Alcohol Alters Sensory Processing to Respiratory Stimuli in Healthy ...

ALCOHOL AND RESPIRATION DURING WAKING: MEN VERSUS WOMEN

Alcohol Alters Sensory Processing to Respiratory Stimuli in Healthy Men and Women During Wakefulness Danny J. Eckert, PhD1,2; Nathan J. Elgar, BSc (Hons)1,2; R. Doug McEvoy, MD1-3; Peter G. Catcheside, PhD1-3 Adelaide Institute for Sleep Health, Repatriation General Hospital, Daw Park, SA, Australia; 2School of Molecular and Biomedical Science, Discipline of Physiology, The University of Adelaide, Adelaide, SA, Australia; 3Department of Medicine, Flinders University, Bedford Park, SA, Australia 1

Study Objectives: Alcohol can cause sleep-disordered breathing in healthy men, increase O2 desaturation in men who snore, and worsen obstructive sleep apnea (OSA) severity in men with OSA. These findings are less consistent among women, and the underlying mechanisms are incompletely understood. Respiratory-load sensory processing, which underpins upper-airway and respiratory responses to increased breathing load, is potentially impaired by alcohol. Using respiratory-related evoked potentials (RREPs) during wakefulness, this study aimed to test the hypothesis that alcohol impairs respiratory-load sensory processing and to explore potential sex differences. Design: Within-subjects cross-over design in men versus women. Setting: Sleep physiology laboratory. Participants: Twenty healthy individuals (9 women) aged 18 to 38 years. Interventions: Within each subject, RREP waveform components were generated by ~60 brief early-inspiratory negative-pressure pulses (-13 cm H2O mask pressure, 200 ms) before and after acute alcohol administration (1.5 mL/kg body weight). Choanal and epiglottic pressures were recorded to monitor stimulus magnitude and upper-airway resistance. Measurements and Results: The latency of several RREP waveform components increased after the administration of alcohol (ΔN1 = 11 ± 5 ms, ΔN2 = 6 ± 3 ms, ΔP3 = 26 ± 10 ms), and P2 amplitude decreased (3.4 ± 1.5 µV vs 1.2 ± 0.8 µV). There were no changes in P1 latency or amplitude. During relaxed breathing, nasal resistance increased after alcohol ingestion (1.38 ± 0.16 vs 1.86 ± 0.18 cm H2O·l-1·s-1), but pharyngeal and supraglottic resistances remained unchanged. RREP waveform components and upper-airway resistance measures were not different in men versus women before or after alcohol ingestion. Conclusions: These data demonstrate that alcohol alters sensory processing of respiratory neural information, but not early neural transmission (P1), to a similar extent in healthy men and women. Altered sensory processing to respiratory stimuli, as well as nasal congestion, may be important mechanisms contributing to alcohol-related sleep disordered breathing. Keywords: Respiratory-related evoked potential, upper airway, sleep-disordered breathing, sex Citation: Eckert DJ; Elgar NJ; McEvoy RD; Catcheside PG. Alcohol alters sensory processing to respiratory stimuli in healthy men and women during wakefulness. SLEEP 2010;33(10):1389-1395.

ALCOHOL IS WELL KNOWN TO HAVE CENTRAL NERVOUS SYSTEM DEPRESSIVE EFFECTS,1 WHICH CAN HAVE DELETERIOUS EFFECTS ON RESPIRATORY function. For instance, alcohol exacerbates respiratory failure in patients with advanced respiratory disease.2 Furthermore, mild to moderate alcohol consumption immediately prior to sleep can lead to sleep disordered breathing (SDB) in otherwise healthy men,3 greater O2 desaturation in men who snore,4,5 and augment the severity of SDB in men with obstructive sleep apnea (OSA).5,6 These findings are less consistent among women.7-10 In addition, increased regular alcohol consumption appears to be associated with more of an increased risk of SDB in men than in women.11-13 Although the underlying mechanisms contributing to alcoholrelated SDB and the apparent increased male vulnerability are incompletely understood, multiple factors are likely involved. In healthy individuals, moderate alcohol consumption increases

upper-airway resistance (particularly nasal resistance) during wakefulness14-16 and during sleep in men.17 Indeed, alcohol is a potent vasodilator that can cause nasal obstruction,18 which may lead directly to SDB19-22 or which may lead indirectly to SDB via mouth-breathing–related mechanisms.23,24 Alcohol has also been shown to impair upper-airway muscle function in healthy men and women and delays the arousal response to respiratory occlusion during sleep in healthy men.25-27 These factors would also be predicted to lead to greater vulnerability to snoring and worsening of blood arterial O2 status during respiratory events. However, the underlying mechanisms responsible for these alcohol-induced changes are poorly understood. For example, it is unclear if alcohol impairs upper-airway sensory function and respiratory afferent neural transmission, the sensory processing of respiratory afferent information, or a combination of the transmission and processing of information. Furthermore, it remains uncertain whether these mechanisms are differentially affected by alcohol in men, compared with in women, thereby potentially helping to explain sex differences in vulnerability to alcohol-related SDB. Communication between neurons occurs continuously within the central nervous system and can be measured by way of surface electrical activity. Event-related potentials are measured by recording electrical activity at the scalp in response to multiple time-locked stimuli to improve the signalto-noise ratio from non-stimulus–related electrophysiologic

