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Keywords:

  • constipation;
  • cortical processing;
  • electroencephalography;
  • inverse modeling;
  • rectal evoked potentials;
  • rectal hyposensitivity

Abstract

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Conclusions
  7. Funding
  8. Disclosure
  9. Contributors
  10. References

Background  Blunted rectal sensation (rectal hyposensitivity: RH) is present in almost one-quarter of patients with chronic constipation. The mechanisms of its development are not fully understood, but in a proportion, afferent dysfunction is likely. To determine if, in patients with RH, alteration of rectal sensory pathways exists, rectal evoked potentials (EPs) and inverse modeling of cortical dipoles were examined.

Methods  Rectal EPs (64 channels) were recorded in 13 patients with constipation and RH (elevated thresholds to balloon distension) and 11 healthy controls, in response to electrical stimulation of the rectum at 10 cm from the anal verge using a bipolar stimulating electrode. Stimuli were delivered at pain threshold. Evoked potential peak latencies and amplitudes were analyzed, and inverse modeling was performed on traces obtained to determine the location of cortical generators.

Key Results  Pain threshold was higher in patients than controls [median 59 (range 23–80) mA vs 24 (10–55) mA; = 0.007]. Median latency to the first negative peak was 142 (±24) ms in subjects compared with 116 (±15) ms in controls (= 0.004). There was no difference in topographic analysis of EPs or location of cortical activity demonstrated by inverse modeling between groups.

Conclusions & Inferences  This study is the first showing objective evidence of alteration in the rectal afferent pathway of individuals with RH and constipation. Prolonged latencies suggest a primary defect in sensory neuronal function, while cerebral processing of visceral sensory information appears normal.

Constipation is a common condition affecting 14% of community dwelling adults,1 predominantly females.2 It causes significant social and psychological disability, consuming considerable health resources,3–5 and its management is compromised by limited effectiveness of current treatments.6 Increased understanding of the processes underlying symptom generation is fundamental for developing more focused therapies.

Traditionally, the principal mechanisms underlying chronic constipation have been considered as colonic dysmotility and rectal evacuatory dysfunction, although considerable overlap is recognized.5 However, integrity of sensory function is also fundamental to the process of defecation.7,8 Impaired/blunted rectal sensation is termed rectal hyposensitivity (RH), clinically defined as elevated perception thresholds to rectal balloon distension.9 Rectal hyposensitivity is found in almost one-quarter of adults10 and two-thirds of children with chronic constipation.11 Alteration in rectal sensation may be allied to loss or attenuation of the call to stool; indeed RH may be the only discernible physiological abnormality on comprehensive testing, suggesting that sensory impairment may be an important mechanism in symptom generation.10

Complete understanding of the mechanisms involved in the development of RH is currently lacking. Although first recorded in patients with spinal transection/trauma,12 suggesting possible neuronal dysfunction, it is also frequently seen in patients without overt spinal cord injury. Recent studies13 indicate that RH may be due either to the impairment of rectal afferent function, the presence of altered rectal wall biomechanics (e.g. increased capacity or compliance) or a combination of both. In those with presumed afferent dysfunction without clinical explanation, the level at which pathology occurs (i.e. receptor/peripheral nerve/spinal pathways/central processing) remains unknown.

Somatosensory evoked potentials are a widely used neurophysiological tool to investigate afferent neuronal function14,15; however, the use of visceral evoked potentials in clinical research is still evolving. The technique has been assessed extensively in healthy volunteer studies,15–19 and more recently used to demonstrate changes in afferent neuronal function in patients with visceral hypersensitivity and irritable bowel syndrome20,21 and also in childhood chronic constipation.22,23 In addition to yielding information regarding conduction velocity and response amplitude, spatial localization of brain generators (dipole sources) can be extrapolated via analysis using “inverse modeling” of recorded data.24,25 This allows estimation of pathways taken by the neuronal impulse as it moves through higher cerebral centers. This form of mathematical modeling has been validated in healthy volunteers,24 patients with irritable bowel syndrome,26 and patients with chronic abdominal pain,27 but has yet to be employed in constipated patients.

By using somatic and visceral evoked potentials, and modeling of spatiotemporal processing of cortical information, this exploratory pilot study aimed to confirm that in patients with constipation allied to blunted rectal perception (RH), the impairment of sensory function is secondary to an alteration in peripheral/spinal afferent neuronal function or central processing.

