Influence of tegaserod on proximal gastric tone and on the perception of gastric distention in functional dyspepsia.

BACKGROUND: Abnormalities in gastric sensorimotor function (hypersensitivity to distention and impaired meal accommodation) have been implicated in the pathophysiology of functional dyspepsia (FD). To study the effect of the 5-HT(4) agonist tegaserod on sensitivity to gastric distention and gastric accommodation in FD. METHODS: Thirty FD patients (7 males, mean age 42 ± 2 years) underwent a gastric barostat study on two separate occasions, 2 weeks apart, after 5 days of pretreatment with placebo or tegaserod 6 mg b.i.d. in a double-blind randomized order. After introduction of the barostat bag, graded isobaric distentions (2 mmHg increments/2 min) were performed to determine gastric compliance and sensitivity to distention. Subsequently, the pressure level was set at intra-abdominal pressure [minimal distending pressure (MDP)] + 2 mmHg for 90 min, with administration of a liquid meal (200 mL; 300 kcal) after 30 min. KEY RESULTS: Tegaserod had no influence on MDP (7.9 ± 0.4 vs 7.4 ± 0.4 mmHg) or fasting gastric compliance (44 ± 10 vs 61 ± 6 mL mmHg(-1)) and on fasting thresholds for first perception (3.6 ± 0.4 vs 4.2 ± 0.2 mmHg above MDP) or discomfort (9.9 ± 0.7 vs 10.5 ± 0.5 mmHg above MDP). Tegaserod did not alter intra-balloon volumes before and after the meal [respectively 146 ± 14 vs 120 ± 11 and 297 ± 28 vs 283 ± 29 mL, not significant (NS)], or the amplitude of the meal-induced gastric relaxation (151 ± 23 vs 162 ± 23 mL, NS). In the subgroup with normal gastric emptying (n = 22), tegaserod significantly enhanced meal-induced accommodation (126 ± 23 vs 175 ± 29 mL, ANOVA P < 0.001). CONCLUSIONS & INFERENCES: Tegaserod does not alter gastric sensorimotor function in FD patients as a group. In the subgroup with normal gastric emptying, tegaserod 6 mg b.i.d enhanced gastric accommodation.

The effect of sham feeding on neurocardiac regulation in healthy human volunteers.

BACKGROUND: Distension and electrical stimuli in the esophagus alter heart rate variability (HRV) consistent with activation of vagal afferent and efferent pathways. Sham feeding stimulates gastric acid secretion by means of vagal efferent pathways. It is not known, however, whether activation of vagal efferent pathways is organ- or stimulus-specific. OBJECTIVE: To test the hypothesis that sham feeding increases the high frequency (HF) component of HRV, indicating increased neurocardiac vagal activity in association with the known, vagally mediated, increase in gastric acid secretion. METHODS: Continuous electrocardiography recordings were obtained in 12 healthy, semirecumbent subjects during consecutive 45 min baseline, 20 min sham feeding (standard hamburger meal) and 45 min recovery periods. The R-R intervals and beat-to-beat heart rate signal were determined from digitized electrocardiography recordings; power spectra were computed from the heart rate signal to determine sympathetic (low frequency [LF]) and vagal (HF) components of HRV. RESULTS: Heart rate increased during sham feeding (median 70.8 beats/min, 95% CI 66.0 to 77.6; P<0.001), compared with baseline (63.6, 95% CI 60.8 to 70.0) and returned to baseline levels within 45 min. Sham feeding increased the LF to HF area ratio (median: 1.55, 95% C.I 1.28 to 1.77; P<0.021, compared with baseline (1.29, 95% CI 1.05 to 1.46); this increase in LF to HF area ratio was associated with a decrease in the HF component of HRV. CONCLUSIONS: Sham feeding produces a reversible increase in heart rate that is attributable to a decrease in neurocardiac parasympathetic activity despite its known ability to increase vagally mediated gastric acid secretion. These findings suggest that concurrent changes in cardiac and gastric function are modulated independently by vagal efferent fibres and that vagally mediated changes in organ function are stimulus- and organ-specific.

A comparison of autonomic function in patients with inflammatory bowel disease and in healthy controls.