Submitted for publication October, 2009 Submitted in final revised form April, 2010 Accepted for publication June, 2010 Address correspondence to: Danny Eckert, Brigham and Women’s Hospital, Division of Sleep Medicine, Sleep Disorders Program, 221 Longwood Avenue, Boston, MA; Tel: (617) 732-5619; Fax: (617) 732-7337; E-mail: [email protected] SLEEP, Vol. 33, No. 10, 2010

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Alcohol and the Respiratory-related Evoked Potential—Eckert et al

activity.28 Respiratory-related evoked potentials (RREPs) provide valuable insight into the underlying processes mediating respiratory sensation, afferent transmission, and cortical processing.29-33 RREPs are characterized by positive (P) and negative (N) waveform components within time-locked windows relative to the onset of a respiratory stimulus. During wakefulness, the first positive peak (P1) occurs 35 to 110 ms after stimulus onset, depending on specific stimulus characteristics,30-32,34-38 and is believed to reflect the arrival of ascending respiratory afferent information at the somatosensory cortex.32 Recent evidence suggests that the first negative RREP peak (N1) reflects respiratory central neural gating.39 The neural origin and functional significance of the intermediate RREP peaks (N2 and P2) are less well defined, but, similar to other sensory modalities, these peaks likely reflect early sensory processing.37,40 The third positive peak (P3) occurs after 250 ms from the stimulus onset and reflects cognitive and perceptual sensory processing.29 RREP techniques have been utilized to reveal impaired respiratory sensation and processing in a variety of respiratory conditions, including in patients with OSA.33,34,41-46 The aim of this study was to utilize the RREP to test the hypothesis that alcohol impairs sensory processing of respiratory afferent information during wakefulness, before further separate investigations in sleep. Specifically, we wished to determine which RREP components (i.e., P1 [sensory transmission], N1 [neural gating], P2/N2 [early sensory processing], P3 [late sensory processing]) are impaired by alcohol to gain insight into possible sensory mechanisms contributing to alcohol-related SDB. A secondary aim was to determine if alcohol affects the RREP to a greater extent in men than in women, given the apparent male predominance of this phenomenon.

most patent nostril to measure pressure changes across the collapsible portion of the upper airway (between the choanae [Pcho] and epiglottis [Pepi], respectively), as has been previously described.47,48 Each catheter had a pressure transducer (Spectramed) attached to its proximal end and was perfused at a constant flow of approximately 1 to 2 mL/min to prevent catheter blockage. Upper-airway negative-pressure pulses (Pmask ~-13 cm H2O, 200-ms duration) were delivered during early inspiration (~250300 ms after the onset of inspiration) every 4 to 8 breaths via a computer-controlled, rapid-actuating, solenoid-valve system (Isostar, SXE9575-A70-00, Norgren, Switzerland). This technique is similar to procedures previously described.47,48 Blood alcohol concentration (BAC) was estimated using a calibrated hand-held Breathalyzer unit (Alcotest 7410, Dräger, Australia). All ventilatory and RREP data were acquired using a Windaq data acquisition system (DI-720 DATAQ Instruments, Akron, OH) sampled at 200 Hz per channel. Protocol Subjects attended the laboratory in the afternoon following a light lunch. Spirometry was performed to ensure normal lung function (JLab software version 4.53; Compactlab, Jaeger). A small blood sample was taken from women, and chemiluminescence was performed (ACS:180 Progesterone assay, Chrion Diagnostics, Chrion Healthcare, Victoria, Australia) to ensure high progesterone levels indicative of the luteal phase (above 15 mmol). Once all the equipment was fitted, several negative-pressure pulses were delivered for familiarization purposes. Following a 5-minute baseline period to record upper-airway resistance measures during relaxed breathing, each subject received approximately 60 negative-pressure pulses within a 25-minute period (prealcohol protocol). Subjects then received 1.5 mL/kg (body weight) of 100 proof vodka with an equal volume of orange juice over a 15-minute period, in accordance with similar protocols.4,7,8,10,14,25 Following a 45-minute break to allow BACs to stabilize, the protocol was repeated (postalcohol protocol). BAC was recorded immediately prior to and at the completion of the postalcohol protocol. A schematic of the study design is displayed in Figure 1.

METHODS Subjects Twenty young, healthy, volunteers (9 premenopausal women) were studied. Subjects were nonsmokers without a history of cardiorespiratory disease, metabolic disorders, SDB, or regular medication use and had baseline forced expiratory volume in the first second of expiration and forced vital capacity greater than 80% of the predicted values. Women were studied in the luteal phase of their menstrual cycle, defined as days 20 to 23, with day 1 being the first day of the menses. All subjects gave informed written consent to participate. The study was approved by the Daw Park Repatriation General Hospital and Adelaide University Human Research and Ethics Committees. Subjects were studied supine in a temperature-controlled laboratory.

