R0' remained 0.3. In the present study, an increased extrinsic background R load was added to produce a total R0', making the R2/R0' ratio less than 0.3, i.e., below the R50/R0 detection threshold. The detectable R2 was made undetectable by the increased R0', and the R2/R0' ratio was less than 0.15, well below the R50/R0 detection threshold (9, 20, 26). Making the R2 below the detection threshold caused the R2 to no longer elicit the RREP. The RREP could be elicited with the elevated R0' if the added load (R3 and occlusion) was above the detection threshold (R3/R0' > 0.3). This means that the RREP can be elicited by a suprathreshold R load or occlusion, but the increased R0' forced the R2 below the detection threshold ratio and below the R threshold for eliciting the RREP. These results support the hypothesis that the threshold for eliciting the RREP is directly correlated with the cognitive detection threshold for eliciting the RREP. In addition, these results demonstrated that changing the background ventilatory state (increased R0') alters the RREP threshold (Fig. 2). These results further support the hypothesis that the RREP is a neural correlate of central respiratory sensory information processing directly related to cognitive load detection.
The relationship between the RREP peak amplitude and the resistive load magnitude indicates that the relative afferent activation of the cortex (the RREP peak amplitude) is also changed by increasing the background resistance. Adding the background R0' decreased the RREP peak amplitudes elicited by the load that remained detectable (R3). Variation in RREP amplitudes suggests that neural activity in the cerebral cortex is modulated by background ventilatory state (increased R0') through sensory information projecting to the cerebral cortex (17).
These results support the sensory neural processing mechanisms (9, 17) proposed to explain cortical activation by respiratory afferent information. If there is a change in the respiratory-related sensory information in response to disruptions of breathing, such as inspiratory resistive load application, cortical neural activity will be elicited in the cerebral cortex and the respiratory information will be perceived (17). Respiratory sensory information does not normally activate cognitive cortical neural regions (referred to as gated-out) during eupneic breathing (17). Inspiratory loads change the mechanosensory neural activity, and if this change in neural activity is of sufficient magnitude, respiratory mechanosensory afferent activity is passed into cognitive centers by subcortical neural mechanisms (17), which can then lead to conscious awareness of a change in breathing (15). In the present study, the Nf, P1, and N1 peaks of the RREP were not present with the increased R0' for R1 and R2 loads because the R was below the R50/R0' detection threshold ratio. If the background load had been presented as a transient increase in resistance, the 13.3 cmH2O·l–1·s load magnitude would have elicited the RREP (9). Yet steady-state breathing against this load magnitude did not elicit a RREP, and the subject verbally reported little awareness of the increased R0' background. The fact that the RREP was not present with steady-state increased R0' suggests central neural accommodation to the elevated R0', and inspiratory R load information was not passed through to the cortical cognitive centers during the R0' background ventilatory state. Hence, as proposed previously (17), respiratory afferent information could be passed through subcortical neural systems to the cognitive cortical regions only if the added transient stimulus is above the detection threshold (referred to as gated-in). Thus a subcortical threshold mechanism has been hypothesized to gate-in or gate-out the respiratory afferent input to higher brain centers (17). However, the neural mechanisms that subserve respiratory sensory information processing remain unknown.
In summary, the present study demonstrated that activation of cortical neural activity was correlated with the perceptual processing of resistive load information. The inspiratory load threshold for eliciting the RREP was increased by the increased background resistance. If the resistive load was greater than R/R0 0.30, the RREP was present. If the load was less than R/R 0.30 or became less with increased background R0' load, the RREP was not present. These results demonstrate that the RREP response can be changed by increasing the background R0' load coincident with a shift in the detection threshold. Further, increasing the R0 to make a load subthreshold for detection, causes that load to be below the central neural threshold for eliciting the RREP.
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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  P.-Y. S. Chan and P. W. Davenport Respiratory-related evoked potential measures of respiratory sensory gating J Appl Physiol, October 1, 2008; 105(4): 1106 - 1113. [Abstract] [Full Text] [PDF]
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