Methods

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Conclusions
  7. Funding
  8. Disclosure
  9. Contributors
  10. References

Ethics and consent

The study was performed at the Academic Surgical Unit (GI Physiology Unit), Barts and the London School of Medicine and Dentistry, UK, and the Department of Gastroenterology, Aalborg Hospital, Denmark. Approval was granted by local research ethics committees in both the UK and Denmark prior to recruitment (Ethics committee reference codes 10/H0704/11 and N-20090008 respectively). Before participation, individuals were given full information about the study, and written consent was obtained.

Subjects

Healthy volunteers  Thirteen healthy volunteers (nine female, median age 35, range 20–62) were recruited at both sites via advertisement. Subjects were excluded if there was any history of gastrointestinal (GI) disease, symptoms of GI dysfunction at the time of the study, or if they were taking medications known to affect GI function. One healthy volunteer was taking ramipril for hypertension; the remainder were not taking any medications.

Patients  Seventeen patients with constipation and RH (all female, median age 46, range 20–62) were recruited from those who had previously undergone anorectal physiological investigation during their clinical diagnostic workup within the GI Physiology Unit (London). As part of this clinical examination, rectal sensory testing to simple balloon distension was performed, by inflating a latex balloon, mounted upon a Foley catheter placed 10 cm above the anal verge, with air at a rate of 1 mL sec−1.28 Rectal hyposensitivity was defined as elevation of two or more sensory thresholds above the normal ranges (unit normal data derived from 50 female and 41 male healthy controls: female/male = first constant sensation <110/150 mLs; defecatory desire volume <200/190 mLs; maximal tolerable volume <290/330 mLs29,30). All patients reported symptoms of chronic constipation, and fulfilled criteria for functional constipation.31 Patients with a history of anorectal surgery, rectal prolapse, systemic neurological disease, significant back injury, spinal surgery, or chronic medical conditions associated with peripheral neuropathy were excluded, as were pregnant women. Patients with an organic or secondary cause for constipation (i.e. medications, bowel malignancy, electrolyte disturbance or diagnosed neurogenic cause) were also excluded. Patients were allowed to continue their standard laxatives. Two patients were taking oral bisacodyl, two senna, two polyethylene glycol, two glycerine suppositories, one flaxseed, one weekly sodium picosulfate/magnesium citrate and one patient was taking prucalopride and domperidone. One patient was taking fluoxetine as an antidepressant.

All healthy volunteers underwent rectal sensory function testing (as above), and were not included if the results fell outside the normal range.

Experimental protocol

GI symptoms were assessed via practitioner-directed history, validated comprehensive bowel symptom questionnaire,28 and Cleveland Clinic constipation score32 (score 0 = no constipation symptoms, 30 = severe constipation symptoms). All subjects underwent a full neurological examination to exclude overt neurological disease. Digital rectal examination was performed to ensure an empty rectum and if significant stool was present, a warm 120 mL tap water enema was administered to aid rectal emptying. Rectal sensation to electrical stimulation was determined using a previously validated stimulation device33 (GMC ApS, Hornslet, Denmark). The stimulator contained two stainless steel electrodes mounted at the tip, with an inter-electrode distance of 2 mm, connected to a computer-controlled constant-current stimulator (IES 230; JNI Biomedical ApS, Klarup, Denmark). The subject was positioned in the left lateral position and the probe was advanced through the anus with the tip placed 10 cm from the anal verge and was secured to the buttock using adhesive tape to avoid movement. An upper safety limit of 80 mA was set.

Prior to experimental stimulations, subjects were instructed to report: “first sensation”, the point at which a definite sensation was experienced; “pain threshold”, the intensity at which the stimulus became uncomfortable; and “maximally tolerated sensation”, the intensity at which the stimulus was unable to be tolerated and the patient requested to stop.

Evoked potentials

Electroencephalograph (EEG) signals were recorded from 64 electrodes using the extended 10–20 system montage (Quick-Cap International, Neuroscan, Charlotte, NC, USA). The cap was placed in a standardized position, with the center of the anterior border 4 cm above the nasium. Electro-conductive gel (ECI Electro Gel, Electro Cap International, Easton, OH, USA) was applied to each electrode ensuring good contact between electrodes and scalp. Inter-electrode impedances were monitored and kept below 10 kΩ at all sites. Recordings were obtained in a darkened room with unnecessary electrical equipment turned off to avoid electromagnetic interference. Subjects were requested to lie relaxed with their eyes closed. Evoked potentials were recorded with open online filters and stored offline for analysis.