Data Analysis Nasal (Pmask-Pcho), pharyngeal (Pcho-Pepi), and supraglottic (Pmask-Pepi) resistances were derived from the within-breath slope of the change in pressure versus flow during the 5-minute relaxed-breathing period before and after alcohol administration. Negative-pressure pulses were excluded from analysis if (1) they were delivered during, or in the breath following, a sigh or a swallow; (2) they were delivered in a 30-second epoch immediately following any intrusion of sleep (as determined by electroencephalography); (3) the magnitude of the pulse (min Pmask) was not within the range -10 to -15 cm H2O; or (4) there was a loss of signal integrity (e.g., movement artifact or mucus accumulation on pressure catheters). All remaining trials were grouped and ensemble averaged to derive the RREP for the prealcohol and postalcohol conditions, respectively, for each subject. Negative-pressure pulse-stimulus onset (time 0) was defined in the conventional manner as the

Measurements and Equipment Subjects breathed via a nasal mask (Respironics, Murrysville, PA) fitted with a pressure transducer (Spectramed, Mt. Vernon, OH; Pmask) and pneumotachograph (Jaeger, Höchberg, Germany). Electroencephalography (C3-A2) was measured to monitor wakefulness and record RREPs (Compumedics, Abbotsford, Australia; band pass filter, 0.1-30 Hz). Two custom-made air-perfused catheters (2.1 mm OD, Microtube Extensions, North Rocks, Australia) were inserted via the SLEEP, Vol. 33, No. 10, 2010

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BAC1

BAC2

5min

25min

15min

45min

5min

25min

B

NPP

Alcohol

Break

B

NPP

Pre - Alcohol Protocol

Post - Alcohol Protocol

Figure 1—Schematic of the experimental protocol. B refers to baseline; NPP, negative-pressure pulses; Alcohol, 1.5 mL/kg (body weight) 100-proof vodka in orange juice; BAC, estimated blood alcohol concentration via Breathalyzer test.

Pmask -10 cmH2O

Pcho Pepi

N2*

N1* RREP P1

5µv

P2†

Pre-Alcohol Post-Alcohol

P3* -100

0

100

200

300

400

500

Time (ms) Figure 2—Respiratory-related evoked potential (RREP) group-average waveforms and stimulus characteristics. Pmask refers to mask pressure, Pcho: choanal pressure, Pepi: epiglottic pressure before and after alcohol consumption. *Denotes a significant difference in the latency of a peak between conditions. † Indicates a significant difference in the amplitude of a peak between conditions.

last point preceding the sudden decrement in the ensembleaveraged Pmask following solenoid activation (vertical dashed line in Figure 2). Stimulus magnitude was calculated as the minimum pressure derived from the ensemble-averaged Pmask, Pcho, and Pepi for each subject.

cago, IL). Where significant analysis of variance interaction effects were observed, posthoc comparisons were performed using student paired t-tests. Statistical significance was inferred when the P value was less than 0.05. All data are reported as mean ± SEM.

Statistical Procedures Analysis of variance for repeated measures was used to examine alcohol, sex, and alcohol × sex interaction effects on the latency and amplitude of each RREP component and on upper-airway resistance (SPSS version 11, SPSS Inc, Chi-

RESULTS

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Anthropometric and Descriptive Characteristics The age and body mass index of the 20 subjects were 21 ± 1 years and 23 ± 1 kg/m2, respectively. Subjects had normal lung 1391


Table 1—Upper-airway resistance during relaxed breathing and negative-pressure pulse-stimulus characteristics before and after alcohol consumption

Table 2—RREP data: mean latency and amplitude before and after alcohol consumption

Breathing Condition, Parameter

RREP parameter P1 N1 P2 N2 P3

During relaxed breathing Resistance, cm H2O·L-1·s-1 Nasal Pharyngeal Total supraglottic

Alcohol Condition Before

After

1.38 ± 0.16 1.86 ± 0.18a 1.17 ± 0.29 0.97 ± 0.14 2.43 ± 0.30 2.64 ± 0.26

During negative-pressure pulses Minimum pressure, cm H2O Mask -13.1 ± 0.4 Choanal -12.7 ± 0.3 Epiglottic -9.7 ± 0.4 Artifact-free pulse presentations, no. 62 ± 4

-13.2 ± 0.4 -12.0 ± 0.4 -9.2 ± 0.4 62 ± 5

Alcohol Condition

Upper-Airway Resistance and RREP Stimulus and Waveform Characteristics Before and After Alcohol Ingestion Nasal resistance increased after alcohol consumption, whereas pharyngeal and supraglottic resistances were not significantly different, compared with the prealcohol condition (Table 1). There were no sex × alcohol interaction effects in any resistance measure. Negative-pressure pulse-stimulus magnitude and the number of artifact-free pulses used to derive ensemble-average waveforms for event-related analyses were not different before, compared with after, alcohol ingestion (Table 1). The latencies of N1, N2, and P3 RREP waveform components increased after alcohol consumption, whereas P1 and P2 latencies remained unchanged. The amplitude of the P2 RREP component decreased after alcohol consumption. The amplitudes of the remaining RREP components were not different before, compared with after, alcohol consumption (Figure 2, Table 2). Stimulus magnitude during negative-pressure pulse application did not differ between sexes, and there were no sex or sex × alcohol interaction effects for any of the RREP latency or amplitude components (Table 3).