We evaluated autonomic function, symptoms and psychological parameters in patients with ulcerative colitis (UC), Crohn's disease (CD) and matched controls to assess whether UC patients have greater basal sympathetic autonomic activity. Outpatients with UC (n = 15), CD (n = 13) and healthy controls (n = 28) underwent spectral analysis of heart rate variability to assess cardiac autonomic function, a methacholine challenge to assess cholinergic pulmonary responsiveness, and questionnaires assessing disease severity, anxiety and depression. UC but not CD patients had greater sympathetic activity than controls with increased absolute (6600 vs 5884; P = 0.04) and relative (62.8%vs 54.8%; P = 0.02) low frequency areas. This was not because of increased overall autonomic nervous system (ANS) activation and was independent of disease activity. In UC patients, trait (personality-related) anxiety correlated strongly with disease symptoms (R = 0.84; P < 0.001) and quality of life (R = -0.81; P < 0.001) while situational (state) anxiety did not. In CD patients, ANS measures were similar to controls and disease activity was unrelated to psychological measures. Cholinergic pulmonary responsiveness was normal in both UC and CD patients. UC patients have an increased sympathetic ANS activity which is independent of symptom severity. In these patients symptom severity is strongly associated with measures of personality related (but not current) anxiety.

Clinical trial: effects of tegaserod on gastric motor and sensory function in patients with functional dyspepsia.

BACKGROUND Tegaserod, a serotonin receptor type-4 partial agonist, stimulates gastrointestinal motility and has been shown to increase gastric volumes before and after a meal in healthy volunteers. Its effect on gastric motor and sensory function in patients with functional dyspepsia is unclear. AIM To evaluate the effects of tegaserod on gastric compliance, accommodation and gastric sensory function in patients with functional dyspepsia and healthy volunteers. METHODS Sixteen patients with functional dyspepsia and 12 healthy volunteers were studied on two occasions, each after a 7-day treatment with either placebo or tegaserod 6 mg b.d. using a double-blind, randomized, crossover design. After each treatment period a gastric barostat study was performed fasting and during intraduodenal lipid infusion. RESULTS Tegaserod increased postprandial gastric compliance in functional dyspepsia patients (P = 0.04). Healthy volunteers showed enhanced postprandial gastric compliance after placebo (P = 0.03). Between-treatment analysis of gastric accommodation revealed a significant increase in intrabag volumes after tegaserod in healthy volunteer (P = 0.04); no difference could be seen in functional dyspepsia patients. Tegaserod had no effect on gastric sensation. CONCLUSIONS Tegaserod enhances postprandial gastric compliance in functional dyspepsia patients and gastric accommodation in healthy volunteers. The improvement of proximal gastric motor function suggests a beneficial role of tegaserod in patients with functional dyspepsia.

Intramuscular interstitial cells of Cajal associated with mast cells survive nitrergic nerves in achalasia.

Achalasia is dominated by injury to inhibitory nerves. As intramuscular interstitial cells of Cajal (ICC-IM) are proposed to form functional units with nitrergic nerves, their fate in achalasia may be critically important. We studied the relationship between loss of nitrergic nerves and injury to ICC-IM in patients with achalasia and determined associations between ICC-IM and mast cells (MC), using quantitative immunohistochemistry and electron microscopy. Loss of neuronal nitric oxide synthase (nNOS) immunoreactivity was completed within 3 years of acquiring achalasia. Thereafter, progressive ultrastructural injury to remaining nerve structures was evident. Within the first 2 years, the number of ICC-IM did not decline although ultrastructural injury was already present. Thereafter, loss of ICC-IM occurred unrelated to duration of disease. Damage to ICC-IM appeared unrelated to nerve injury. A significant MC infiltration was observed in the musculature; the number of MC was positively related to the persistent number of ICC-IM. Mast cell formed close contacts with ICC-IM and piecemeal-degranulation occurred towards ICC-IM. In conclusion, injury to ICC-IM in achalasia is variable, but not related to duration of disease and injury to nitrergic nerves. MC are prominent and form close functional contact with ICC-IM which may be responsible for their relatively long survival.

Inhibitory effects of Lactobacillus reuteri on visceral pain induced by colorectal distension in Sprague-Dawley rats.

