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Autonomic functioning during REM sleep differentiates IBS symptom subgroups
THE AMERICAN JOURNAL OF GASTROENTEROLOGY © 2002 by Am. Coll. of Gastroenterology Published by Elsevier Science Inc.
Vol. 97, No. 12, 2002 ISSN 0002-9270/02/$22.00 PII S0002-9270(02)05529-6
Autonomic Functioning During REM Sleep Differentiates IBS Symptom Subgroups Jennifer J. Thompson, M.A., Sigrid Elsenbruch, Ph.D., Michael J. Harnish, Ph.D., and William C. Orr, Ph.D. Lynn Institute for Healthcare Research, Oklahoma City, Oklahoma; and Institute for Medical Psychology, University Clinic of Essen, Essen, Germany
OBJECTIVE: The aim of this study was to investigate autonomic activity by means of heart rate variability analysis in a sample of irritable bowel syndrome (IBS) patients, allowing stratification into IBS symptom subgroups. METHODS: Thirty-three female IBS patients (mean age 37 yr) and 21 healthy female controls (mean age 38 yr) participated. Patients were stratified into 16 subjects with only lower bowel symptoms (IBS only) and 17 subjects with both lower bowel and dyspeptic symptoms (IBS⫹D). The protocol included standard polysomnography to assess stages of sleep with concomitant electrocardiographic measurement of beat-to-beat intervals of the cardiac cycle. Fifteenmin segments were selected from presleep waking, stage 2 of non-rapid eye movement (REM), and REM sleep and analyzed by spectral analysis of heart rate variability to calculate the high-frequency band, a measure of vagal tone, and the low-frequency/high-frequency ratio, an indicator of sympathovagal balance. RESULTS: The high-frequency band power during REM sleep was significantly lower, indicating substantial vagal withdrawal in IBS-only patients compared with IBS⫹D patients and controls. The low-frequency/high-frequency band ratio was significantly higher during REM sleep for IBS-only patients. CONCLUSIONS: IBS-only patients had greater sympathetic dominance, indicated by elevated low-frequency/high-frequency band ratio, during REM sleep because of vagal withdrawal. Autonomic functioning, unique to REM sleep, differentiates IBS symptom subgroups, suggesting that autonomic functioning during REM sleep may be a useful biological marker to identify IBS patient subgroups. (Am J Gastroenterol 2002;97:3147–3152. © 2002 by Am. Coll. of Gastroenterology)
INTRODUCTION At least two etiological mechanisms, altered bowel motility and increased visceral sensitivity, have been proposed to account for the GI symptoms observed in patients with irritable bowel syndrome (IBS) (1). It has been suggested that the autonomic nervous system can modulate visceral sensitivity and that the central nervous system can influence
the motility and secretory activity of the GI tract by way of autonomic pathways via the enteric nervous system (2– 4). It was suggested that subtle abnormalities in the autonomic nervous system are an underlying factor in the symptoms reported by patients with functional GI disorders (5–7). Smart and Atkinson (8) examined autonomic functioning in IBS patients during awake conditions by measuring vagal functioning via pulse rate variability with deep respiration. They found that IBS patients had lower vagal tone than controls. Aggarwal et al. (9) differentiated constipationpredominant patients from diarrhea-predominant patients based on autonomic responses to stimuli (e.g., vasoconstrictor response to cold stress, postural adjustment ratio, skin temperature, and deep respiration). The diarrhea subgroup had increased sympathetic activity on the postural adjustment ratio compared with controls. The constipation subgroup of patients had diminished vagal tone as measured by variability in pulse rate during deep respiration compared with controls. Iovino et al. (2) activated the sympathetic nervous system by inducing negative lower body pressure in normal individuals and found that sympathetic nervous system activation decreases the threshold for discomfort secondary to duodenal distention. They also suggested that the sympathetic nervous system modulates visceral perception, but the exact mechanisms are not currently known. Measurements of the beat-to-beat variation in heart rate have been used to evaluate autonomic functioning because the combined effects of vagal and sympathetic input control heart rate variability (HRV) (10, 11). Heitkemper et al. (12) investigated HRV during a 24-h period in IBS patients and detected diminished vagal tone relative to controls. Orr et al. (13) used the stages of sleep as a model to detect autonomic differences by measuring HRV in IBS patients and found that IBS patients had elevated sympathovagal dominance compared with healthy controls during rapid eye movement (REM) sleep. It is not known whether these autonomic abnormalities are unique to IBS or are also present in other functional bowel disorders such as functional dyspepsia. Investigations of the presence of dyspeptic symptoms in IBS patients was based on work by David et al. (14) and Fass et al. (15), suggesting that IBS patients with dyspeptic symptoms have complaints of increased sleep disturbance (e.g., repeated awakenings, difficulty falling asleep). Thus,
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it may be clinically important to distinguish IBS patients based on symptom profiles (16). The current study focused on detecting differences in autonomic functioning during sleep in IBS patients with and without dyspeptic symptoms compared with controls. The IBS patients with dyspeptic symptoms (IBS⫹D) have both upper and lower GI pain, whereas the IBS patients without dyspeptic symptoms (IBS only) report only lower bowel pain. Thus, the IBS-only patients having only lower bowel pain are hypothesized to have different autonomic activity during REM sleep than the IBS⫹D patients. We hypothesized that patients who have concomitant dyspeptic symptoms in addition to IBS (IBS⫹D) represent individuals whose abdominal pain and GI symptoms may be more globalized and not attributable to abnormal autonomic activity. Thus, IBS-only patients would be expected to exhibit an increased sympathetic dominance (elevated low-frequency [LF]/high-frequency [HF] ratio) because of vagal withdrawal during REM sleep when compared with IBS⫹D patients and healthy controls. Polysomnography (PSG) was used to reveal sleep stages with concomitant electrocardiograph (ECG) measurement of beat-to-beat heartbeat intervals to assess autonomic nervous system functioning via spectral analysis of HRV.