Denotes a significant difference compared with the equivalent prealcohol condition.

Table 3—RREP data: mean stimulus magnitude, latency, and amplitude before and after alcohol consumption in men and women Parameter

Alcohol Condition Before After Men Women Men Women Stimulus magnitude—minimum pressure, cm H2O Mask -13.4 ± 0.6 -13.2 ± 0.7 -13.4 ± 0.5 -13.4 ± 0.5 Choanal -12.5 ± 0.5 -13.0 ± 0.6 -11.6 ± 0.6 -12.6 ± 0.6 Epiglottic -10.0 ± 0.6 -9.6 ± 0.9 -9.6 ± 0.4 -8.8 ± 0.7

Amplitude, µV P1 1.8 ± 0.3 N1 -2.7 ± 1.1 P2 2.2 ± 2.1 N2 -3.3 ± 1.6 P3 11.0 ± 1.8

1.9 ± 0.3 -3.4 ± 1.1 4.7 ± 2.2 -2.9 ± 1.7 10.9 ± 1.9

1.3 ± 0.4 -3.0 ± 0.7 0.5 ± 1.1 -3.6 ± 1.2 10.0 ± 1.4

38.3 ± 3.8 90.6 ± 9.6 130.6 ± 13.1 175.6 ± 14.6 307.8 ± 18.1

DISCUSSION The main findings of this study were that alcohol impairs sensory processing of respiratory afferent information and increases nasal resistance to a similar extent in both healthy young men and women. Specifically, these data show that the early P1 component of the RREP, indicative of sensory neural transmission, remains intact during acute moderate alcohol administration, but several other intermediate (N1 and N2) and later (P3) sensory-processing components are delayed, and P2 amplitude is reduced. The finding that sensory processing to respiratory stimuli, but not sensory transmission, is delayed with alcohol is consistent with the majority of event-related potential studies in other sensory modalities, such as with visual and auditory stimuli.49-53 The presence of P3 impairment, in particular, appears to be consistent across sensory modalities. However, 1 study did show differences in sensory transmission and sensory processing to visual stimuli,54 suggesting that the visual system may be more vulnerable to the inhibitory effects of alcohol. The finding that nasal resistance increased after alcohol consumption during normal relaxed breathing in the current study is consistent with previous reports.14-16 Increased nasal resis-

2.1 ± 0.4 -2.6 ± 0.8 1.9 ± 1.2 -3.1 ± 1.3 9.0 ± 1.5

There were no sex or sex × alcohol interaction effects for any stimulus measure or respiratory-related evoked potential (RREP) latency or amplitude component.

function (mean forced expiratory volume in the first second of expiration 110 ± 3 and forced vital capacity 104% ± 3% predicted). Men and women did not differ with respect to age or body mass index (22 ± 2 years vs 21 ± 1 years and 23 ± 1 kg/m2 vs 23 ± 1 kg/m2, respectively). Consistent with the luteal phase of the menstrual cycle, all women had progesterone levels in excess of 15 mmol. The mean BAC immediately prior to the postalcohol protocol was 77 ± 3 mg/dL and decreased to 65 ± 2 mg/dL by the end of the 30-minute protocol. SLEEP, Vol. 33, No. 10, 2010

After Latency, ms Amplitude, µV 35.0 ± 2.6 1.7 ± 0.3 83.7 ± 6.6a -2.8 ± 0.5 117.1 ± 9.3 1.2 ± 0.8a a 162.4 ± 10.2 -3.4 ± 0.9 299.5 ± 12.2a 9.5 ± 1.0

RREP refers to respiratory-related evoked potential. aDenotes a significant difference compared with the equivalent prealcohol condition.

a

Latency, ms P1 34.0 ± 3.7 43.3 ± 3.9 32.0 ± 3.6 N1 72.0 ± 5.9 73.3 ± 6.2 77.5 ± 9.2 P2 110.0 ± 9.2 123.9 ± 9.7 105.0 ± 12.4 N2 143.5 ± 13.2 170.0 ± 13.9 150.5 ± 13.8 P3 254.5 ± 20.9 293.9 ± 22.0 292.0 ± 17.1

Before Latency, ms Amplitude, µV 38.4 ± 2.8 1.9 ± 0.2 72.6 ± 4.2 -3.0 ± 0.8 116.6 ± 6.7 3.4 ± 1.5 156.1 ± 9.8 -3.1 ± 1.2 273.2 ± 15.4 11.0 ± 1.3