Prior to rectal evoked potential acquisition, median nerve somatosensory evoked potentials were recorded. Stimuli were delivered using two surface electrodes 2.5 cm apart, placed on the radial border of the volar aspect of the non-dominant forearm, 1 cm from the wrist crease. Stimuli were delivered at an intensity that evoked twitching of the thenar or flexor digitorum muscles (indicating electrical stimulation of the median nerve). Five hundred electrical stimuli were applied with square wave pulse of 0.2 ms duration at a frequency of 2 Hz.

Rectal evoked potentials were then recorded. Impedance between the electrodes was maintained below 3 kΩ. If impedance was >3 kΩ, or the subject did not report a perception of intra-rectal stimulation, a latex balloon mounted on a catheter was placed aside the electrode and inflated to 10 mLs below sensation threshold to ensure good electrode apposition to the rectal wall. Recordings were obtained under the same conditions as somatosensory recordings. As a large variation between sensory thresholds in patients and controls was expected, precluding the use of a standardized value, stimulus intensity was individualized and delivered at the subjects’ pain threshold.24,34 This threshold was chosen in preference to maximal tolerable sensation (as used in some studies15,18,35), as, given the patients’ known hyposensitivity, it was predicted that MTS would not be reached in a proportion within the preset safety limit. Four sets of 50 electrical stimuli were applied with square wave pulse of 0.2 ms duration at a frequency of 0.2 Hz. Patients were asked to describe the location and sensation experienced during the stimulations.

Evoked potential preprocessing

All preprocessing was performed via neuroscan software (Neuroscan version 4.3.1; Neuroscan). For each of the four trials, data were band-pass filtered between 0.5 and 200 Hz and epoched to 50 ms before, until 350 ms after the stimulus onset. Epochs contaminated by eye movement were manually rejected. The remaining “clean” epochs were averaged. The best average trace of the four sets of stimuli was re-referenced to a linked ear reference for final analysis.

Evoked potential analysis

Analysis of EP latencies and amplitudes was performed from the central electrode (Cz). Peak amplitudes were consistently greatest at this electrode, in line with previously published literature.15 Peak latencies were determined as the time (ms) from stimulus to the mid-point of that peak. Peak amplitude was determined by peak-to-peak analysis.

Inverse modeling and topographical analysis

The EP analysis was guided by simultaneous topographic mapping based on spline interpolation,36 which shows scalp distribution derived from all electrodes simultaneously. Topographical analysis was completed using the neuroscan software, and dipolar source modeling was performed using brain electrical source analysis (BESA) software (BESA Research 5.3, MEGIS Software GmbH, Gräfelfing, Germany). Brain electrical source analysis uses evoked potential data to calculate potential voltage distributions over the scalp, and evaluates agreement between recorded and calculated field distributions to determine spatiotemporal activation of the brain in response to the stimuli. The percentage of data that cannot be explained by the model is expressed as residual variance (RV). A RV of less than 10% is considered to be a good fit.37

Grand mean data for each group were used for dipole source analysis. Current density analysis (SW-LORETA algorithm)38 was employed to guide inverse modeling. LORETA is a current density method yielding blurred source images. The advantage of LORETA is that no a priori constraints regarding the number or location of sources are required. Its accuracy has been proven high.38 Symmetric constraints were applied to the bilateral sources based on symmetry assumption between the two hemispheres. The latency interval from 40 ms prestimulus to 350 ms was used for analysis.

Statistical analysis

Descriptive statistics are reported as median (range), or mean (SD), where appropriate. Perceptual thresholds were analyzed using Mann–Whitney U test. Evoked potential peak data were compared by analysis of variance (anova). Contingency tables were analyzed using Fishers exact test. A P value of <0.05 was considered statistically significant.

Results

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Conclusions
  7. Funding
  8. Disclosure
  9. Contributors
  10. References

All subjects underwent all tests without complication. However, four patients and two healthy volunteers were excluded from analysis, as a clear EP trace was unable to be recorded. The study cohort therefore comprised of 11 HV (nine female, median age 33, range 20–62) and 13 RH (all female, median age 46, range 20–62). A tap water enema was administered to two patients. Five patients and one healthy volunteer required the placement of an intra-rectal balloon inflated to subsensory volume to optimize electrode-mucosa contact. All patients and volunteers had a normal neurological examination.