MATERIALS AND METHODS Recruitment and Screening of Participants IBS patients were recruited from a GI research database at the Lynn Institute for Healthcare Research and referrals by local gastroenterologists. Controls were recruited from the surrounding community through public advertisement. All participants were initially screened for eligibility over the telephone followed by a personal interview for further assessment. The screening also included an appointment with the staff gastroenterologist to confirm the IBS diagnosis. The Institutional Review Board of Integris Baptist Medical Center of Oklahoma approved the study protocol. After participants provided informed consent, they completed a series of questionnaires. Information was obtained regarding their medical history with specific questions about any previous psychiatric, cardiovascular, neurological, and/or sleep disorders. Participants were also asked about their substance abuse and/or current medication use, and their sleep/wake cycle. The Beck Depression Inventory (BDI) was used for assessment of depressive symptoms, and persons with a BDI score above 17 were considered ineligible for participation. Exclusion criteria also included individuals who were night shift workers, currently taking antidepressant medication or other psychotropic medication, or diagnosed with a sleep disorder (17). The ROME I criteria for IBS were used to assess the presence and frequency of GI symptoms (18, 19). Patients with other functional bowel disorders, such as chronic constipation and chronic functional abdominal pain, were excluded from the study. Individuals were classified as IBS⫹D if they experienced both recurrent upper abdominal
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pain at least twice a week and had at least two of the following symptoms at least twice a week—nausea, vomiting, or excessive belching. Patients who had heartburn symptoms at least three times per week were ineligible to participate. It is therefore unlikely, albeit not impossible, that this group of patients had significant gastroesophageal reflux disease. Procedures and Experimental Protocol On the day of the study, participants refrained from medication for a minimum of 24 h before the PSG monitoring and from caffeine at least 6 h before reporting to the laboratory. They consumed their dinner before 6:00 PM and refrained from any food and drink (other than water) after 6:00 PM. Upon arrival in the laboratory, participants were prepared for PSG recordings, which included a channel of ECG that was used for the HRV analysis. The protocol included a 30-min presleep waking period followed by an overnight study in the sleep laboratory. During the 30-min presleep waking period, the participant remained in the supine position and watched television. Standard PSG recordings included four channels of electroencephalogram (central channels C3 and C4 and occipital channels 01 and 02), two channels of electrooculogram, and one channel of chin electromyogram. PSG recordings were blindly scored according to internationally accepted sleep staging criteria (20). Data Acquisition and Analysis GI SYMPTOM PROFILE. A GI symptom questionnaire was used to assess the presence of abdominal pain (upper and lower), severity and duration of pain, severity of abdominal distension, frequency of constipation and/or diarrhea, medication use, and interference of symptoms on personal or professional life. ACQUISITION AND ANALYSIS OF HRV. HRV data were derived from the ECG signal by measuring the beatto-beat intervals of the cardiac cycle (i.e., R-R intervals). Standard silver/silver chloride cutaneous electrodes were applied to the lower left side of the thorax on the midaxillary line and on the right and left shoulder over the clavicle. A single channel of ECG was recorded at a sampling rate of 6000 Hz and analyzed after being downsampled to 500 Hz. The R-R intervals were calculated, resampled, and interpolated by computer software, yielding the HRV signal for 15-min periods of presleep waking, non-REM stage 2, and REM sleep. Only one 15-min period for each state of consciousness (wake, non-REM stage 2, REM) was selected for each participant. The selected REM period for the spectral analysis had the least amount of artifacts and was at least 15 min in duration. The digitized ECG signal was analyzed using programs written with the digital signal processing toolbox of MATLAB (Math Works, Natick, MA). The segments were analyzed by spectral analysis characterizing the autoregulation of heart rate by calculating endogenous cycles of cardiac activity, such as the vagally
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Table 1. Participant Characteristics IBS Symptom Group
Age, yr Body mass index, kg/m2 Ethnicity, white, % BDI score Postmenopausal, % (n) Postmenopausal taking hormone replacement therapy, % (n) Premenopausal taking birth control medication, % (n) Follicular phase (n) Ovulation phase (n) Luteal phase (n)
IBS only (n ⫽ 16)
IBS ⫹ D (n ⫽ 16)
Controls (n ⫽ 21)
p
37 ⫾ 2 25 ⫾ 1 88 4.94 ⫾ 0.97 31 (5)
37 ⫾ 2 28 ⫾ 1 81 8.53 ⫾ 1.4 31 (5)
38 ⫾ 2 25 ⫾ 1 90 2.14 ⫾ 0.48 33 (7)
ns ns ns ⬍0.05 ns
20 (1)
40 (2)
57 (4)
*
27 (3) 0 5 3
36 (4) 4 4 2
36 (5) 7 5 2
*
Data are shown as mean ⫾ SEM or %. * Categories too small to calculate significance.
All results are shown as mean ⫾ SEM.
seen in Table 1, the IBS patients were similar with respect to age, body mass index, and ethnicity. The IBS⫹D group had significantly (p ⬍ 0.05) higher BDI scores when compared with IBS-only patients and controls. Although the IBS⫹D patients had higher BDI scores, they reported never having been diagnosed with a depressive disorder, not currently being prescribed antidepressants, and were not taking any herbal medications for depression (i.e., St. John’s Wort). The percent of women who were postmenopausal was similar across the groups. As shown in Table 1, more of the postmenopausal women in the control group were taking hormone replacement therapy than with IBS. Table 1 also shows what phase of the menstrual cycle the premenopausal women were in at the time of the PSG recording. The GI symptom profiles for each of the IBS symptom subgroups are shown in Table 2. Fifteen of the IBS patients were constipation predominant, 10 IBS patients were diarrhea predominant, and seven patients alternated between constipation and diarrhea symptoms. The percentage of IBS patients who had been diagnosed with IBS more than 5 yr ago was similar for IBS symptom subgroups. The IBS⫹D patients reported a significant (p ⫽ 0.02) increase in days with upper GI pain compared with IBS-only patients. The IBS⫹D patients also reported significantly (p ⫽ 0.01) increased symptom severity compared with IBS-only patients. The symptom severity was calculated by the sum of severity (days per week) divided by the number of GI symptoms (upper and lower) experienced by each individual.