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tance or obstruction has been shown experimentally to cause SDB.19-22 Thus, this is likely to be an important mechanism contributing to alcohol-induced SDB. Other studies have also revealed increased pharyngeal and total supraglottic resistance after alcohol consumption,14,15,17 although this was not shown in the current study. The apparent disparity between our findings and those of previous studies may relate to methodologic differences in the timing and quantity of the alcohol administered. Robinson and colleagues14 found a positive correlation between increased pharyngeal resistance with alcohol and age. Our population was younger (mean age 21 vs 38 years), and upper-airway function is known to deteriorate with age, such that differences between studies could indicate age-related susceptibility to changes in upper-airway resistance following alcohol ingestion. Nonetheless, given the consistency between studies, increased nasal resistance would appear to be a key factor contributing to SDB independent of age.

been considered an important airway-protective mechanism in sleep.58 In healthy men, Berry and colleagues demonstrated blunted arousal responses to occlusive stimuli following acute alcohol administration.27 In the presence of diminished genioglossus responsiveness with alcohol, as has been observed in other studies,25,26,55 impaired arousal responses would be predicted to lead to worsening gas exchange and O2 desaturation in SDB. However, the underlying mechanisms contributing to impaired arousal responses with alcohol remain unknown. Changes in sensory processing to respiratory stimuli, as measured by the P3 component of the RREP, have been shown to correlate with load-magnitude perception in asthma.44 In the same manner, changes in the RREP observed in the current study suggest that impaired arousal responses to respiratory stimuli following alcohol ingestion are not likely to be caused by impaired sensory transmission (P1) but, rather, by diminished sensory integration and higher processing, as evidenced by blunted P2 amplitude and delayed N1, N2, and P3.

Insights from the RREP: Potential Mechanisms Mediating Alcohol-Induced SDB Although nasal resistance increased after alcohol consumption during relaxed breathing, upper-airway mechanics, as measured by minimal choanal and epiglottic pressures during brief negative-pressure pulses, were not different in the prealcohol versus postalcohol conditions. Thus, the stimulus magnitude for RREP generation was well matched between conditions. During these experimental conditions, respiratory afferent transmission, as measured by the P1 component of the RREP, remained intact, but intermediate and later sensory-processing components were altered. These findings provide important new insight into the potential mechanisms mediating alcoholinduced changes in upper-airway function and the propensity for SDB. For example, using alcohol doses similar to those used in the present study, several studies have revealed impaired genioglossus (the largest upper-airway dilator muscle) function after alcohol ingestion in animals and humans,25,26,55 an effect that is likely to worsen SDB. The lack of change in the amplitude and latency of the P1 component of the RREP (indicative of respiratory-sensory transmission) suggests that primary upper-airway respiratory-sensory afferent information is preserved following acute moderate alcohol administration and is in accordance with other sensory evoked-potential modalities.49-53 In addition, consistent with a lack of change in the P1 component of the RREP, other upper-airway reflexes have been shown to be preserved following moderate alcohol administration.56,57 Thus, these data suggest that reductions in the activity of the largest upper-airway dilator muscle following alcohol may not be the result of impaired sensory function that subsequently diminishes reflex responsiveness to negative airway pressure. Rather, as evidenced by reduced P2 amplitude and delayed N1, N2, and P3 RREP components following alcohol ingestion, impairment of other feedback mechanisms to the hypoglossal motor nucleus (responsible for motor output to genioglossus), such as impaired sensory gating and higher processing, may be more important contributing factors. Impaired respiratory-sensory processing with alcohol has important implications for respiratory-related arousals from sleep. During SDB, most respiratory events are terminated in association with a brief arousal, such that the arousal has long SLEEP, Vol. 33, No. 10, 2010

Sex Effects We did not observe any effect of sex on upper-airway resistance or changes in RREP latency or amplitude components to negative-pressure pulse stimuli, with or without alcohol ingestion. Large systematic differences in vulnerability to alcohol-induced changes in upper-airway resistance or sensory processing, therefore, appear unlikely to explain the apparent male predominance of alcohol-induced SDB, unless there are sleep-specific effects or sex effects not detected with our relatively small group sizes. In RREP data derived from the first and second half of the prealcohol condition, we observed within-subject standard deviations in RREP latencies on the order of 10 milliseconds (P1-N2) to 20 milliseconds (P3) and in amplitudes of 1.5 µV (P1, N1, P3) to 3 µV (P2, N2). Given this level of variability, differences between sexes in RREP latencies and amplitudes on the order of 10 to 20 milliseconds and 1.5 to 2.5 µV, respectively, and sex × alcohol differences on the order of 15 to 30 milliseconds and 2.5 to 4 µV, respectively, should have been detectable with 2-tailed tests, with approximately 10 subjects per group and 80% power. Given that the observed effects of alcohol were of a similar magnitude, the lack of significant sex effects could indicate Type II error. Therefore, larger studies appear to be warranted to investigate potential sex effects in more detail. We are not aware of any other studies that have explored sex differences in RREP responses to alcohol. Consequently, it also remains to be seen if other factors, such as genioglossus muscle activity and reflex responsiveness to negative pressure, differ between sexes during wake, sleep, or both wake and sleep and whether respiratory-sensory processing, arousal responses to respiratory stimuli, or both differ in sleep following alcohol administration. Methodologic Considerations In this protocol, we studied healthy young men and women during wakefulness. Alcohol effects in older individuals, during sleep, and across the menstrual cycle in women may differ. Although the early RREP components appear to be consistent across sleep states,59 the timing and amplitude of the later sensory-processing components differ from wakefulness to sleep; 1393