Clinical assessment

Symptom severity scores confirmed the presence of constipation in all patients with a median Cleveland constipation score of 14 (range 9–23). All healthy volunteers reported scores of less than five (Table 1, < 0.001), and denied any history of constipation.

Table 1. Comparison of clinical and sensory data between patients with constipation and rectal hyposensitivity (RH) and healthy volunteers (HV)
 HV (= 11)RH (= 13) P
  1. Values are given as median (range).

  2. #balloon was not inflated beyond 360 mL; *upper safety limit of electrical stimulation = 80 mA

Demographics
Gender (female)9130.19
Age33 (20–62)46 (20–62)0.24
Constipation  symptom severity
Cleveland clinic constipation score(32)3 (0–5)14 (9–23) <0.0001
Sensation to balloon distension (mLs)
First constant sensation34 (12–85)120 (30–230) 0.016
Defecatory desire volume#82 (57–146)270 (210–360) <0.0001
Maximum tolerated volume#170 (99–290)300 (255–360) <0.0002
Sensation to rectal electrical stimulation (mA)
First sensation9 (3–29)26 (5–59) 0.008
Pain threshold24 (10–55)59 (23–80)* 0.007
Maximum tolerated44 (14–80)*80 (32–80)*0.05
Sensation to peripheral electrical stimulation (mA)
Perception threshold2.3 (0.7–3)2.3 (1.2–3.4)0.283
Motor threshold7.4 (4.2–9.6)6.1 (4.3–11.5)0.27

Sensory assessment

Somatic  Sensory thresholds to peripheral electrical stimulation at the median nerve were similar between the two groups, as was the motor threshold (Table 1).

Rectal  All healthy volunteers had normal sensory thresholds to balloon distension. As expected, sensory thresholds were significantly higher in patients with RH (first constant sensation: = 0.016; defecatory desire volume: = <0.0001; maximal tolerable volume: = <0.0002) with all median values outside of departmental normal ranges (Table 1).

Sensory thresholds to rectal electrical stimulation were also significantly higher in the patient group (Table 1, first sensation: = 0.008; pain threshold: = 0.007; maximal tolerable sensation: = 0.05). In four patients, pain threshold was not reached at the preset stimulation limit of 80 mA, and in three patients, maximum tolerable threshold was not reached. All healthy volunteers described pain threshold, but two did not reach maximum tolerable sensation. Patients, in contrast with healthy volunteers, also described aberrant sensation, more commonly noting referred sensation to the legs/abdomen or obvious pelvic floor/anal sphincter contractions before pain threshold was reached (= 6 vs n = 0; = 0.01).

Somatosensory evoked potentials

There were no differences between somatosensory EP morphology, latency (both groups had a first peak at 13.5 msec, = 0.5), and amplitude (first peak 1.0 μV in patients, vs 1.3 μV; = 0.1; Table 2).

Table 2. Somatosensory evoked potential latencies and amplitudes
 HV Mean (SD)RH Mean (SD) P
  1. Values are given as mean (±SD).

Peak latency (ms)
P1413.5 ± 0.913.5 ± 0.70.5
N2019.7 ± 1.319.2 ± 0.60.2
Peak amplitude (μV)
P141.3 ± 1.31.0 ± 0.40.1
N201.8 ± 1.31.7 ± 0.61.0

Rectal evoked potential analysis

Morphology  In nine patients and nine healthy volunteers, the classical triphasic EP morphology15,18 was seen consisting of a P1 peak, followed by N1 and P2 peaks (see Fig. 1). In four patients and two healthy volunteers, the P1 component was not identified.

image

Figure 1.  Evoked potential traces to rectal electrostimulation. Grand mean traces for constipated patients with rectal hyposensitivity (black line) and healthy volunteers (gray line) are shown. The N1 component was significantly prolonged within the patient group (= 0.004). There was a tendency to a delay in P2 component (= 0.07).

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Latency  The latency of N1 was significantly delayed in RH patients in comparison to healthy volunteers (142 ± 24 vs 116 ± 15 ms; = 0.004). The latencies of the P1 component were similar, but there was a tendency to a delay in the P2 component (= 0.07). (Fig. 1, Table 3). When patients who did not reach pain threshold (= 4) were excluded from analysis, there remained a trend toward delayed N1 latency (132 ms vs 116 ms, = 0.08).

