Autonomic recovery following sprint interval exercise.

The autonomic nervous activity was assessed following supramaximal exercise through heart rate (HR) and blood pressure (BP) variability (HRV and BPV) and baroreflex sensitivity (BRS). The beat-to-beat HR and BP were recorded during the supine and standing states before (PRE) and at 60 (R60) and 120 min (R120) following single (one Wingate, 1W) and multiple sprint intervals (four Wingates interspersed with 4 min of light cycling, 4W). The supine low frequency (LF) component was increased (P<0.001) and the high frequency (HF) was reduced (P<0.01) at R60 (LF, 178.1 ± 11.0; HF, 74.8 ± 10.5) compared with PRE (LF, 140.2 ± 7.4; HF, 110.4 ± 7.2) after both exercises. Supine systolic BPV LF:HF was higher at R60 (4.6 ± 1.4) compared with PRE (6.8 ± 2.4) only after 4W (P=0.035). Supine BRS was lower (P<0.001) at R60 (6.8 ± 1.1) than at PRE (15.3 ± 1.8) and R120 (11.3 ± 1.3). BRS at R120 remained lower after 4W (P=0.02). Standing BRS was less (P<0.001) at R60 (2.3 ± 0.5) than at PRE (5.6 ± 0.8) or R120 (3.7 ± 0.6) and returned to PRE values only after 1W. We concluded that (a) autonomic balance is shifted to a greater sympathetic and less parasympathetic activation following both types of exercise, (b) it takes longer than 1 h to recover following supramaximal exercise and (c) the recovery is longer after 4W than 1W.

Heightened central affective response to visceral sensations of pain and discomfort in IBS.

BACKGROUND Typically, conventional functional imaging methods involve repeated exposures to sensory stimulation. In rectal distension (RD) studies that involve multiple distensions, however, it is difficult to disambiguate the central response to RD from pathological alterations in peripheral neural responses associated with relaxation and accommodation of the rectum. METHODS This study addressed potential confounders found in previous imaging studies by collecting functional magnetic resonance imaging studies (fMRI) data during a single slow ramp-tonic distension paradigm and analysing fMRI signal changes using independent component analysis. KEY RESULTS Compared with controls, IBS participants showed increased activation of the anterior cingulate cortices, insula and ventral medial prefrontal regions suggesting heightened affective responses to painful visceral stimuli. In addition, the failure by IBS patients to down-regulate activity within ventral medial prefrontal and the posterior cingulate/precuneus regions was suggestive of reduced sensitivity to somatic changes and delayed shifts away from rest in ;default network' activity patterns. Controls showed heightened activation of the thalamus, striatal regions and dorsolateral prefrontal cortex suggesting greater arousal and salience-driven sustained attention reactions and greater modulation of affective responses to discomfort and pain. CONCLUSION&INFERENCES This work points to alterations in the central response to visceral pain and discomfort in IBS, highlighting diminished modulation and heightened internalization of affective reactions.

Vagal dysfunction in irritable bowel syndrome assessed by rectal distension and baroreceptor sensitivity.