ACKNOWLEDGMENTS This work was funded by the National Health and Medical Research Council of Australia. Dr. Eckert is supported by an Overseas Based Biomedical Fellowship from the National Health and Medical Research Council of Australia (510392).

the K complex dominates the response during non-rapid eye movement sleep.33,60 However, if sensory-processing changes are present in healthy young individuals during wakefulness, as has been shown in this study, it appears likely that altered sensory processing would persist in older age groups and during sleep. Nonetheless, RREP studies during sleep in a more vulnerable population are clearly required to definitively address the potential for sleep-specific effects to account for an apparent male vulnerability to the detrimental effects of alcohol on upper-airway function in sleep. RREP components were derived overlaying the somatosensory area of the cortex at C3-A2, so it remains possible that alcohol-related effects on RREP components may differ at other areas of the cortex. Additionally, broadening the filter settings, increasing the sampling frequency, and increasing the number of replicate trials may have improved the signal-to-noise characteristics and the likelihood of observing additional changes in some of the RREP components that occurred with alcohol ingestion. Although this remains a possibility, other studies using similar replicate trial numbers, sampling frequencies, and filter settings have observed changes in early and late RREP components.29,36,46 This was a nonrandomized and unblinded trial such that order and subjective influences could have biased the main outcomes. However, we believe this to be very unlikely and chose a pragmatic design primarily on the basis that there is greater day-to-day, as compared with within-day, variability in the main outcomes, and it is not possible to meaningfully blind patients to the consumption of alcohol at clinically relevant doses. Increased upper-airway resistance is a consistent outcome with alcohol ingestion.14-17 RREP responses have previously been shown to produce repeatable responses over time.36,59 Indeed, during 2 relaxed-breathing conditions separated by an approximately 90-minute interval, RREP amplitudes and latencies to approximately 90 replicate, brief, resistive loads were not different.36 Similarly, when we compared RREP responses during the first half and the second half of the prealcohol condition in the current study, we found no significant time effects in any RREP latency or amplitude component (data not presented). Therefore, systematic temporal effects appear to be unlikely in accounting for RREP changes after alcohol ingestion. Furthermore, non-alcohol–related subjective influences on upper-airway resistance and short-latency RREP responses also appear to be highly unlikely.

DISCLOSURE STATEMENT This was not an industry supported study. Dr. Eckert is a consultant for Apnex Medical and has participated in an investigator-initiated research study supported by Sepracor. Dr. McEvoy has received research support from Fisher Paykel and the use of equipment from Respironics and Resmed. Dr. Catcheside has received research support from Apnex and the use of equipment from Philips Respironics and Gorman ProMed Pty. Ltd. Mr. Elgar has indicated no financial conflicts of interest. REFERENCES

1. Ma W, Pancrazio JJ, Andreadis JD, et al. Ethanol blocks cytosolic Ca2+ responses triggered by activation of GABA(A) receptor/Cl- channels in cultured proliferating rat neuroepithelial cells. Neuroscience 2001;104(3):913-22. 2. Krumpe PE, Cummiskey JM, Lillington GA. Alcohol and the respiratory tract. Med Clin North Am 1984;68(1):201-19. 3. Taasan VC, Block AJ, Boysen PG, Wynne JW. Alcohol increases sleep apnea and oxygen desaturation in asymptomatic men. Am J Med 1981;71(2):240-5. 4. Mitler MM, Dawson A, Henriksen SJ, Sobers M, Bloom FE. Bedtime ethanol increases resistance of upper airways and produces sleep apneas in asymptomatic snorers. Alcohol Clin Exp Res 1988;12(6):801-5. 5. Issa FG, Sullivan CE. Alcohol, snoring and sleep apnea. J Neurol, Neurosurg Psychiatry 1982;45(4):353-9. 6. Scanlan MF, Roebuck T, Little PJ, Redman JR, Naughton MT. Effect of moderate alcohol upon obstructive sleep apnoea. Eur Respir J 2000;16(5):909-13. 7. Block AJ. Alcohol ingestion does not cause sleep-disordered breathing in premenopausal women. Alcohol Clin Exp Res 1984;8(4):397-8. 8. Block AJ, Hellard DW, Slayton PC. Minimal effect of alcohol ingestion on breathing during the sleep of postmenopausal women. Chest 1985;88(2):181-4. 9. Block AJ, Wynne JW, Boysen PG. Sleep-disordered breathing and nocturnal oxygen desaturation in postmenopausal women. Am J Med 1980;69(1):75-9. 10. Block AJ, Hellard DW, Slayton PC. Effect of alcohol ingestion on breathing and oxygenation during sleep. Analysis of the influence of age and sex. Am J Med 1986;80(4):595-600. 11. Peppard PE, Austin D, Brown RL. Association of alcohol consumption and sleep disordered breathing in men and women. J Clin Sleep Med 2007;3(3):265-70. 12. Tanigawa T, Tachibana N, Yamagishi K, et al. Usual alcohol consumption and arterial oxygen desaturation during sleep. JAMA 2004;292(8):923-5. 13. Valipour A, Lothaller H, Rauscher H, Zwick H, Burghuber OC, Lavie P. Gender-related differences in symptoms of patients with suspected breathing disorders in sleep: a clinical population study using the sleep disorders questionnaire. Sleep 2007;30(3):312-9. 14. Robinson RW, White DP, Zwillich CW. Moderate alcohol ingestion increases upper airway resistance in normal subjects. Am Rev Respir Dis 1985;132(6):1238-41. 15. Series F, Cormier FY, Desmeules M. Alcohol and the response of upper airway resistance to a changing respiratory drive in normal man. Respir Physiol 1990;81(2):153-63. 16. Eccles R, Tolley NS. The effect of alcohol ingestion upon nasal airway resistance. Rhinology 1987;25(4):245-8. 17. Dawson A, Bigby BG, Poceta JS, Mitler MM. Effect of bedtime alcohol on inspiratory resistance and respiratory drive in snoring and nonsnoring men. Alcohol Clin Exp Res 1997;21(2):183-90. 18. May M, West JW. The “stuffy” nose. Otolaryngol Clin North Am 1973;6(3):655-74.