Patient Characteristics and GI Symptom Profile Of the 54 participants (33 patients, 21 controls), one IBS patient was excluded from all of the analyses because of an out-of-range value for the LF/HF ratio (⬎3 SD from the group mean). Therefore, 32 IBS patients were stratified into 16 subjects without dyspeptic symptoms (IBS only) and 16 subjects with both lower bowel and dyspeptic symptoms (IBS⫹D). IBS patients and controls were compared for several demographic variables, and one IBS patient in the IBS⫹D group did not complete her GI symptom profile. As
Sleep Architecture There was no significant difference between the IBS subgroups with regard to sleep architecture, and neither group had any parameter that was significantly different from controls (Table 3). The morning after their PSG sleep, study participants rated their sleep satisfaction from the previous night. Of the 32 IBS patients, 10 rated their sleep as satisfactory, whereas 22 (69%) rated their sleep as unsatisfactory (12 IBS only, 10 IBS⫹D). Of the 21 controls, 16 rated their
mediated respiratory sinus arrythmia. These autonomic influences can be discerned by frequencies in the spectral analysis of HRV (11, 21, 22). The % power of the HF band of the HRV power spectrum can be used as a marker of vagal tone defined as the % power in the 0.15– 0.50-Hz range, and the LF band in the 0.04 – 0.15-Hz range reflects mainly sympathetic activity but can include vagal influence. Each segment was analyzed by spectral analysis to calculate the % power in the HF band, a measure of vagal tone, and the LF/HF ratio as an indicator of sympathovagal balance. Statistical Analyses Independent t tests were conducted to detect differences for the GI symptom profile questionnaire items. Multivariate analysis of variance (MANOVA) was used to assess group differences for sleep architecture and autonomic activity during each state of consciousness (wake, non-REM stage 2, and REM sleep). A MANOVA was conducted for each state of consciousness. The MANOVA-dependent variables of autonomic activity were % LF band power, % HF band power, and the LF/HF ratio. Specific multiple comparisons were conducted using the Fisher’s least significant difference method for (between)-group differences. The ␣ level was set at 0.05 for all statistical analyses.
RESULTS
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Table 2. GI Symptom Profile for the IBS Symptom Groups IBS Symptom Group
IBS diagnosed ⬎ 5 yr ago, % Days with lower pain/wk Days with upper pain/wk GI symptom severity score Experience severe abdominal distension, % Typically experience severe pain, % Significant interference with life, % Constipation predominant (n) Diarrhea predominant, (n) Alternating constipation/diarrhea (n)
IBS only (n ⫽ 16)
IBS ⫹ D (n ⫽ 15)
38 2.31 ⫾ 0.18 1.50 ⫾ 0.24 1.25 ⫾ 0.11 63 50 44 8 5 3
41 2.71 ⫾ 0.13 2.33 ⫾ 0.23 1.78 ⫾ 0.08 65 64 47 7 5 4
p ns ns 0.02 0.01 ns ns ns
Data are shown as mean ⫾ SEM or %.
sleep as satisfactory and five (24%) rated their sleep as unsatisfactory. Autonomic Measures There were no significant differences for the % HF band (p ⫽ 0.34) or LF/HF ratio (p ⫽ 0.38) during the 30-min presleep waking period between IBS⫹D patients, IBS-only patients, or controls. Nor were there any significant differences on these measures between groups for non-REM (stage 2) sleep. There were not enough participants who had at least 15 min of slow wave sleep to include in the HRV analysis, most likely because of the novelty of the sleep laboratory setting. The overall MANOVA for REM sleep detected significant group differences (F[2, 98] ⫽ 3.59, p ⬍ 0.01). Multiple comparisons revealed that the % HF power band activity (vagal tone) was reduced in the IBS-only group relative to the IBS⫹D patients (p ⬍ 0.01) and controls (p ⬍ 0.01), as shown in Figure 1. The IBS-only patient group had a significantly (p ⬍ 0.05) higher LF/HF ratio than the IBS⫹D patient group and controls, as shown in Figure 2. The distribution of subjects for the LF/HF ratio values is shown in Figure 3.
DISCUSSION Many IBS patients report a constellation of upper GI symptoms, such as nausea, vomiting, excessive belching, etc,
indicative of functional dyspepsia in addition to their lower GI symptoms. Therefore, the current study was designed to detect autonomic differences in IBS symptom subgroups. Heitkemper et al. (12) and Orr et al. (13) demonstrated that IBS patients have different autonomic activity when compared with healthy controls. The current study extends these findings by revealing a similar pattern of autonomic abnormalities, but specifically confined to the IBS-only group. The IBS-only patients had increased sympathetic dominance, elevated LF/HF ratio, attributable to vagal withdrawal (HF) during REM sleep compared with IBS⫹D patients and controls. The IBS-only patients having autonomic abnormalities during REM sleep clearly distinguishes them from healthy controls and IBS patients with other functional GI complaints. David et al. (14) investigated the relationship between sleep disturbances in patients with functional dyspepsia (FD) and duodenal motor activity. They conducted a twoprotocol experiment comprised of a questionnaire study and a manometric study investigating duodenal motor activity and sleep in FD patients. As described earlier, sleep complaints were increased in the FD patients relative to controls. The manometric study compared FD patients with and without concomitant lower abdominal symptoms indicative of IBS and healthy controls. The FD patients without concomitant IBS symptoms had a decreased number of migrating
Table 3. Polysomnographic Parameters IBS Symptom Group
Total sleep time (TST) (min) Time in bed (TIB) (min) Sleep onset latency (min) Sleep efficiency (TST/TIB) Number of awakenings after sleep onset Stage 2, % Stage 3 and 4 (slow wave sleep), % REM sleep, % REM episodes Mean number of min spent in REM sleep Data are shown as mean ⫾ SEM or %.
