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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; P = 0.007]. Median latency to the first negative peak was 142 (±24) ms in subjects compared with 116 (±15) ms in controls (P = 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.
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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.
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, P < 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 (n = 11)||RH (n = 13)|| P |
|Age||33 (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 sensation||34 (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 sensation||9 (3–29)||26 (5–59)|| 0.008 |
|Pain threshold||24 (10–55)||59 (23–80)*|| 0.007 |
|Maximum tolerated||44 (14–80)*||80 (32–80)*||0.05|
|Sensation to peripheral electrical stimulation (mA)|
|Perception threshold||2.3 (0.7–3)||2.3 (1.2–3.4)||0.283|
|Motor threshold||7.4 (4.2–9.6)||6.1 (4.3–11.5)||0.27|
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: P = 0.016; defecatory desire volume: P = <0.0001; maximal tolerable volume: P = <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: P = 0.008; pain threshold: P = 0.007; maximal tolerable sensation: P = 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 (n = 6 vs n = 0; P = 0.01).
Somatosensory evoked potentials
There were no differences between somatosensory EP morphology, latency (both groups had a first peak at 13.5 msec, P = 0.5), and amplitude (first peak 1.0 μV in patients, vs 1.3 μV; P = 0.1; Table 2).
Table 2. Somatosensory evoked potential latencies and amplitudes
| ||HV Mean (SD)||RH Mean (SD)|| P |
|Peak latency (ms)|
|P14||13.5 ± 0.9||13.5 ± 0.7||0.5|
|N20||19.7 ± 1.3||19.2 ± 0.6||0.2|
|Peak amplitude (μV)|
|P14||1.3 ± 1.3||1.0 ± 0.4||0.1|
|N20||1.8 ± 1.3||1.7 ± 0.6||1.0|
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.
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 (P = 0.004). There was a tendency to a delay in P2 component (P = 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; P = 0.004). The latencies of the P1 component were similar, but there was a tendency to a delay in the P2 component (P = 0.07). (Fig. 1, Table 3). When patients who did not reach pain threshold (n = 4) were excluded from analysis, there remained a trend toward delayed N1 latency (132 ms vs 116 ms, P = 0.08).
Table 3. Comparison of rectal evoked potential latencies and amplitudes between study groups
| ||HV Mean (±SD)||RH Mean (±SD)|| P |
|Peak latency (ms)|
|P1*||65 ± 13||78 ± 18||0.1|
|N1||116 ± 15||142 ± 24|| 0.004 |
|P2||227 ± 31||250 ± 28||0.07|
|Baseline–P1||1.2 ± 0.8||3.3 ± 2.7||0.05|
|P1–N1||4.5 ± 3.0||4.9 ± 3.0||0.7|
|N1–P2||12 ± 4.6||13.9 ± 9.4||0.6|
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; P = 0.05). No other differences in peak-to-peak amplitudes were observed.
The topographic pattern of activity was similar between and within groups (P = 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).
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.
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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.
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).
Heterogeneity exists within the patient group in this pilot study. Consistent with earlier work,59 it was found that a small number of patients (n = 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.
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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.