SUMMARY These data demonstrate that acute moderate alcohol administration (1.5 mL/kg body weight) impairs sensory processing of respiratory neural information (decreased amplitude of the P2 component of the RREP and delayed N1, N2, and P3 components), but not early neural transmission (P1), to a similar extent in healthy young men and women. These data also support previous findings that alcohol increases nasal resistance but with no systematic differences between sexes. Altered sensory processing to respiratory stimuli leading to blunted arousal responses during sleep, and possibly to reduced upper-airway dilator-muscle activity, as well as nasal congestion, may be important mechanisms contributing to alcohol-related SDB. SLEEP, Vol. 33, No. 10, 2010

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19. Zwillich CW, Pickett C, Hanson FN, Weil JV. Disturbed sleep and prolonged apnea during nasal obstruction in normal men. Am Rev Respir Dis 1981;124(2):158-60. 20. Taasan V, Wynne JW, Cassisi N, Block AJ. The effect of nasal packing on sleep-disordered breathing and nocturnal oxygen desaturation. The Laryngoscope 1981;91(7):1163-72. 21. McNicholas WT, Tarlo S, Cole P, et al. Obstructive apneas during sleep in patients with seasonal allergic rhinitis. Am Rev Respir Dis 1982;126(4):625-8. 22. Carskadon MA, Bearpark HM, Sharkey KM, et al. Effects of menopause and nasal occlusion on breathing during sleep. Am J Respir Crit Care Med 1997;155(1):205-10. 23. Gleeson K, Zwillich CW, Braier K, White DP. Breathing route during sleep. Am Rev Respir Dis 1986;134(1):115-20. 24. Verma M, Seto-Poon M, Wheatley JR, Amis TC, Kirkness JP. Influence of breathing route on upper airway lining liquid surface tension in humans. J Physiol 2006;574(Pt 3):859-66. 25. Krol RC, Knuth SL, Bartlett D, Jr. Selective reduction of genioglossal muscle activity by alcohol in normal human subjects. Am Rev Respir Dis 1984;129(2):247-50. 26. Leiter JC, Doble EA, Knuth SL, Bartlett D, Jr. Respiratory activity of genioglossus. Interaction between alcohol and the menstrual cycle. Am Rev Respir Dis 1987;135(2):383-6. 27. Berry RB, Bonnet MH, Light RW. Effect of ethanol on the arousal response to airway occlusion during sleep in normal subjects. Am Rev Respir Dis 1992;145(2 Pt 1):445-52. 28. Shea SA, Lannsing RW, Banzett RB. Respiratory sensations and their role in the control of breathing. In: Dempsey JA, Pack AI, eds. Regulation of Breathing, 2nd ed. New York, NY: Marcel Dekker Inc; 1995:923-57. 29. Webster KE, Colrain IM. The relationship between respiratory-related evoked potentials and the perception of inspiratory resistive loads. Psychophysiology 2000;37(6):831-41. 30. Daubenspeck JA, Manning HL, Baird JC. Midlatency respiratory-related somatosensory activity and perception of oral pressure pulses in normal humans. J Appl Physiol 2001;90(6):2048-56. 31. Knafelc M, Davenport PW. Relationship between resistive loads and P1 peak of respiratory-related evoked potential. J Appl Physiol 1997;83(3):918-26. 32. Davenport PW, Friedman WA, Thompson FJ, Franzen O. Respiratoryrelated cortical potentials evoked by inspiratory occlusion in humans. J Appl Physiol 1986;60(6):1843-8. 33. Colrain IM, Campbell KB. The use of evoked potentials in sleep research. Sleep Med Rev 2007;11(4):277-93. 34. Gora J, Trinder J, Pierce R, Colrain IM. Evidence of a sleep-specific blunted cortical response to inspiratory occlusions in mild obstructive sleep apnea syndrome. Am J Respir Crit Care Med 2002;166(9):1225-34. 35. Webster KE, Colrain IM. The respiratory-related evoked potential: effects of attention and occlusion duration. Psychophysiology 2000;37(3):310-8. 36. Eckert DJ, Catcheside PG, McDonald R, et al. Sustained hypoxia depresses sensory processing of respiratory resistive loads. Am J Respir Crit Care Med 2005;172(8):1047-54. 37. Bloch-Salisbury E, Harver A, Squires NK. Event-related potentials to inspiratory flow-resistive loads in young adults: stimulus magnitude effects. Biol Psychol 1998;49(1-2):165-86. 38. Knafelc M, Davenport PW. Relationship between magnitude estimation of resistive loads, inspiratory pressures, and the RREP P(1) peak. J Appl Physiol 1999;87(2):516-22. 39. Chan PY, Davenport PW. Respiratory-related evoked potential measures of respiratory sensory gating. J Appl Physiol 2008;105(4):1106-13.