IBS only (n ⫽ 16)
IBS ⫹ D (n ⫽ 16)
Controls (n ⫽ 21)
p
391 ⫾ 11 444 ⫾ 9 29 ⫾ 5 88 ⫾ 2 8⫾1 56 ⫾ 2 16 ⫾ 2 23 ⫾ 1 4 ⫾ 0.48 24 ⫾ 2
379 ⫾ 12 446 ⫾ 14 32 ⫾ 10 85 ⫾ 2 8⫾2 56 ⫾ 1 19 ⫾ 2 20 ⫾ 1 4 ⫾ 0.23 22 ⫾ 2
379 ⫾ 9 440 ⫾ 6 23 ⫾ 4 86 ⫾ 2 9⫾1 57 ⫾ 2 16 ⫾ 1 22 ⫾ 1 4 ⫾ 0.19 24 ⫾ 1
ns ns ns ns ns ns ns ns ns ns
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Figure 1. Changes in HF band power in IBS symptom subgroups and controls. *The IBS-only patients had significant (p ⬍ 0.05) vagal withdrawal (lower HF band power) during REM sleep relative to IBS⫹D patients and healthy controls. No significant differences were found during the 30-min presleep waking period and non-REM stage 2 sleep.
motor complex complexes during sleep, and the FD patients with IBS symptoms did not differ from the controls. Consistent with David et al.’s (14) findings, our study did not detect any autonomic differences between IBS⫹D patients and healthy controls. Our results indicate that although IBS⫹D patients had increased somatic (sleep and GI) complaints, their symptomatology does not seem to be associated with autonomic dysfunction. Although the IBS⫹D patients had increased symptom severity, this was expected as they have both upper and lower GI symptoms. The increased symptom severity in the IBS⫹D group was related to their having both upper and lower pain and symptoms rather than a reflection of the severity of their IBS symptoms per se. It is also our contention that the increase in symptom severity in the IBS⫹D group was more related to their increased psychological disturbances, such as anxiety, rather than any alteration in autonomic activity or visceral sensitivity (16).
Figure 2. Changes in the LF/HF ratio in IBS symptom subgroups and controls. *The IBS-only patients had significantly (p ⬍ 0.05) enhanced sympathetic dominance (higher LF/HF ratio) during REM sleep relative to IBS⫹D patients and healthy controls. No significant differences were found during the 30-min presleep waking period and non-REM sleep.
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Figure 3. Frequency distribution of LF/HF ratio during REM sleep in IBS symptom subgroups and controls. *More of the IBS-only patients had higher LF/HF ratios during REM sleep than the IBS⫹D patients and healthy controls.
It was suggested that IBS patients with FD have distinct motility patterns compared with IBS patients without dyspeptic symptoms (14). Thus, the presence of FD could be the possible contributor to sleep dysfunction because IBS patients with dyspeptic symptoms reported significant sleep disturbances (waking up repeatedly during the night and waking up feeling tired) when compared with patients with only lower GI symptomatology (IBS) and healthy controls (15, 16). Because our results suggest that IBS patients with dyspeptic symptoms are more similar to healthy controls in autonomic functioning during sleep than to patients with IBS only, the symptomatology of IBS patients with dyspeptic symptoms seems to be related to factors other than autonomic abnormalities. Both increased peripheral sympathetic activity and diminished vagal tone have been detected in individuals diagnosed with major depression (23–25). Stein et al. (24) investigated the relationship between depression and HRV in a large sample of cardiac patients. They detected higher heart rates, and all indices of HRV were reduced in depressed cardiac patients compared with the nondepressed cardiac patients. A recent study compared depressed patients with acute myocardial infarction patients free of depression during 24-h ambulatory HRV analysis (25). The authors also found that the depressed patients had lower vagal tone during the 24-h period than the myocardial infarction patients without depression. A correlation analysis of HRV detected a significant negative correlation coefficient with HF band power (vagal tone) and BDI scores (24). The IBS⫹D symptom subgroup did have a higher BDI mean score, indicating more depressive symptoms than the IBS-only patients and controls. Hence, we conducted a correlation analysis to determine if there was a relationship between BDI scores and indices of HRV and did not detect any significant correlations. It has been demonstrated in our laboratory that subgroups of IBS patients have differences in autonomic activity in
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response to food intake. IBS diarrhea-predominant patients have been shown to have autonomic and cortisol hyperresponsiveness to a standard meal (26). The IBS diarrheapredominant patients had enhanced sympathetic dominance (LF/HF ratio) after food ingestion compared with the constipation-predominant IBS patients and controls. Although our study had enough patients to determine autonomic differences in IBS symptom subgroups, there were not enough patients who were classified as diarrhea or constipation predominant to be able to compare their autonomic activity. We are in the process of collecting more data to be able to determine if there are any autonomic differences resulting from predominant bowel pattern in IBS patients. Elsenbruch et al. (16) proposed that there is an abnormal ascending (gut) feedback to the brain leading to this increased endocrine and autonomic activity during food intake in the diarrhea-predominant IBS patients. The current results of autonomic abnormalities in the IBS-only patients during REM sleep further support a disturbance in the interaction between the gut, the brain, and the autonomic nervous system, possibly altering the regulation of bowel motility (motor function) and/or sensory function. Iovino et al. (2) demonstrated that sympathetic activation induced by lower body negative pressure sensitizes responses to visceral stimulation. Orr et al. (13) previously posed the question of whether vagal withdrawal would produce similar changes in visceral sensitivity, or if visceral sensitivity was the result of sympathetic activation, such as demonstrated by Iovino et al. (2). The IBS-only patients had sympathetic activation caused by vagal withdrawal during REM sleep, a state uniquely associated with cortical activation. Our previous study demonstrated enhanced sympathetic dominance, as indicated by elevated LF/HF ratio, in IBS patients compared with controls during REM sleep (13). The current study supports the conclusions from our previous research that enhanced sympathetic dominance during REM sleep in the IBS-only patients is attributable to vagal withdrawal. The vagal withdrawal detected in IBSonly patients during REM sleep may be related to visceral hypersensitivity in this subset of IBS patients. Investigations of autonomic physiology during sleep may further unmask abnormalities in autonomic functioning that are not apparent during waking. These findings are specific to female IBS patients, although most likely generalizable to a population of male IBS patients. In conclusion, autonomic abnormalities detected during REM sleep are not a characteristic of all patients with functional bowel disorders, but rather a distinguishing characteristic of patients with only lower GI symptomatology.
ACKNOWLEDGMENTS We thank Dr. Deborah Blalock for help in confirming the patients’ diagnosis, and the sleep technicians of the Lynn Institute for Healthcare Research for their expertise in ensuring quality sleep recordings.
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Reprint requests and correspondence: Jennifer J. Thompson, M.A., Lynn Institute for Healthcare Research, 5300 N. Independence, Suite 130, Oklahoma City, OK 73112. Received Oct. 25, 2001; accepted Apr. 11, 2002.