Autonomic nervous system dysfunction has been implicated in the pathophysiology of irritable bowel syndrome (IBS). This study characterized the autonomic response to rectal distension in IBS using baroreceptor sensitivity (BRS), a measure of autonomic function. Rectal bag pressure, discomfort, pain, ECG, blood pressure and BRS were continuously measured before, during and after rectal distension in 98 healthy volunteers (34 +/- 12 years old, 52 females) and 39 IBS patients (39 +/- 11 years old, 35 females). In comparison with the healthy volunteers, IBS patients experienced significantly more discomfort (69 +/- 2.2% vs 56 +/- 3.6%; P < 0.05), but not pain (9 +/- 1.4% vs 6 +/- 2.4%; ns) with rectal distension despite similar distension pressures (51 +/- 1.4 vs 54 +/- 2.4 mmHg; ns) and volumes (394 +/- 10.9 vs 398 +/- 21.5 mL; ns). With rectal distension, heart rate increased in both healthy volunteers (66 +/- 1 to 71 +/- 1 bpm; P < 0.05) and IBS patients (66 +/- 2 to 74 +/- 3 bpm; P < 0.05). Systolic blood pressure also increased in both healthy volunteers (121 +/- 2 to 143 +/- 2 mmHg; P < 0.05) and patients (126 +/- 3 to 153 +/- 4 mmHg (P < 0.05) as did diastolic blood pressure, 66 +/- 2 to 80 +/- 2 mmHg (P < 0.05), compared with 68 +/- 3 to 84 +/- 3 mmHg (P < 0.05) in IBS patients. The systolic blood pressure increase observed in IBS patients was greater than that seen in healthy volunteers and remained elevated in the post distension period (139 +/- 3 mmHg vs 129 +/- 2 mmHg; P < 0.05). IBS patients had lower BRS (7.85 +/- 0.4 ms mmHg(-1)) compared with healthy volunteers (9.4 +/- 0.3; P < 0.05) at rest and throughout rectal distension. Greater systolic blood pressure response to rectal distension and associated diminished BRS suggests a compromise of the autonomic nervous system in IBS patients.

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.

The effects of body-weight supported treadmill training on cardiovascular regulation in individuals with motor-complete SCI.

STUDY DESIGN: Four-month longitudinal within-subject exercise training study. OBJECTIVE: Although body-weight supported treadmill training (BWSTT) has not shown promise as a means of improving ambulation in individuals with motor-complete spinal cord injury (SCI), it may still improve cardiovascular health and function in this population. The purpose of this study was to (i) investigate the effects of BWSTT on peripheral muscular and elastic artery dimension and function and measures of heart rate variability (HRV) and blood pressure variability (BPV) in individuals with motor-complete SCI, and (ii) to make a preliminary examination of what factors may predict favourable cardiovascular outcomes following BWSTT in this population. SETTING: Centre for Health Promotion and Rehabilitation, McMaster University, Hamilton, Ontario, Canada. METHODS: Six individuals (four male, two female; age 37.7+/-15.4 years) with chronic SCI (C4-T12; ASIA A-B; 7.6+/-9.4 years post-injury) were included in the present investigation. Doppler ultrasound was used to determine femoral (exercising; muscular), carotid (elastic) and brachial (non-exercising control; muscular) artery dimension and function before and after 4 months of BWSTT. Continuous heart rate and blood pressure were also recorded before and after 4-months of BWSTT to determine frequency domain measures of HRV and BPV; clinically valuable indices of neurocardiac and neurovascular control, respectively. RESULTS: Two-way ANOVA (vessel x time) revealed no exercise-induced change in femoral or carotid artery cross-sectional area, blood flow or resistance and no change in carotid artery compliance following the 4 months of BWSTT compared to the non-exercising control brachial artery. However, there was a significant exercise-induced increase in femoral artery compliance. There were no exercise-induced changes in HRV or BPV when all participants were considered together. However, the results suggest that the subgroup of individuals who had a substantial heart rate response to BWSTT (n=3), experienced exercise-training induced changes in HRV reflective of a relative shift toward cardiac vagal predominance and reductions in BPV. CONCLUSIONS: BWSTT may cause an increase in femoral artery compliance in individuals with motor-complete SCI and therefore, should be encouraged as a means of improving cardiovascular health in this population. BWSTT may also cause modest improvements in measures of HRV and BPV in a select subgroup of individuals who respond to ambulation with moderate to large increases in HR. In the present study, factors associated with a substantial HR response to BWSTT were a propensity to orthostatic intolerance and muscular spasticity.

Separation of antihemophilic factor VII from human plasma by column chromatography.