SLEEP, Vol. 33, No. 10, 2010

40. Crowley KE, Colrain IM. A review of the evidence for P2 being an independent component process: age, sleep and modality. Clin Neurophysiol 2004;115(4):732-44. 41. Afifi L, Guilleminault C, Colrain IM. Sleep and respiratory stimulus specific dampening of cortical responsiveness in OSAS. Respir Physiol Neurobiol 2003;136(2-3):221-34. 42. Akay M, Leiter JC, Daubenspeck JA. Reduced respiratory-related evoked activity in subjects with obstructive sleep apnea syndrome. J Appl Physiol 2003;94(2):429-38. 43. Davenport PW, Cruz M, Stecenko AA, Kifle Y. Respiratory-related evoked potentials in children with life-threatening asthma. Am J Respir Crit Care Med 2000;161(6):1830-5. 44. Webster KE, Colrain IM. P3-specific amplitude reductions to respiratory and auditory stimuli in subjects with asthma. Am J Respir Crit Care Med 2002;166(1):47-52. 45. Huang J, Colrain IM, Melendres MC, et al. Cortical processing of respiratory afferent stimuli during sleep in children with the obstructive sleep apnea syndrome. Sleep 2008;31(3):403-10. 46. Huang J, Marcus CL, Bandla P, et al. Cortical processing of respiratory occlusion stimuli in children with central hypoventilation syndrome. Am J Respir Crit Care Med 2008;178(7):757-64. 47. Eckert DJ, McEvoy RD, George KE, Thomson KJ, Catcheside PG. Genioglossus reflex inhibition to upper-airway negative-pressure stimuli during wakefulness and sleep in healthy males. J Physiol 2007;581(Pt 3):1193-205. 48. Hilditch CJ, McEvoy RD, George KE, et al. Upper airway surface tension but not upper airway collapsibility is elevated in primary Sjogren’s syndrome. Sleep 2008;31(3):367-74. 49. Rohrbaugh JW, Stapleton JM, Parasuraman R, et al. Dose-related effects of ethanol on visual sustained attention and event-related potentials. Alcohol 1987;4(4):293-300. 50. Colrain IM, Taylor J, McLean S, Buttery R, Wise G, Montgomery I. Dose dependent effects of alcohol on visual evoked potentials. Psychopharmacology (Berl) 1993;112(2-3):383-8. 51. Jensen OL, Krogh E. Visual evoked response and alcohol intoxication. Acta Ophthalmol 1984;62(4):651-7. 52. Teo RK, Ferguson DA. The acute effects of ethanol on auditory eventrelated potentials. Psychopharmacology (Berl) 1986;90(2):179-84. 53. Oscar-Berman M. Alcohol-related ERP changes in cognition. Alcohol 1987;4(4):289-92. 54. Rhodes LE, Obitz FW, Creel D. Effect of alcohol and task on hemispheric asymmetry of visually evoked potentials in man. Electroencephalogr Clin Neurophysiol 1975;38(6):561-8. 55. Bonora M, Shields GI, Knuth SL, Bartlett D, Jr., St John WM. Selective depression by ethanol of upper airway respiratory motor activity in cats. Am Rev Respir Dis 1984;130(2):156-61. 56. Juvin P, Dureuil B, Montravers P, Desmonts JM. Effects of acute alcoholic intoxication on the upper respiratory tract function. Ann Fr Anesth Reanim 1993;12(5):447-51. 57. Erskine R, Murphy P, Langton JA. The effect of ethyl alcohol on the sensitivity of upper airway reflexes. Alcohol Alcoholism 1994;29(4):425-31. 58. Phillipson EA, Sullivan CE. Arousal: the forgotten response to respiratory stimuli. Am Rev Respir Dis 1978;118(5):807-9. 59. Webster KE, Colrain IM. Multichannel EEG analysis of respiratory evoked-potential components during wakefulness and NREM sleep. J Appl Physiol 1998;85(5):1727-35. 60. Colrain IM. The K-complex: a 7-decade history. Sleep 2005;28(2):255-73.

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