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21. Pomeranz B, MaCaulay RJ, Caudill MA, et al. Assessment of autonomic function in humans by heart rate spectral analysis. Am J Physiol 1985;248:151–3. 22. Lahmeyer H, Bellur S. Cardiac regulation and depression. J Psych Res 1987;21:1– 6. 23. Carney RM, Rich M, TeVelde A, et al. The relationship between heart rate, heart rate variability and depression in patients with coronary artery disease. J Psychosom Res 1988;32:159 – 64. 24. Stein P, Carney R, Freedland K, et al. Severe depression is
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Autonomic Functioning During REM Sleep Differentiates IBS Symptom Subgroups Jennifer J. Thompson, M.A., Sigrid Elsenbruch, Ph.D., Michael J. Harnish, Ph.D., and William C. Orr, Ph.D. Lynn Institute for Healthcare Research, Oklahoma City, Oklahoma; and Institute for Medical Psychology, University Clinic of Essen, Essen, Germany
OBJECTIVE: The aim of this study was to investigate autonomic activity by means of heart rate variability analysis in a sample of irritable bowel syndrome (IBS) patients, allowing stratification into IBS symptom subgroups. METHODS: Thirty-three female IBS patients (mean age 37 yr) and 21 healthy female controls (mean age 38 yr) participated. Patients were stratified into 16 subjects with only lower bowel symptoms (IBS only) and 17 subjects with both lower bowel and dyspeptic symptoms (IBS⫹D). The protocol included standard polysomnography to assess stages of sleep with concomitant electrocardiographic measurement of beat-to-beat intervals of the cardiac cycle. Fifteenmin segments were selected from presleep waking, stage 2 of non-rapid eye movement (REM), and REM sleep and analyzed by spectral analysis of heart rate variability to calculate the high-frequency band, a measure of vagal tone, and the low-frequency/high-frequency ratio, an indicator of sympathovagal balance. RESULTS: The high-frequency band power during REM sleep was significantly lower, indicating substantial vagal withdrawal in IBS-only patients compared with IBS⫹D patients and controls. The low-frequency/high-frequency band ratio was significantly higher during REM sleep for IBS-only patients. CONCLUSIONS: IBS-only patients had greater sympathetic dominance, indicated by elevated low-frequency/high-frequency band ratio, during REM sleep because of vagal withdrawal. Autonomic functioning, unique to REM sleep, differentiates IBS symptom subgroups, suggesting that autonomic functioning during REM sleep may be a useful biological marker to identify IBS patient subgroups. (Am J Gastroenterol 2002;97:3147–3152. © 2002 by Am. Coll. of Gastroenterology)
INTRODUCTION At least two etiological mechanisms, altered bowel motility and increased visceral sensitivity, have been proposed to account for the GI symptoms observed in patients with irritable bowel syndrome (IBS) (1). It has been suggested that the autonomic nervous system can modulate visceral sensitivity and that the central nervous system can influence
the motility and secretory activity of the GI tract by way of autonomic pathways via the enteric nervous system (2– 4). It was suggested that subtle abnormalities in the autonomic nervous system are an underlying factor in the symptoms reported by patients with functional GI disorders (5–7). Smart and Atkinson (8) examined autonomic functioning in IBS patients during awake conditions by measuring vagal functioning via pulse rate variability with deep respiration. They found that IBS patients had lower vagal tone than controls. Aggarwal et al. (9) differentiated constipationpredominant patients from diarrhea-predominant patients based on autonomic responses to stimuli (e.g., vasoconstrictor response to cold stress, postural adjustment ratio, skin temperature, and deep respiration). The diarrhea subgroup had increased sympathetic activity on the postural adjustment ratio compared with controls. The constipation subgroup of patients had diminished vagal tone as measured by variability in pulse rate during deep respiration compared with controls. Iovino et al. (2) activated the sympathetic nervous system by inducing negative lower body pressure in normal individuals and found that sympathetic nervous system activation decreases the threshold for discomfort secondary to duodenal distention. They also suggested that the sympathetic nervous system modulates visceral perception, but the exact mechanisms are not currently known. Measurements of the beat-to-beat variation in heart rate have been used to evaluate autonomic functioning because the combined effects of vagal and sympathetic input control heart rate variability (HRV) (10, 11). Heitkemper et al. (12) investigated HRV during a 24-h period in IBS patients and detected diminished vagal tone relative to controls. Orr et al. (13) used the stages of sleep as a model to detect autonomic differences by measuring HRV in IBS patients and found that IBS patients had elevated sympathovagal dominance compared with healthy controls during rapid eye movement (REM) sleep. It is not known whether these autonomic abnormalities are unique to IBS or are also present in other functional bowel disorders such as functional dyspepsia. Investigations of the presence of dyspeptic symptoms in IBS patients was based on work by David et al. (14) and Fass et al. (15), suggesting that IBS patients with dyspeptic symptoms have complaints of increased sleep disturbance (e.g., repeated awakenings, difficulty falling asleep). Thus,
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it may be clinically important to distinguish IBS patients based on symptom profiles (16). The current study focused on detecting differences in autonomic functioning during sleep in IBS patients with and without dyspeptic symptoms compared with controls. The IBS patients with dyspeptic symptoms (IBS⫹D) have both upper and lower GI pain, whereas the IBS patients without dyspeptic symptoms (IBS only) report only lower bowel pain. Thus, the IBS-only patients having only lower bowel pain are hypothesized to have different autonomic activity during REM sleep than the IBS⫹D patients. We hypothesized that patients who have concomitant dyspeptic symptoms in addition to IBS (IBS⫹D) represent individuals whose abdominal pain and GI symptoms may be more globalized and not attributable to abnormal autonomic activity. Thus, IBS-only patients would be expected to exhibit an increased sympathetic dominance (elevated low-frequency [LF]/high-frequency [HF] ratio) because of vagal withdrawal during REM sleep when compared with IBS⫹D patients and healthy controls. Polysomnography (PSG) was used to reveal sleep stages with concomitant electrocardiograph (ECG) measurement of beat-to-beat heartbeat intervals to assess autonomic nervous system functioning via spectral analysis of HRV.