TMAE-Fractogel 650 (M) (Trimethylaminoethyl) is an ion exchange medium can be used to capture factor VIII (F VIII) directly from plasma. Previous reports have focused on the use of DEAE-Fractogel 650 (M) (Dimethylaminoethyl) ion exchange medium to capture F VIII from cryoprecipitate and plasma. Our main objectives were (I) to standardise the purification of FVIII from human plasma by column chromatographic technique. (II) to study the recovery of FVIII activity in purified fraction at 18-20°C process condition. (III) to study the effect of virucidal step on recovery of FVIII activity and (IV) to study the effect of lyophilisation on FVIII activity. In this report, Citrate Phosphate Dextrose (CPD) plasma was batch stirred with dry DEAE-Sephadex A50, filtered, diluted, loaded on to a column packed with TMAE-Fractogel and chromatographed. Most of the unwanted proteins flowed through the gel unadsorbed. Bound F VIII was eluted by increasing the ionic strength of the buffer. This purification step gave an overall 80% recovery from the plasma with a specific activity of 0.97 IU FVIII/mg protein. The purified F VIII fraction was made virus safe by employing the virucidal technique developed by New York Blood Centre (NYBC). There was 48.43% loss of FVIII activity in Virus inactivation treatment and the loss of FVIII activity in lyophilisation was 8.45% which is acceptable. This method of purification gave a higher yield of FVIII than cryoprecipitation, and is a promising alternative method to cryoprecipitation of F VIII.

Effect of sertraline on the recovery rate of cardiac autonomic function in depressed patients after acute myocardial infarction.

BACKGROUND: Brain serotonin is known to possess sympathoinhibitory properties. The aim of this clinical physiologic study was to determine whether sertraline, a selective serotonin reuptake inhibitor, facilitates the rate of recovery of cardiac autonomic function after an acute myocardial infarction (MI) in patients with depression. METHODS AND RESULTS: Thirty-eight post-MI depressed patients were randomized to receive either sertraline 50 mg per day or placebo for 6 months. Depression was defined as a score >15 on the standardized Inventory to Diagnose Depression questionnaire taken at prehospital discharge and again within 2 weeks of the acute infarct. Eleven stable post-MI nondepressed patients served as a nonrandomized reference group during follow-up. Twenty-seven patients completed the randomization. All 3 groups were followed up closely in a multidisciplinary post-MI clinic where they underwent serial testing for both time and frequency domain heart rate variability (HRV) indices at baseline (1-2 weeks after MI) and at 6, 10, 14, 18, and 22 weeks. The rate of recovery of HRV was determined by use of a growth curve model based on repeated-measures analysis of variance. There was a linear rate of increase in the SD of 24-hour N-N intervals (SDNN) in the sertraline-treated group that paralleled that of the nondepressed reference group. This contrasted with a modest but significant decline in SDNN in the placebo group from 2 to 22 weeks (t = 2.10, P <.05). However, the short-term power spectral indices, while trending toward a more rapid rate of recovery in the treated group, did not reach statistical significance compared with the placebo group. CONCLUSION: In depressed patients who have survived the acute phase of an MI sertraline facilitates the rate of recovery of SDNN, a recognized predictor of clinical outcome.

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.

Objective assessment of cognitive factors involved in visceral perception by using event-related cerebral evoked responses to esophageal target stimulation in man.