BACKGROUND AND AIMS: Probiotic bacteria are being investigated as possible treatments for many intestinal disorders. The present study aimed to explore the effects of live, heat killed, or gamma irradiated Lactobacillus reuteri on cardio-autonomic response and single fibre unit discharge in dorsal root ganglia to colorectal distension in healthy Sprague-Dawley rats housed under conventional conditions. The effects of this treatment on somatic pain were also examined. METHODS: 1x10(9) bacteria were given by gavage for nine days. Colorectal distension occurred under anaesthesia. Heart rate was measured through continuous electrocardiography. Single fibre unit discharge was recorded from the 6th left lumbar dorsal root ganglion. Somatic pain was evaluated by the tail flick and paw pressure tests. RESULTS: Colorectal distension caused a pressure dependent bradycardia in the control (native medium) group. Treatment with live, heat killed, or gamma irradiated bacteria as well as their products (conditioned medium) prevented the pain response even during the maximum distension pressure (80 mm Hg). Both viable and non-viable bacteria significantly decreased dorsal root ganglion single unit activity to distension. No effects on somatic pain were seen with any treatment. CONCLUSIONS: Oral administration of either live or killed probiotic bacteria or conditioned medium inhibited the constitutive cardio-autonomic response to colorectal distension in rats through effects on enteric nerves. These data may provide a novel explanation for beneficial probiotic effects on visceral pain.

Functional dyspepsia, delayed gastric emptying, and impaired quality of life.

BACKGROUND: It remains controversial as to whether delayed gastric emptying in functional dyspepsia is associated with a specific symptom pattern, and it is unknown if gastric emptying in functional dyspepsia is a driver of impaired health related quality of life (HRQOL). We aimed to evaluate the relationship between functional dyspepsia symptoms, gastric emptying, and HRQOL. METHODS: US patients (n=864; mean age 44 years (range 18-82); 74% female) with functional dyspepsia, as defined by Rome II criteria, were enrolled into one of four clinical trials. All patients had a baseline scintigraphic assessment of gastric emptying of an egg substitute meal, and the trials were stratified on this assessment. Delayed gastric emptying was defined as having at least 6.3% residual volume at four hours. A total of 290 (34%) patients had delayed gastric emptying. HRQOL was assessed by the SF 36 and Nepean dyspepsia index (NDI). RESULTS: Postprandial fullness was independently associated with delayed gastric emptying but the association was weak (odds ratio (OR) 1.98 (95% confidence interval (CI) 1.02, 3.86); p=0.04). No independent association was seen with epigastric pain, early satiety, nausea, or bloating. Mean SF 36 physical composite score (PCS) was 42.3 (95% CI 41.6, 43.0) and the mean SF 36 mental composite score (MCS) was 46.8 (95% CI 46.0, 47.5); both mean scores were significantly lower than age and sex adjusted national norms of 50 (p<.0001). Female sex, increasing age, and higher symptom scores for fullness, epigastric pain, and nausea were each independently associated with decreased PCS scores (all p<0.05). Higher baseline nausea symptom score, lower gastric emptying rates at one hour, and lower body mass index were associated with decreased MCS (all p<0.05). Female sex, epigastric pain, and nausea, but not gastric emptying, were associated with an impaired score on the NDI. However, the magnitude of the significant associations were all small. CONCLUSIONS: In patients with functional dyspepsia selected for a clinical trial programme, gastric emptying did not usefully stratify them symptomatically. Quality of life of patients with functional dyspepsia enrolled in this clinical trial programme was significantly impaired but this was not explained by delayed gastric emptying.

Omeprazole delays gastric emptying in healthy volunteers: an effect prevented by tegaserod.

BACKGROUND: Proton-pump inhibitors effectively suppress stomach acidity. They are widely used for treating gastro-oesophageal reflux disease and related conditions. While generally safe, omeprazole and other proton-pump inhibitors can delay gastric emptying. AIM: To test the hypothesis that tegaserod can normalize or prevent omeprazole-induced delay in gastric emptying. METHODS: This was a randomized, double-blind, placebo-controlled, parallel group study in 40 healthy male volunteers. After informed consent and screening, qualified volunteers were treated with unblinded omeprazole 20 mg b.d. and either blinded tegaserod 6 mg t.d.s. (active treatment group) or placebo-matching tegaserod t.d.s. (control group) for 14 days. Gastric emptying was assessed before and after treatment, using a scintigraphy method. RESULTS: Omeprazole monotherapy significantly delayed gastric emptying expressed by duration of lag-phase (P < 0.007), time to gastric half-emptying (P < 0.003), and gastric retention of the meal at 60 (P < 0.002) and 120 min (P < 0.04) after its ingestion. Tegaserod taken together with omeprazole effectively prevented development of the above effects. Combined treatment was safe and well tolerated. CONCLUSION: Concomitant administration of tegaserod 6 mg t.d.s. prevented development of the delayed gastric emptying induced by omeprazole monotherapy.