MATERIALS AND METHODS Recruitment and Screening of Participants IBS patients were recruited from a GI research database at the Lynn Institute for Healthcare Research and referrals by local gastroenterologists. Controls were recruited from the surrounding community through public advertisement. All participants were initially screened for eligibility over the telephone followed by a personal interview for further assessment. The screening also included an appointment with the staff gastroenterologist to confirm the IBS diagnosis. The Institutional Review Board of Integris Baptist Medical Center of Oklahoma approved the study protocol. After participants provided informed consent, they completed a series of questionnaires. Information was obtained regarding their medical history with specific questions about any previous psychiatric, cardiovascular, neurological, and/or sleep disorders. Participants were also asked about their substance abuse and/or current medication use, and their sleep/wake cycle. The Beck Depression Inventory (BDI) was used for assessment of depressive symptoms, and persons with a BDI score above 17 were considered ineligible for participation. Exclusion criteria also included individuals who were night shift workers, currently taking antidepressant medication or other psychotropic medication, or diagnosed with a sleep disorder (17). The ROME I criteria for IBS were used to assess the presence and frequency of GI symptoms (18, 19). Patients with other functional bowel disorders, such as chronic constipation and chronic functional abdominal pain, were excluded from the study. Individuals were classified as IBS⫹D if they experienced both recurrent upper abdominal
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pain at least twice a week and had at least two of the following symptoms at least twice a week—nausea, vomiting, or excessive belching. Patients who had heartburn symptoms at least three times per week were ineligible to participate. It is therefore unlikely, albeit not impossible, that this group of patients had significant gastroesophageal reflux disease. Procedures and Experimental Protocol On the day of the study, participants refrained from medication for a minimum of 24 h before the PSG monitoring and from caffeine at least 6 h before reporting to the laboratory. They consumed their dinner before 6:00 PM and refrained from any food and drink (other than water) after 6:00 PM. Upon arrival in the laboratory, participants were prepared for PSG recordings, which included a channel of ECG that was used for the HRV analysis. The protocol included a 30-min presleep waking period followed by an overnight study in the sleep laboratory. During the 30-min presleep waking period, the participant remained in the supine position and watched television. Standard PSG recordings included four channels of electroencephalogram (central channels C3 and C4 and occipital channels 01 and 02), two channels of electrooculogram, and one channel of chin electromyogram. PSG recordings were blindly scored according to internationally accepted sleep staging criteria (20). Data Acquisition and Analysis GI SYMPTOM PROFILE. A GI symptom questionnaire was used to assess the presence of abdominal pain (upper and lower), severity and duration of pain, severity of abdominal distension, frequency of constipation and/or diarrhea, medication use, and interference of symptoms on personal or professional life. ACQUISITION AND ANALYSIS OF HRV. HRV data were derived from the ECG signal by measuring the beatto-beat intervals of the cardiac cycle (i.e., R-R intervals). Standard silver/silver chloride cutaneous electrodes were applied to the lower left side of the thorax on the midaxillary line and on the right and left shoulder over the clavicle. A single channel of ECG was recorded at a sampling rate of 6000 Hz and analyzed after being downsampled to 500 Hz. The R-R intervals were calculated, resampled, and interpolated by computer software, yielding the HRV signal for 15-min periods of presleep waking, non-REM stage 2, and REM sleep. Only one 15-min period for each state of consciousness (wake, non-REM stage 2, REM) was selected for each participant. The selected REM period for the spectral analysis had the least amount of artifacts and was at least 15 min in duration. The digitized ECG signal was analyzed using programs written with the digital signal processing toolbox of MATLAB (Math Works, Natick, MA). The segments were analyzed by spectral analysis characterizing the autoregulation of heart rate by calculating endogenous cycles of cardiac activity, such as the vagally
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Table 1. Participant Characteristics IBS Symptom Group
Age, yr Body mass index, kg/m2 Ethnicity, white, % BDI score Postmenopausal, % (n) Postmenopausal taking hormone replacement therapy, % (n) Premenopausal taking birth control medication, % (n) Follicular phase (n) Ovulation phase (n) Luteal phase (n)
IBS only (n ⫽ 16)
IBS ⫹ D (n ⫽ 16)
Controls (n ⫽ 21)
p
37 ⫾ 2 25 ⫾ 1 88 4.94 ⫾ 0.97 31 (5)
37 ⫾ 2 28 ⫾ 1 81 8.53 ⫾ 1.4 31 (5)
38 ⫾ 2 25 ⫾ 1 90 2.14 ⫾ 0.48 33 (7)
ns ns ns ⬍0.05 ns
20 (1)
40 (2)
57 (4)
*
27 (3) 0 5 3
36 (4) 4 4 2
36 (5) 7 5 2
*
Data are shown as mean ⫾ SEM or %. * Categories too small to calculate significance.
All results are shown as mean ⫾ SEM.
seen in Table 1, the IBS patients were similar with respect to age, body mass index, and ethnicity. The IBS⫹D group had significantly (p ⬍ 0.05) higher BDI scores when compared with IBS-only patients and controls. Although the IBS⫹D patients had higher BDI scores, they reported never having been diagnosed with a depressive disorder, not currently being prescribed antidepressants, and were not taking any herbal medications for depression (i.e., St. John’s Wort). The percent of women who were postmenopausal was similar across the groups. As shown in Table 1, more of the postmenopausal women in the control group were taking hormone replacement therapy than with IBS. Table 1 also shows what phase of the menstrual cycle the premenopausal women were in at the time of the PSG recording. The GI symptom profiles for each of the IBS symptom subgroups are shown in Table 2. Fifteen of the IBS patients were constipation predominant, 10 IBS patients were diarrhea predominant, and seven patients alternated between constipation and diarrhea symptoms. The percentage of IBS patients who had been diagnosed with IBS more than 5 yr ago was similar for IBS symptom subgroups. The IBS⫹D patients reported a significant (p ⫽ 0.02) increase in days with upper GI pain compared with IBS-only patients. The IBS⫹D patients also reported significantly (p ⫽ 0.01) increased symptom severity compared with IBS-only patients. The symptom severity was calculated by the sum of severity (days per week) divided by the number of GI symptoms (upper and lower) experienced by each individual.