Evoked potential (EP) studies provide an objective measure of the neural pathways involved with perception of gastrointestinal stimulation. The effects of cognitive factors, such as anticipation or awareness, on EP responses are not known. We compared the EP response to esophageal electrical stimulation with the cortical activity associated with target detection and anticipation of the same stimulus. In 12 healthy men (26.8+/-6 years old), esophageal electrical stimulation (0.2 Hz, 0.2 msec, 15 mA) was applied, and the EP recorded using scalp electrodes. A computerized model of randomly applied target stimuli (1:5 ratio) was used to separately record the EP associated with stimulation and the event-related cognitive EP associated with a dual task-related or anticipated stimulation approach. A periodic electrical stimulus represented the nontarget stimulus and a second electrical impulse (oddball model) or an omitted stimulus (anticipatory model) the target stimulus. The event-related cognitive EP responses were also compared with standard and anticipatory auditory P300 evoked potentials. The esophageal and auditory oddball stimulus approach elicited event-related P300EP in all subjects. P300EP associated with electrical stimulation had a longer peak latency (P < 0.0001) and smaller amplitude than those obtained with auditory stimulation. Anticipatory evoked potentials could be obtained by electrical skipped stimulation in 8 of 12 subjects. These EP were similar to those obtained with omitted auditory target stimulation, although of significantly smaller amplitude than auditory standard P300EP (P < 0.001). In conclusion, the brain response associated with directed effortful processing of discriminate esophageal stimuli consists of a large event-related potential (P300EP). Anticipatory stimulation produces a similar event-related cortical response, which is associated with attention to and awareness of the actual stimulus. The P300EP to gastrointestinal stimuli may provide an objective and powerful electrophysiological tool for the assessment of the cognitive factors associated with visceral perception.

Abnormal cerebral processing of oesophageal stimuli in patients with noncardiac chest pain (NCCP).

In noncardiac chest pain (NCCP), altered visceral perception may result from abnormal cerebral processing of sensory input rather than abnormalities of afferent pathways. However, the interactions between symptoms, autonomic function and oesophageal stimuli are poorly studied. Oesophageal stimulation elicits reproducible cortical evoked potentials [CEP] and modulates heart rate variability via vagal pathways, as visible on power spectrum analysis of heart rate variability [PS-HRV]. These methods are increasingly used to study the function of visceral afferent neural pathways in human. The aim of this study was to compare EP and PS-HRV during oesophageal stimuli in NCCP and controls. Twelve healthy volunteers (one female, 11 male; aged 24-51 years; mean 32 +/- 8 years), and eight NCCP patients (three female, five male; age range 26-58, mean 40.5 +/- 10 years) were studied. Electrical oesophageal stimulation (EOS; 200 microseconds, 0.2 Hz, 25 stimuli) was applied to the oesophageal wall 5 cm above the lower oesophageal sphincter (LOS), and perception thresholds (measured in mA) determined. EP responses were recorded using 22 standard electroencephalogram scalp electrodes. Autonomic activity was assessed using PS-HRV, before, during, and after oesophageal stimulation. Measured PS-HRV indices included high frequency (HF; 0. 15-0.5 Hz) and low frequency (LF; 0.06-0.15 Hz) power, respectively, assessing vagal and sympathetic activity, and the LF/HF ratio. EOS perception occurred at lower thresholds in NCCP than in controls (3. 6 +/- 1 vs. 7.8 +/- 2 mA, P < 0.05). EP amplitude was greater (13 +/- 2 vs. 6 +/- 1 microV, P < 0.0001), and latency longer in controls vs. NCCP (191 +/- 7 ms vs. 219 +/- 6 ms, P < 0.001). In NCCP, EOS decreased sympathetic outflow (low frequency peak on PS-HRV) and increased cardiovagal activity (high frequency peak, P < 0.02) to a significantly higher degree in comparison with controls. During EOS, heart rate decreased in NCCP from 68 vs. 62 beats min-1 (P < 0.003) but not in controls. In NCCP patients, EOS was perceived at lower intensities and was associated with a greater cardiovagal reflex response. EP responses associated with EOS were smaller in NCCP than in controls, suggesting that an increased perception of oesophageal stimuli results from an enhanced cerebral processing of visceral sensory input in NCCP, rather than from hyperalgesic responses in visceral afferent pathways.

Effects of esophageal stimulation in healthy subjects.