A randomized-controlled trial comparing an educational intervention alone vs education and biofeedback in the management of faecal incontinence in women.

Biofeedback (BF) training is an accepted therapy in the treatment of faecal incontinence (FI) despite a paucity of data demonstrating benefit. This study aims to determine whether BF has any specific effect above and beyond an educational intervention. Twenty-three women with regular and frequent idiopathic FI were randomized to education and pelvic exercise vs education and BF therapy. Complete data is available for 18 women. Overall, 61% of participants demonstrated a complete response. There was no difference in response rate between treatment arms. Women with FI demonstrate a good response to treatment with education and exercise and education plus BF thus questioning the specific effect of BF.

Pseudo-affective visceromotor responses and HPA axis activation following colorectal distension in rats with increased cholinergic sensitivity.

We analysed visceromotor (VMR) and corticosterone responses to colorectal stimuli under control conditions and following acoustic stress in rats selectively bred for increased sensitivity to cholinergic agonists, the Flinders Sensitive Line (FSL) rats, compared with Flinders Resistant Line (FRL) rats. FSL rats demonstrated a significant VMR response at the smallest distension pressure, whereas no response was evident in FRL controls. FSL rats also demonstrated enhanced VMR responses at both larger distension levels compared with FRL rats. Colorectal distension (CRD) produced significant increases in serum corticosterone levels, which were comparable in FRL and FSL. Noise stress induced divergent corticosterone responses in FRL and FSL, but did not affect VMR to CRD in either group. These data suggest that FSL rats show altered VMR responses to CRD and disturbed hypothalamic-pituitary-adrenal axis responses to acute stress.

Phenotypic differences in cholinergic responses of distal colonic epithelium.

The Flinders sensitive line (FSL) rats exhibit an increased cholinergic responsiveness in vivo when compared to their counterparts, the Flinders resistant line (FRL) rats. The functional consequences of this phenotypic difference on colonic mucosal function are not known. We sought to determine whether isolated distal colonic mucosa from the two strains exhibit differential responses to cholinergic agonists. The responses of the distal colonic mucosa from two lines of rats to carbachol were compared by recording changes in short-circuit current. The ion movements associated with these changes were assessed by flux analysis of the radiotracers, 22Na and 36Cl. The anticipated hyper-responsiveness to cholinergic stimulation in FSL rats was not seen. Carbachol responses were significantly enhanced by indomethacin pretreatment only in FRL rats. Tetrodotoxin (TTX) pretreatment significantly reduced responses to carbachol in FSL rats at all concentrations tested, though this was only seen with lower concentrations in FRL rats. Flux analysis indicated that both lines absorbed Na+ and Cl- under basal conditions and that a significant residual flux was present. Stimulation with carbachol led to significant reductions in net Na+ and Cl- fluxes in both lines. The changes in net Na+ and Cl- flux in both lines stem largely from a decrease in mucosal to serosal fluxes of both ions with an increase in serosal to mucosal flux of Cl-. The striking difference is the significant reduction in residual flux seen only in FRL rats. Indomethacin pretreatment abolished the changes in residual flux seen in FRL rats. Thus the responses to carbachol in these rats had at least three components: (a) a direct effect on the transporting colonocyte, (b) an indirect effect mediated by an arachidonic acid metabolite, and (c) another indirect effect involving a neurotransmitter. The relative contributions of each of these components were different in the two lines.

Functional heartburn: the stimulus, the pain, and the brain.

Functional heartburn is a common disorder and appears to be composed of several distinct subgroups. Identifying the different subgroups based on clinical history only is not achievable at present. The mechanisms responsible for pain, clinical characteristics, and the optimal therapeutic approach remain poorly understood. Response to potent antireflux treatment is relatively limited. Current and future treatment strategies for functional heartburn patients who have failed standard dose proton pump inhibitors (PPIs) include increased PPI dose in some, as well as addition of pain modulators in others.

Long-term safety of tegaserod in patients with constipation-predominant irritable bowel syndrome.