Table 3. Comparison of rectal evoked potential latencies and amplitudes between study groups
 HV Mean (±SD)RH Mean (±SD) P
  1. Values are given as mean (±SD).

  2. *P1 peaks observed in 9 of 11 healthy volunteers and 9 of 13 patients only.

Peak latency (ms)
P1*65 ± 1378 ± 180.1
N1116 ± 15142 ± 24 0.004
P2227 ± 31250 ± 280.07
Peak amplitude(μV)
Baseline–P11.2 ± 0.83.3 ± 2.70.05
P1–N14.5 ± 3.04.9 ± 3.00.7
N1–P212 ± 4.613.9 ± 9.40.6

Amplitude  Results are presented in Table 3. The P1 amplitude in patients tended to be of greater magnitude than that in controls (3.3 ± 2.7 μV vs 1.2 ± 0.8 μV; = 0.05). No other differences in peak-to-peak amplitudes were observed.

Topographical analysis

The topographic pattern of activity was similar between and within groups (= 0.5). The P1 component, when evident, was displayed bilaterally in the temporal areas, the N1 component was displayed in the temporal area and also centrally, and the later P2 component centrally (Fig. 2A).

image

Figure 2.  Source localization results: (A) two distinct LORETA solutions for the evoked potential at time points where LORETA current density was the highest. These solutions likely represent upper Sylvian fissure (SII), lower Sylvian fissure (insula), and activity around the central cingulate cortex. (B) The BESA model based on the grand-mean. Dipolar sources are shown to the right and the waveforms to the left show the source activity over time. Colors of the waveforms correspond to colors of dipolar sources: red – cingulate cortex; blue – insula; green – secondary somatosensory cortex. The box over the waveforms is the time interval under analysis.

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Dipole source modeling

In both patients and healthy volunteers, brain activity was localized bilaterally within the opercular regions (SII and insula) and the mid cingulate gyrus (Fig. 2B). While there appeared to be no differences in cortical activation between groups, a delay in EP latency in patients was seen. Residual variance was 6.4% in the healthy volunteer model and 7.2% in the patient group.

Discussion

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Conclusions
  7. Funding
  8. Disclosure
  9. Contributors
  10. References

Rectal hyposensitivity (RH) is associated with hindgut dysfunction10; however, the pathophysiology of impaired sensation remains unknown. One possible mechanism is that RH is secondary to afferent nerve dysfunction, with the site of this defect potentially occurring anywhere from the receptor level to the cerebral cortex. This pilot study is the first to provide direct evidence of altered visceral nerve transmission in adult constipated patients, as evidenced by delayed EP latencies.

We believe that the current study is unique in helping to elucidate the localization of the proposed afferent pathway defect. Electrical stimulation bypasses end-organ receptors and directly stimulates neuronal axons. Therefore, any changes seen in evoked potential latencies are not an effect of aberrant receptor function alone (although a concurrent receptor defect cannot be excluded), but suggests abnormal peripheral or central nerve conduction. Subsequent modeling of cortical activity using inverse modeling of the EP data indicated that there were no differences in areas of cortical activation, only a temporal delay. This has potential clinical implications as, unlike patients with irritable bowel syndrome, who have been shown to have altered cortical processing in inverse modeling and function brain imaging studies,26,39–41 these patients may be less likely to benefit from psychoemotional therapeutic interventions designed to influence cortical function. The finding of similar peak latencies recorded from median nerve EPs suggests that the neurological dysfunction is an isolated visceral phenomenon and not a generalized defect of sensory function.

Comparison with previous studies

Previously, EPs have been established in healthy control studies to be effective in measuring the integrity of the afferent nerve supply to the bowel, providing robust and temporally reproducible data.15,18,19,42 In the current study, traces were obtained with similar morphologies to those recorded in prior studies,15,42 with latencies at N1 and P2 within the ranges previously reported in healthy volunteers, although the amplitude of each peak was somewhat reduced. This may be a consequence of pain threshold, rather than maximal tolerated sensation being used to evoke the cortical potentials in this study. With regard to the patient group, only one prior study (published in abstract form only) has used a similar technique and reported cortical evoked potentials in patients with constipation allied to dyssynergic defecation.43 Similar results were found to those presented here, with increased sensory thresholds and prolonged EP latencies, providing further supportive evidence toward brain-gut axis dysfunction. Unfortunately, patients were not stratified by sensory subtype. A similar study has also been carried out in constipated children with encopresis.22 However, balloon rather than electrical stimulation was used to elicit EPs, and thus direct comparison of latencies is not possible. Nevertheless, that study did also show prolonged EP latencies in comparison to controls, suggesting afferent dysfunction. Rectal sensory status was, again, not reported, although it is recognized that up to two-thirds of chronically constipated children have RH.11