We studied the effects of esophageal electrical stimulation on heart rate variability power spectra (PS/HRV) and cortical evoked potentials (EPs) in healthy subjects. The intensity of stimulation was varied from 2.7 to 20 mA. We found that the amplitude of the cortical evoked potentials (amplitude of the N2/P2 peak) increased from 5.1 +/- 0.7 microV at 5 mA to 16.3 +/- 1.1 microV at 20 mA. The PS/HRV showed an increase in the vagal modulation of the sinus node. When the stimulation frequency was varied from 0.1 to 1 Hz at a constant intensity of 15 mA, the amplitude of cortical EPs (N2/P2 peak) decreased with increase in the frequency of stimulation (p < 0.05). The LF:HF ratio decreased significantly for all frequencies of stimulation (p < 0.005). An experimental paradigm to evoke the cognitive component in the cortical EPs yielded a peak around 354 ms following the stimulus.

Effects of esophageal stimulation in patients with functional disorders of the gastrointestinal tract.

We studied the effects of esophageal electrical stimulation on cortical-evoked potentials (EPs) and power spectrum of heart rate variability (PS/HRV) in patients with diabetes and non-cardiac chest pain (NCCP). We also recorded cognitive-evoked potentials (P300 EPs) in response to an odd-ball stimulation in patients with NCCP. Diabetic patients did not yield reproducible cortical EPs. Their power spectra of heart rate variability (PS/HRV) showed an increased vagal modulation during stimulation. In patients with NCCP the P300 EPs were of greater amplitude (17 +/- 3 microV vs. 12 +/- 1 microV in controls, p < 0.04), while peak latencies were slightly elongated in patients (382 +/- 22 ms vs. 354 +/- 12 ms in controls). The PS/HRV in these patients also showed an increased vagal modulation of the sinus node activity. Our results suggest the following: (1) in patients with diabetes, afferent pathways and processing of sensory signals are likely to be impaired; (2) an increased perception of esophageal stimulation reflects an exaggerated brainstem response and altered cortical processing of visceral sensation in patients with NCCP.

Evaluation of neurocardiac signals in pediatric patients with cyclic vomiting syndrome through power spectral analysis of heart rate variability.

OBJECTIVE: To investigate autonomic regulation of neurocardiac signals in pediatric patients with cyclic vomiting syndrome (CVS). METHODS: Fourteen patients with CVS, ages 3 to 16 years, were screened to eliminate any underlying cause for their symptoms, although 11 of the 14 patients had a history of migraine in the immediate family. Analysis of autonomic regulation was accomplished through power spectral analysis of the beat-to-beat heart rate variability signal. Data from affected patients were compared with data from 38 control subjects, ages 5 to 16 years, by a one-way analysis of variance. A measure of sympathovagal balance was obtained by computing a ratio of power in the low-frequency band (0. 02-0.15 Hz) to the power in the high-frequency band (0.15-0.4 Hz). RESULTS: Pediatric patients with CVS have an elevated sympathetic modulation of the sinus node as represented by the low frequency/high frequency ratio (1.45 +/- 0.42 in patients vs 0.89 +/- 0.29 in healthy control subjects, P <.001). CONCLUSIONS: The patients with CVS we studied have an autonomic imbalance with enhanced sympathetic and diminished parasympathetic vagal modulation of the heart.

Cognitive evoked potentials to anticipated oesophageal stimulus in humans: quantitative assessment of the cognitive aspects of visceral perception.