BACKGROUND: Tegaserod is a 5-hydroxytryptamine-4 receptor partial agonist. Oral administration causes gastrointestinal effects resulting in increased gastrointestinal motility and attenuation of visceral sensation. AIM: : To determine the long-term safety and tolerability of tegaserod in patients suffering from irritable bowel syndrome with constipation as the predominant symptom of altered bowel habits. METHOD: A multicentre, open-label study with flexible dose titration of tegaserod in out-patients suffering from constipation-predominant irritable bowel syndrome. RESULTS: A total of 579 patients with constipation-predominant irritable bowel syndrome were treated with tegaserod. Of these, 304 (53%) completed the trial. The most common adverse events, classified as related to tegaserod for any dose, were mild and transient diarrhoea (10.1%), headache (8.3%), abdominal pain (7.4%) and flatulence (5.5%). Forty serious adverse events were reported in 25 patients (4.4% of patients) leading to discontinuation in six patients. There was one serious adverse event, acute abdominal pain, classified as possibly related to tegaserod. There were no consistent differences in adverse events between patients previously exposed to tegaserod and those treated de novo. No pattern-forming tegaserod-related abnormalities in haematological and biochemical laboratory tests, urinalysis, blood pressure, pulse rate or electrocardiograms were found. CONCLUSIONS: Tegaserod appears to be well tolerated in the treatment of patients with constipation-predominant irritable bowel syndrome. The adverse event profile, clinical laboratory evaluations, vital signs and electrocardiogram recordings revealed no evidence of any unexpected adverse events, and suggest that treatment is safe over a 12-month period.

Assessment of the afferent vagal nerve in patients with gastroesophageal reflux.

BACKGROUND: The objective of this study was to assess the integrity of the vagal nerve afferent pathways in patients with gastroesophageal reflux disease (GERD). METHODS: Seven GERD patients (4 males and 3 females, mean age 39 +/- 8 years) were studied. Twelve healthy volunteers (11 males and 1 female, mean age 32 +/- 8 years) were used as the control group. Cortical evoked potentials were measured. Electrical stimulation of the esophageal mucosa was performed through a custom-built device. Latencies and N2/P2 amplitude were measured. RESULTS: Reproducible cortical evoked potentials were obtained from all subjects. The stimulation threshold for GERD patients to electrical esophageal stimulation was 5.1 +/- 1.5 mA compared to 7.8 +/- 2.0 mA in healthy volunteers (p <0.05). There was no difference in peak latencies or N2/P2 amplitude between GERD patients and controls. CONCLUSIONS: GERD patients have a normal vagal nerve function, but they exhibit a decreased threshold for esophageal perception. The mechanism responsible for increased esophageal sensitivity observed in GERD patients is still undetermined and warrants further study.

Development of a systematic observation protocol of physical exposure of the back: a preliminary study.

OBJECTIVE: At present there is no systematic observation protocol for the assessment of the multi-factorial aspects of physical exposure related to the back used within the constraints of occupational epidemiological research. In this context, a new preliminary systematic observation protocol is proposed to assess exposure to physical loading of the back using nine categories of physical risk factors: the SOPE back protocol. The objective of this study was to investigate whether the new protocol can correctly identify the level of exposure related to measured physical loading of the back. METHODS: The subjects of this closed cohort study were 451 manual workers at a natural gas distribution company. The assessment of exposure was made with the protocol using groups with different job titles. The workers were followed for a 2 yr period to establish the risk of a new occurrence of complete disability related to the back (NOCD back injury) in each job grouping. RESULTS: Based on the median of the total scores derived from the protocol, two levels of exposure were identified (high and low). CONCLUSION: Taking into account the limitations of this study, the protocol in development may be a good tool to establish two levels of exposure to physical loading of the back in large epidemiological studies of occupational low back pain. Further research is needed to replicate these results with larger samples and to test the reliability and predictive validity of the protocol.

Intestinal inflammation and activation of sensory nerve pathways: a functional and morphological study in the nematode infected rat.

BACKGROUND: In the rat, gastric distension elicits an intensity dependent pseudoaffective bradycardia mediated via capsaicin sensitive afferent and cholinergic efferent vagal pathways. Inflammation alters visceral perception although the mediators responsible have not been identified. In the nematode infected rat, there is a substantial increase in neuronal substance P (SP) content of the gut. AIMS: To examine the effects of inflammation on perception of a noxious visceral stimulus and on SP and neurokinin 1 (NK-1) receptor immunoreactivity (IR) in visceral afferent pathways. METHODS: Immunohistochemistry was performed on sections from the jejunum, dorsal root ganglia (DRG), and spinal cord (T1-L1) using SP and NK-1 rabbit polyclonal antibodies. In the DRG, the number of SP-IR or NK-1-IR neurones per section was visually quantified. The pseudoaffective cardiac reflex response to gastric stimulation was compared in control and Trichinella spiralis infected rats. RESULTS: Intestinal inflammation induced a rightward shift in the intensity dependent bradycardic response to gastric distension. This was associated with a marked increase in SP-IR not only in the gut wall but also in the DRG and dorsal horn of the spine. In contrast, NK-1-IR was not increased in the gut wall. Moreover, inflammation evoked a decrease in NK-1-IR in the dorsal horn. No NK-1-IR was identified in the DRG of either control or infected animals. CONCLUSIONS: Intestinal inflammation modulates the capsaicin sensitive pseudoaffective autonomic response to gastric distension, increases SP-IR in afferent pathways, and downregulates dorsal horn NK-1-IR. As the pseudoaffective response is capsaicin sensitive, the rightward shift of the response is likely the consequence of the decrease in NK-1 receptors in the sensory pathways.