In patients with the irritable bowel syndrome, which is commonly associated with rectal hypersensitivity, a reduction in EP latency has been reported.20,44 This has been hypothesized as due to: increased recruitment of mucosal receptors; earlier activation of afferent fibers; faster neuronal conduction; or altered cortical processing.44 It is possible that the same mechanisms (albeit the inverse) explain the delay in latencies seen in the current study. In our hyposensate patient group, increased EP latencies may be a result of either: receptor dysfunction; reduced activation of afferent nerves; or slowed peripheral neuronal conduction. Damage to the pelvic or spinal nerves as a result of childbirth,45 chronic straining at stool,46 or surgery may perhaps be a contributing factor.8,47 It is also possible that neuronal transmission may be influenced by alterations in cerebral outflow mediated via the extrinsic autonomic nerves.48 Notably, previous studies have suggested that patients with RH have intact spinal reflexes49 as the rectoanal inhibitory reflex, rectoanal contractile response and sensorimotor response are preserved, although higher volumes of rectal distension are required to induce these responses. This suggests that any potential neuronal abnormality lies above the level of the reflex arc, but below the cortex, as we showed no a difference in cortical processing on inverse modeling.

Methodological aspects

There are of course limitations to the techniques used within the study. Most obviously, electrical stimuli may not be considered physiological. The nerve supply to the rectum mostly consists of primary afferents comprising small myelinated A-delta fibers and non-myelinated C-fibers, both of which respond to rectal wall distension. Electrical stimulation results in non-specific activation of these fibers. The advantage of electrical stimulation, however, is that it has a rapid on/off, thus producing better quality EPs than that of balloon distension. The stimulus is also better quantified than balloon distension, which is affected by rectal wall compliance. This is particularly important in patients with RH where altered rectal compliance commonly coexists,13 or indeed may be causative. Finally, the morphology of EPs to electrical stimulation and distension of the rectum is similar, indicating activation of the same fiber population.42

The advantage of evaluating brain signals using EPs is the excellent time resolution, being in the order of milliseconds, compared with fMRI and PET, with time resolutions in the order of seconds. The disadvantage of EPs, however, is their limited spatial resolution. Recent mathematical techniques attempt to overcome this by estimating the brain sources generating the EPs via inverse modeling. In this study, BESA was utilized. The model calculated by BESA is a hypothetical one and does not exclude other solutions, but nevertheless, it can be validated when applied to individual data and is consistent with anatomical and physiological knowledge of identified source areas.50 Indeed, our inverse model fits with what has previously been found in the visceral evoked potential literature.24

There is controversy as to the appropriate stimulation point within the rectum. In this study, to ensure the rectum (and not sigmoid colon) was being stimulated, the probe was placed at 10 cm. This is consistent with a recent study, using electrodes attached to the rectal wall, which found the optimal stimulating distance to be between 8 and 16 cm16 from the anal verge. Stimulation of the mid to upper rectum should preclude any involvement of the somatic nerves as Chan et al.51 showed that the pudendal nerve does not innervate the distal rectum until a level well below our site of stimulation. As with some,27,52 but not all17 studies, we recorded triphasic or biphasic waveforms in both groups with onsets of 65 ± 13 ms for healthy controls and 78 ± 18 ms for the patients. This corresponds to previous findings,15,18,27 and in contrast with Loening-Baucke et al.,17 who reported an “early onset” multiphasic EP (20–30 ms: proposed to relate to the activation of somatosensory nerves), indicates that only visceral nerves were activated. Also consistent with other studies,15,42 P1 at the vertex was not observed in all subjects (absent in 31% of patients and 18% of healthy volunteers). This finding may be secondary to the analysis techniques utilized, as P1 is more easily seen in temporal electrodes.