Evoked potential studies provide an objective measure of the neural pathways involved with perception. The effects of cognitive factors, such as anticipation or awareness, on evoked potentials are not known. The aim was to compare the evoked potential response to oesophageal stimulation with the cortical activity associated with anticipation of the same stimulus. In 12 healthy men (23.5 +/- 4 years), oesophageal electrical stimulation (15 mA, 0.2 Hz, 0.2 msec) was applied, and the evoked potentials recorded using scalp electrodes. A computerized model of randomly skipped stimuli (4:1 ratio) was used to separately record the evoked potentials associated with stimulation and those associated with an anticipated stimulus. The electrical stimulus represented the nontarget stimulus and the skipped impulse the target (anticipatory) stimulus. This anticipatory evoked potential was also compared to auditory P300 evoked potentials. Reproducible evoked potentials and auditory P300 responses were elicited in all subjects. Anticipatory evoked potentials (peak latency 282.1 +/- 7.9 msec, amplitude 8.2 +/- 0.7 microV, P < 0.05 vs auditory P300 evoked potential) were obtained with the skipped stimulus. This anticipatory evoked potential was located frontocentrally, while the auditory P300 potential was located in the centro-parietal cortex. The anticipatory evoked potential associated with expectation of an oesophageal stimulus, although of similar latency to that of the auditory P300 evoked response, originates from a different cortical location. The recording of cognitive evoked potentials to an expected oesophageal stimulus depends on attention to, and awareness of, the actual stimulus. Anticipatory evoked potentials to GI stimuli may provide an objective electrophysiological tool for the assessment of the cognitive factors associated with visceral perception.

Assessment of the visceral afferent and autonomic pathways in response to esophageal stimulation in control subjects and in patients with diabetes.

OBJECTIVE: To examine the effects of esophageal stimulation on vagal afferent and efferent pathways in volunteers without diabetes and patients with diabetes. DESIGN: Prospective physiological study. PARTICIPANTS: Fourteen control subjects without diabetes and 6 patients with diabetes. INTERVENTIONS: Electrical and mechanical stimulation of the esophagus. OUTCOME MEASURES: Cortical evoked potentials and the power spectra of heart rate variability. RESULTS: For the control subjects, there was a significant decrease in the ratio of the low frequency to high frequency (LF:HF) power (i.e., increased vagal efferent modulation) during stimulation. Reproducible cortical evoked potentials were obtained from all control subjects. In the 6 patients with diabetes, who had viscerosensory and autonomic neuropathy, the cortical evoked potentials showed an erratic non-reproducible response to electrical esophageal stimulation; however, the LF:HF ratio decreased in these patients during stimulation, suggesting an intact subcortical reflex circuit. CONCLUSIONS: Vago-afferent fibres can be studied using minimally invasive techniques, and the power spectral analysis of heart rate variability permits study of autonomic vago-efferent pathways.

Assessment of afferent gut--brain function using cerebral evoked responses to esophageal stimulation.

Increasing awareness is attributed to altered sensory perception in the pathogenesis of gastrointestinal disorders. Evoked potentials (EP), which represent the brain's electrical response to peripheral stimulation, have recently been used to investigate where and how (GI) afferent information is processed along the brain-gut axis. EP can be obtained with electrical stimulation or balloon distention in the esophagus in humans. Stimulation of afferent neural pathways in the esophagus produces cerebral evoked responses allowing assessment of the peripheral afferent neural pathways involved, and of the function of integrative neural centers within the brain. Recent studies using esophageal EP indicate that the cerebral response to either mode of stimulation depends on the perception of the stimuli. Using electrical stimulation, a clear dose-response relationship is found. The EP response obtained with electrical stimulation is in keeping with those recorded using direct cervical stimulation of the vagus nerve, supporting evidence that esophageal EP are produced by activation of afferent vagal pathways. From the conduction velocity of the autonomic (vagal) nerves conveying information from esophagus to brain, it was concluded that non-painful electrical stimuli predominantly activate fast conducting myelinated afferent sensory fibers (A-fibers), while EP to balloon distention are largely due to activation of unmyelinated C-fibers. Techniques, however, vary widely amongst different investigators, and some electrophysiological parameters remain controversial, as there is no standard approach. Using balloon distention, EP waveforms vary widely between laboratories, suggesting that EP are substantially influenced by the stimulator devices (pump, respirator). EP to balloon distention are hampered by a relatively low signal-to-noise ratio (SNR), which is probably due to long inflation-deflation time (> 200 ms). With electrical stimulation, there is much less variability between different groups, and SNR is distinctly higher. This method appears to be most attractive for studies of afferent esophageal function. Standardization of the techniques is important, before esophageal EP can be regarded as a useful diagnostic approach in patient groups.