Patient Characteristics and GI Symptom Profile Of the 54 participants (33 patients, 21 controls), one IBS patient was excluded from all of the analyses because of an out-of-range value for the LF/HF ratio (⬎3 SD from the group mean). Therefore, 32 IBS patients were stratified into 16 subjects without dyspeptic symptoms (IBS only) and 16 subjects with both lower bowel and dyspeptic symptoms (IBS⫹D). IBS patients and controls were compared for several demographic variables, and one IBS patient in the IBS⫹D group did not complete her GI symptom profile. As
Sleep Architecture There was no significant difference between the IBS subgroups with regard to sleep architecture, and neither group had any parameter that was significantly different from controls (Table 3). The morning after their PSG sleep, study participants rated their sleep satisfaction from the previous night. Of the 32 IBS patients, 10 rated their sleep as satisfactory, whereas 22 (69%) rated their sleep as unsatisfactory (12 IBS only, 10 IBS⫹D). Of the 21 controls, 16 rated their
mediated respiratory sinus arrythmia. These autonomic influences can be discerned by frequencies in the spectral analysis of HRV (11, 21, 22). The % power of the HF band of the HRV power spectrum can be used as a marker of vagal tone defined as the % power in the 0.15– 0.50-Hz range, and the LF band in the 0.04 – 0.15-Hz range reflects mainly sympathetic activity but can include vagal influence. Each segment was analyzed by spectral analysis to calculate the % power in the HF band, a measure of vagal tone, and the LF/HF ratio as an indicator of sympathovagal balance. Statistical Analyses Independent t tests were conducted to detect differences for the GI symptom profile questionnaire items. Multivariate analysis of variance (MANOVA) was used to assess group differences for sleep architecture and autonomic activity during each state of consciousness (wake, non-REM stage 2, and REM sleep). A MANOVA was conducted for each state of consciousness. The MANOVA-dependent variables of autonomic activity were % LF band power, % HF band power, and the LF/HF ratio. Specific multiple comparisons were conducted using the Fisher’s least significant difference method for (between)-group differences. The ␣ level was set at 0.05 for all statistical analyses.
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Table 2. GI Symptom Profile for the IBS Symptom Groups IBS Symptom Group
IBS diagnosed ⬎ 5 yr ago, % Days with lower pain/wk Days with upper pain/wk GI symptom severity score Experience severe abdominal distension, % Typically experience severe pain, % Significant interference with life, % Constipation predominant (n) Diarrhea predominant, (n) Alternating constipation/diarrhea (n)
IBS only (n ⫽ 16)
IBS ⫹ D (n ⫽ 15)
38 2.31 ⫾ 0.18 1.50 ⫾ 0.24 1.25 ⫾ 0.11 63 50 44 8 5 3
41 2.71 ⫾ 0.13 2.33 ⫾ 0.23 1.78 ⫾ 0.08 65 64 47 7 5 4
p ns ns 0.02 0.01 ns ns ns
Data are shown as mean ⫾ SEM or %.
sleep as satisfactory and five (24%) rated their sleep as unsatisfactory. Autonomic Measures There were no significant differences for the % HF band (p ⫽ 0.34) or LF/HF ratio (p ⫽ 0.38) during the 30-min presleep waking period between IBS⫹D patients, IBS-only patients, or controls. Nor were there any significant differences on these measures between groups for non-REM (stage 2) sleep. There were not enough participants who had at least 15 min of slow wave sleep to include in the HRV analysis, most likely because of the novelty of the sleep laboratory setting. The overall MANOVA for REM sleep detected significant group differences (F[2, 98] ⫽ 3.59, p ⬍ 0.01). Multiple comparisons revealed that the % HF power band activity (vagal tone) was reduced in the IBS-only group relative to the IBS⫹D patients (p ⬍ 0.01) and controls (p ⬍ 0.01), as shown in Figure 1. The IBS-only patient group had a significantly (p ⬍ 0.05) higher LF/HF ratio than the IBS⫹D patient group and controls, as shown in Figure 2. The distribution of subjects for the LF/HF ratio values is shown in Figure 3.
DISCUSSION Many IBS patients report a constellation of upper GI symptoms, such as nausea, vomiting, excessive belching, etc,
indicative of functional dyspepsia in addition to their lower GI symptoms. Therefore, the current study was designed to detect autonomic differences in IBS symptom subgroups. Heitkemper et al. (12) and Orr et al. (13) demonstrated that IBS patients have different autonomic activity when compared with healthy controls. The current study extends these findings by revealing a similar pattern of autonomic abnormalities, but specifically confined to the IBS-only group. The IBS-only patients had increased sympathetic dominance, elevated LF/HF ratio, attributable to vagal withdrawal (HF) during REM sleep compared with IBS⫹D patients and controls. The IBS-only patients having autonomic abnormalities during REM sleep clearly distinguishes them from healthy controls and IBS patients with other functional GI complaints. David et al. (14) investigated the relationship between sleep disturbances in patients with functional dyspepsia (FD) and duodenal motor activity. They conducted a twoprotocol experiment comprised of a questionnaire study and a manometric study investigating duodenal motor activity and sleep in FD patients. As described earlier, sleep complaints were increased in the FD patients relative to controls. The manometric study compared FD patients with and without concomitant lower abdominal symptoms indicative of IBS and healthy controls. The FD patients without concomitant IBS symptoms had a decreased number of migrating
Table 3. Polysomnographic Parameters IBS Symptom Group
Total sleep time (TST) (min) Time in bed (TIB) (min) Sleep onset latency (min) Sleep efficiency (TST/TIB) Number of awakenings after sleep onset Stage 2, % Stage 3 and 4 (slow wave sleep), % REM sleep, % REM episodes Mean number of min spent in REM sleep Data are shown as mean ⫾ SEM or %.