Stimulation intensity also remains controversial. In this study, patients and volunteers were stimulated at pain threshold. This is a subjective measure, resulting in individualized stimulation intensities, and is consistent with all previous literature establishing visceral EPs in humans as an investigative technique.15,17,20,24,26,34,35,42,53 Nevertheless, it is appreciated that such an approach relies on the assumption that two individuals experience the same quality of sensation (although at different stimulation intensities), and it is known that visceral sensation is, of course, affected by mood, stress levels etc.54–58 However, standardizing an optimal stimulation intensity was not possible, as the mean pain threshold in patients was greater than that of the maximal tolerable sensation of healthy volunteers. Conversely, the intensity required to stimulate pain in our healthy subjects would have been subsensory in almost 50% of the patients with RH. Use of individualized stimulation intensity was thus considered valid (although is accepted as an unavoidable limitation of the investigative technique).

Subjects

Heterogeneity exists within the patient group in this pilot study. Consistent with earlier work,59 it was found that a small number of patients (= 4) did not have elevated electrical thresholds despite elevated balloon distension volumes. In these patients, altered biomechanics of the rectal wall would likely account for the finding of hyposensitivity to simple balloon distension. It would be expected therefore that recorded EP latencies in these subjects would be similar to healthy controls and indeed there was a trend toward this. However, the sample size was too small for it to be substantiated.

Also, despite attempts to avoid variation in stimulation intensity by using the individualized pain threshold, four patients did not reach this level by the previously set safety cutoff, and thus EPs were recorded at lower subjective intensity than in healthy individuals. This may provide an alternative explanation for the finding of delayed EP latencies in the RH group. Prior studies show, as subjective appreciation of the intensity of stimulation increases, EP latency decreases.35 Nevertheless, when patients not stimulated at pain threshold were excluded from analysis, there remained a clear trend toward a delay in EP latency.

Patients were also more likely to report aberrant sensations (i.e. referred sensation or anal motor contraction) in response to rectal stimulation. This may be due to the higher stimulus intensity required in patients than volunteers, which would increase the field of stimulation, perhaps recruiting nerves lying outside the rectum before rectal thresholds were reached. While this raises the possibility that somatic nerves were also stimulated in these individuals, this should not influence the outcome of the study. Somatosensory evoked potentials from the lower limb or pelvis are usually detected within a time frame of 60 ms17,60,61 whereas onset of visceral evoked potentials tends to be found beyond this point.15,18

Future implications for research

This study highlights the need for more detailed studies examining visceral afferent pathways in patients with constipation. Particularly, our knowledge of the clinical impact of RH and its role in the development of constipation requires further work. Future studies should focus on examining the neuronal pathways in patients with RH and elevated electrosensory thresholds in whom rectal biomechanics (as measured by the barostat) are normal, compared with those with normal electrosensory thresholds, but abnormal biomechanics. In addition, constipated patients with RH should be compared to a group of similarly constipated individuals with normal rectal sensation to balloon distension. To these ends, a study within our unit is ongoing.

Conclusions

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Conclusions
  7. Funding
  8. Disclosure
  9. Contributors
  10. References

This exploratory mechanistic study is the first to provide evidence of impairment of visceral nerve function in patients with constipation and RH. Prolonged peak latencies in such patients suggest defective neuronal conduction, while cerebral cortical processing of visceral sensory information seems normal. This adds further weight to the hypothesis that afferent nerve dysfunction is important in the development of functional hindgut disorders.

Funding

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Conclusions
  7. Funding
  8. Disclosure
  9. Contributors
  10. References

This work was internally funded by the GI Physiology Unit, Queen Mary, University of London, the Obel Family Foundation and Christian og Ottilia Brorsons rejselegat.

Contributors

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Conclusions
  7. Funding
  8. Disclosure
  9. Contributors
  10. References

RB assisted in experimental design, collected data, analyzed data and contributed to the manuscript and was involved in data interpretation; EC collected data and contributed to the manuscript; DL collected data, analyzed data, assisted in data interpretation and contributed to the manuscript; SO analyzed EP data; SS contributed toward the conduct of the study, contributed to the manuscript and data interpretation; AD contributed to the conduct of the study, was involved in the manuscript and data interpretation; PL contributed to the conduct of the study, was involved in manuscript and data interpretation; SMS assisted in experimental design, contributed to the conduct of the study, contributed to the manuscript and data interpretation.

References

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Conclusions
  7. Funding
  8. Disclosure
  9. Contributors
  10. References