Cardiac autonomic dysfunction in survivors of acute lymphoblastic leukemia in childhood.

The purpose of this study was to investigate autonomic regulation of neurocardiac function in survivors of acute lymphoblastic leukemia (ALL) in childhood, through power spectral and time domain analyses of the heart rate variability signal. Studies were conducted on 34 unselected patients and 34 age matched controls. Patients were in remission, off therapy for at least 20 months and from high risk (HR, n=21) and standard risk (SR, n=13) groups as described by Dana-Farber Cancer Institute protocols 87-01 and 91-01. Twenty-nine patients had received cranial irradiation, 7 on a hyperfractionated schedule. Power spectral analysis of the heart rate (PS/HRV) was performed on 30 min heart rate time series and time domain statistics were computed from 24 h Holter recordings. Left ventricular function was assessed by measuring ejection and shortening fractions on echocardiography. All such measures were normal. Analysis of PS/HRV revealed that the supine low frequency: high frequency (LF:HF) area ratio was elevated in patients compared to controls. Changes in the LF and HF power on standing were attenuated in the patients compared to controls. Circadian analysis revealed a depressed diurnal rhythm of heart rate in the patients. Those from the SR group showed greater reduction of the LF power response to orthostatic stress and a reduced circadian rhythm of the heart rate compared to those with HR ALL. Patients from the HR group showed reductions in both HF and LF power responses to orthostasis compared to controls. Elevated supine LF power and depressed circadian variation in the HF power band were evident only in female subjects. Patients who received standard cranial irradiation had higher LF:HF area ratio and diminished LF and HF power responses to orthostatic stress than did subjects in the hyperfractionated group. These findings suggest that the autonomic nervous regulation of the heart is compromised in patients treated for ALL in childhood even when resting echocardiographic measures provide no evidence of cardiac decompensation. The extent of neurocardiac dysfunction is influenced by risk status, gender and schedule of cranial irradiation.

Neurocardiac and cerebral responses evoked by esophageal vago-afferent stimulation in humans: effect of varying intensities.

OBJECTIVE: This study was designed to determine whether esophageal vago-afferent electrostimulation, over a wide range of stimulus intensities, can sustain a cardiac vago-efferent effect by way of central nervous system processing. METHODS: Studies were performed in ten healthy male subjects (23.9 +/- 6.3 years). Esophageal electrostimulation was carried out using a stimulating electrode placed in the distal esophagus. Stimulation of esophageal vago-afferent fibres was employed using electrical impulses (200 microseconds at 0.2 Hz x 128 s) varying from 2.7 to 20 mA. Respiratory frequencies, beat-to-beat heart rate autospectra and cerebral evoked potentials were recorded at baseline and at each stimulus intensity in random order. RESULTS: With esophageal electrical stimulation, we observed a small non-significant decrease in heart rate. There was a dramatic shift of the instantaneous heart rate power spectra towards enhanced cardiac vagal modulation with intensities as low as 5 mA. This effect was sustained throughout all intensities with no further change in either the low frequency or high frequency power. Conversely, there was a linear dose response relationship between cerebral evoked potential amplitude and stimulus intensity mainly occurring above perception threshold (10 mA). Esophageal stimulation had no significant effect on heart rate or respiratory frequency at any stimulus intensity. CONCLUSIONS: These results indicate that electrical stimulation of the distal esophagus across a wide range of current intensities elicits a reproducible shift in the heart rate power spectrum towards enhanced vagal modulation. The data suggest a closed loop afferent/efferent circuitry wherein tonic visceral afferent impulses appear to elicit a phasic or modulatory vago-efferent cardiac response in healthy subjects.