IBS only (n ⫽ 16)
IBS ⫹ D (n ⫽ 16)
Controls (n ⫽ 21)
p
391 ⫾ 11 444 ⫾ 9 29 ⫾ 5 88 ⫾ 2 8⫾1 56 ⫾ 2 16 ⫾ 2 23 ⫾ 1 4 ⫾ 0.48 24 ⫾ 2
379 ⫾ 12 446 ⫾ 14 32 ⫾ 10 85 ⫾ 2 8⫾2 56 ⫾ 1 19 ⫾ 2 20 ⫾ 1 4 ⫾ 0.23 22 ⫾ 2
379 ⫾ 9 440 ⫾ 6 23 ⫾ 4 86 ⫾ 2 9⫾1 57 ⫾ 2 16 ⫾ 1 22 ⫾ 1 4 ⫾ 0.19 24 ⫾ 1
ns ns ns ns ns ns ns ns ns ns
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Figure 1. Changes in HF band power in IBS symptom subgroups and controls. *The IBS-only patients had significant (p ⬍ 0.05) vagal withdrawal (lower HF band power) during REM sleep relative to IBS⫹D patients and healthy controls. No significant differences were found during the 30-min presleep waking period and non-REM stage 2 sleep.
motor complex complexes during sleep, and the FD patients with IBS symptoms did not differ from the controls. Consistent with David et al.’s (14) findings, our study did not detect any autonomic differences between IBS⫹D patients and healthy controls. Our results indicate that although IBS⫹D patients had increased somatic (sleep and GI) complaints, their symptomatology does not seem to be associated with autonomic dysfunction. Although the IBS⫹D patients had increased symptom severity, this was expected as they have both upper and lower GI symptoms. The increased symptom severity in the IBS⫹D group was related to their having both upper and lower pain and symptoms rather than a reflection of the severity of their IBS symptoms per se. It is also our contention that the increase in symptom severity in the IBS⫹D group was more related to their increased psychological disturbances, such as anxiety, rather than any alteration in autonomic activity or visceral sensitivity (16).
Figure 2. Changes in the LF/HF ratio in IBS symptom subgroups and controls. *The IBS-only patients had significantly (p ⬍ 0.05) enhanced sympathetic dominance (higher LF/HF ratio) during REM sleep relative to IBS⫹D patients and healthy controls. No significant differences were found during the 30-min presleep waking period and non-REM sleep.
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Figure 3. Frequency distribution of LF/HF ratio during REM sleep in IBS symptom subgroups and controls. *More of the IBS-only patients had higher LF/HF ratios during REM sleep than the IBS⫹D patients and healthy controls.
It was suggested that IBS patients with FD have distinct motility patterns compared with IBS patients without dyspeptic symptoms (14). Thus, the presence of FD could be the possible contributor to sleep dysfunction because IBS patients with dyspeptic symptoms reported significant sleep disturbances (waking up repeatedly during the night and waking up feeling tired) when compared with patients with only lower GI symptomatology (IBS) and healthy controls (15, 16). Because our results suggest that IBS patients with dyspeptic symptoms are more similar to healthy controls in autonomic functioning during sleep than to patients with IBS only, the symptomatology of IBS patients with dyspeptic symptoms seems to be related to factors other than autonomic abnormalities. Both increased peripheral sympathetic activity and diminished vagal tone have been detected in individuals diagnosed with major depression (23–25). Stein et al. (24) investigated the relationship between depression and HRV in a large sample of cardiac patients. They detected higher heart rates, and all indices of HRV were reduced in depressed cardiac patients compared with the nondepressed cardiac patients. A recent study compared depressed patients with acute myocardial infarction patients free of depression during 24-h ambulatory HRV analysis (25). The authors also found that the depressed patients had lower vagal tone during the 24-h period than the myocardial infarction patients without depression. A correlation analysis of HRV detected a significant negative correlation coefficient with HF band power (vagal tone) and BDI scores (24). The IBS⫹D symptom subgroup did have a higher BDI mean score, indicating more depressive symptoms than the IBS-only patients and controls. Hence, we conducted a correlation analysis to determine if there was a relationship between BDI scores and indices of HRV and did not detect any significant correlations. It has been demonstrated in our laboratory that subgroups of IBS patients have differences in autonomic activity in
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response to food intake. IBS diarrhea-predominant patients have been shown to have autonomic and cortisol hyperresponsiveness to a standard meal (26). The IBS diarrheapredominant patients had enhanced sympathetic dominance (LF/HF ratio) after food ingestion compared with the constipation-predominant IBS patients and controls. Although our study had enough patients to determine autonomic differences in IBS symptom subgroups, there were not enough patients who were classified as diarrhea or constipation predominant to be able to compare their autonomic activity. We are in the process of collecting more data to be able to determine if there are any autonomic differences resulting from predominant bowel pattern in IBS patients. Elsenbruch et al. (16) proposed that there is an abnormal ascending (gut) feedback to the brain leading to this increased endocrine and autonomic activity during food intake in the diarrhea-predominant IBS patients. The current results of autonomic abnormalities in the IBS-only patients during REM sleep further support a disturbance in the interaction between the gut, the brain, and the autonomic nervous system, possibly altering the regulation of bowel motility (motor function) and/or sensory function. Iovino et al. (2) demonstrated that sympathetic activation induced by lower body negative pressure sensitizes responses to visceral stimulation. Orr et al. (13) previously posed the question of whether vagal withdrawal would produce similar changes in visceral sensitivity, or if visceral sensitivity was the result of sympathetic activation, such as demonstrated by Iovino et al. (2). The IBS-only patients had sympathetic activation caused by vagal withdrawal during REM sleep, a state uniquely associated with cortical activation. Our previous study demonstrated enhanced sympathetic dominance, as indicated by elevated LF/HF ratio, in IBS patients compared with controls during REM sleep (13). The current study supports the conclusions from our previous research that enhanced sympathetic dominance during REM sleep in the IBS-only patients is attributable to vagal withdrawal. The vagal withdrawal detected in IBSonly patients during REM sleep may be related to visceral hypersensitivity in this subset of IBS patients. Investigations of autonomic physiology during sleep may further unmask abnormalities in autonomic functioning that are not apparent during waking. These findings are specific to female IBS patients, although most likely generalizable to a population of male IBS patients. In conclusion, autonomic abnormalities detected during REM sleep are not a characteristic of all patients with functional bowel disorders, but rather a distinguishing characteristic of patients with only lower GI symptomatology.
ACKNOWLEDGMENTS We thank Dr. Deborah Blalock for help in confirming the patients’ diagnosis, and the sleep technicians of the Lynn Institute for Healthcare Research for their expertise in ensuring quality sleep recordings.
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Reprint requests and correspondence: Jennifer J. Thompson, M.A., Lynn Institute for Healthcare Research, 5300 N. Independence, Suite 130, Oklahoma City, OK 73112. Received Oct. 25, 2001; accepted Apr. 11, 2002.
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