Irritable bowel syndrome: new approaches to its pharmacological management.

The present paper examines approaches to drug therapy for irritable bowel syndrome (IBS). Because IBS is associated with multiple symptoms, no single therapy is effective in all patients. However, issues such as affective and emotional factors also need to be addressed when treating patients with IBS. This paper emphasizes the importance of identifying new pharmaceutical approaches to treat a multitude of symptoms and obtaining a better understanding of the underlying mechanisms of IBS.

Cardiac autonomic function and oesophageal acid sensitivity in patients with non-cardiac chest pain.

BACKGROUND: Acid reflux can elicit non-cardiac chest pain (NCCP), possibly through altered visceral sensory or autonomic function. The interactions between symptoms, autonomic function, and acid exposure are poorly understood. AIM: To examine autonomic function in NCCP patients during exposure to oesophageal acid infusion. SUBJECTS AND METHODS: Autonomic activity was assessed using power spectral analysis of heart rate variability (PSHRV), before and during oesophageal acidification (0.1 N HCl), in 28 NCCP patients (40.5 (10) years; 13 females) and in 10 matched healthy controls. Measured PSHRV indices included high frequency (HF) (0.15-0.5 Hz) and low frequency (LF) (0.06-0.15 Hz) power to assess vagal and sympathetic activity, respectively. RESULTS: A total of 19/28 patients had angina-like symptoms elicited by acid. There were no significant manometric changes observed in either acid sensitive or insensitive patients. Acid sensitive patients had a higher baseline heart rate (82.9 (3.1) v 66.7 (3.5) beats/min; p<0.005) and lower baseline vagal activity (HF normalised area: 31.1 (1.9)% v 38.9 (2.3)%; p< 0.03) than acid insensitive patients. During acid infusion, vagal cardiac outflow increased (p<0.03) in acid sensitive but not in acid insensitive patients. CONCLUSIONS: Patients with angina-like pain during acid infusion have decreased resting vagal activity. The symptoms elicited by perception of acid are further associated with a simultaneous increase in vagal activity in keeping with a vagally mediated pseudoaffective response.

Afferent vagal modulation. Clinical studies of visceral sensory input.

UNLABELLED: The frequency composition of a continuous time series of R-R intervals may be viewed as the phasic output of a central processing system intimately dependent on sensory input from a variety of afferent sources. While different measures of heart rate variability permit a glimpse into the autonomic efferent limb of this complex system, direct access of afferent fibers in humans has remained elusive. Using a specially designed esophageal catheter/manometer probe, we have been able to gain access to vagal afferent fibers in the distal esophagus. Our studies on the effect of vagal afferent electrostimulation on both cerebral evoked potentials (EvP) and the power spectrum of heart rate variability have yielded the following observations: 1. Stimulation of esophageal vagal afferents dramatically and reproducibly increases the high frequency (HF) vagal power and reduces the low frequency (LF) power of the heart rate autospectrum. 2. This effect is constant across stimulation frequencies from 0.1 to 1.0 Hz and across stimulation intensities from 2.5 to 20 mA. 3. Regardless of the stimulation parameters, there are only minimal changes in heart rate (2-6 bpm) and no change in respiratory frequency. 4. There is a linear correlation between electrical stimulation intensity and the amplitude of cerebral evoked potentials, whereas there is a non-linear relationship with all short-term power spectral indices. 5. While cerebral evoked potentials are only elicited at stimulation intensities above perception threshold, there is already a significant shift to increased vagal efferent modulation well below perception threshold. CONCLUSION: These studies support the concept that power spectral indices of heart rate variability represent phasic output responses to tonic afferent viscerosensory signals in humans. These studies also demonstrate the feasibility of accessing vagal afferents in humans.