Differences in activation of endogenous noxious inhibitory pathways were clearly demonstrated between healthy controls and subgroups of IBS patients using a validated method of counterirritation during rectal distension pain. This was evident in clinical pain measures as well as in brain activation by fMRI. Additionally, previously reported differences in brain activation during visceral pain between IBS patients and controls were corroborated and extended.16,24–26,32
Marked group differences in pain processing between IBS patients with diarrhoea and constipation were shown for the first time.
Noxious input underlies multiple endogenous regulatory mechanisms at the spinal and supraspinal levels, which can be both facilitatory and inhibitory. Major modulation of pain perception is coordinated in the PAG-RVM network, with extensive input from the limbic forebrain, diencephalon and brainstem, and the spino-bulbo-spinal DNIC pathway.33
DNIC is a potent source of endogenous analgesia, which has, for example, been shown to be abnormal in fibromyalgia.17,18
Dysfunction in modulatory pathways has also been hypothesised in IBS but has yet to be demonstrated.8,13,16
Assessment of DNIC using the counterirritation technique is well validated and widespread in pain research. DNIC activation is quantified by perceptual modulation of a painful stimulus by a secondary heterotopically applied nociceptive stimulus and has been shown to be distinct from distraction.14,15,17–22,34,35
DNIC is thought to rely on spino-bulbo-spinal loops with minimal input from the PAG-RVM or other supraspinal pathways.15,36,37
In the current study, heterotopic ice water stimulation predictably decreased rectal pain intensity in healthy controls, indicating effective activation of inhibitory pathways. Concurrent changes in cerebral blood flow in the forebrain, diencephalon, and limbic areas were demonstrated, indicating coactivation of supraspinal, possibly PAG-RVM, pathways. Major changes in activation during heterotopic stimulation were seen in the anterior cingulate cortex (ACC, Brodman 24’ and 32’), the insular cortex, and the prefrontal cortex, which have extensive connections to the PAG and RVM.15,38
Diminished activation during heterotopic stimulation in healthy controls in the anterior and posterior insula, the medial thalamus, and the PAG may reflect promotion of inhibitory feedback loops. PAG lies at a crossroads for neural circuits that coordinate rapid and profound somatic, autonomic, and antinociceptive modulation.39
The observed effects are not due to the cold pressor test itself, as all values were baseline corrected.
The absence of a significant inhibitory effect on visceral pain in either IBS subgroup suggests impaired activation of inhibitory controls, and brain activation patterns differed markedly from healthy controls, but also between subgroups. During heterotopic stimulation only IBS-C demonstrated significant activation of the amygdala, hippocampus, and thalamus, and also in the cingulate (Brodman 32’) and prefrontal cortices. IBS-D differed profoundly from IBS-C and controls in only showing decreased activation in the right anterior insula during heterotopic stimulation. The main divergent activations in the IBS subgroups were seen in the brain regions integrating emotions, attention, and cognition, implying dysfunction in the corresponding modulation of nociceptive input. It has been previously proposed by Villanueva et al
, that DNIC may play a physiological role in the detection of nociceptive signals and also constitute both a filter, which allows extraction of the signal for pain, and an amplifier in the transmission system, which increases the potential alarm function of the nociceptive signals.36
Malfunction of this filter would explain several of the postulated sensory disorders in IBS.
Evidence for dysfunction in rectal pain processing without counterirritation has previously been presented in mixed groups of IBS patients.16,24–26,32,40,41
This study corroborates earlier data and adds additional information by separately considering IBS subgroups. In controls, significant bilateral activation compared with baseline was seen during painful rectal stimulation in most of the brain centres classically associated with pain perception and processing, such as the cingulate, insular, prefrontal cortices, the SI and SII regions, the thalamus, and limbic system.42–49
The regions activated are constituents of a complex matrix of connections involved in the primary sensory analysis and secondary integration of emotional, affective, memory, autonomic, and motor responses, as well as feedback and feed-forward regulation of nociceptive stimulation.40,45,50
Activation patterns in the IBS subgroups differed from each other as well as from controls, except for the sensory discriminative SI and SII pain centres, where patterns were similar between all groups, excluding the clear hemispheric lateralisation in both IBS groups. In contrast with healthy controls, both IBS groups showed no significant bilateral activation in the anterior, perigenual cingulate, and prefrontal cortices during painful distension compared with baseline. The absence of ACC activation during rectal pain in IBS patients probably demonstrates a resetting of the gain of the secondary integrative pain processing system and a pre-existing saturation in the entire pain/anxiety network. An analogous seemingly paradoxical absence of cortical activation due to baseline saturation has been observed in other conditions, such as the Gilles de la Tourette syndrome.51
Decreased activation of the ACC has been previously demonstrated in IBS patients where it was interpreted as a diminished antinociceptive response to aversive visceral events, and also in depressed patients.24,52,53
However, in mixed groups of IBS patients, trends to increased activation of the ACC have also been described, emphasising the importance of patient, as well as stimulus selection.25,26,41
In the current study, all patients had significant visceral pain during the study and pain stimulation was individually titrated to similar levels, explaining some discrepancies in imaging data to previous studies. The ACC is a central player in the neural network governing fear and anxiety, otherwise comprised of the amygdala, hippocampus, prefrontal cortex, insular cortex, ventral striatum, and PAG, and also modulates control of arousal and attention and of motor reactions and response selection.54–58
It appears to be critical for integrating chronic pain with memory, allowing full appreciation and evaluation of the meaningfulness of the stimulus in light of previous experience and for integration with autonomic responses and control of hypothalamic stress responses.44,45
Both IBS groups showed deactivation during pain and activation with heterotopic stimulation in the amygdala, and in the hippocampus, which initiates behavioural, autonomic, and endocrine responses to noxious stimuli.26,57,58
This effect was significant in IBS-C and was not observed in healthy controls. Dysfunction in IBS patients in the hypothalamic-pituitary axis is clinically evident in abnormal stress responses.59
Pain related anxiety normally leads to hippocampal activation and correlates with activity in the perigenual ACC and mid-insular regions.60,61
Considerable group differences were seen in thalamic activation. IBS-C showed no increased activation in any thalamic region while IBS-D had increased activity in more nuclei than healthy controls. The majority of nociceptive information entering the brain from the spinal cord is received by nuclei in the thalamus. The anterior thalamic nuclei are closely linked to behavioural, spatial, and memory functions, while the ventral posterior lateral regions and the nucleus gracilis play an important role in the transmission of visceral sensory information and in viscerosomatic convergence and modulation, which are modulated by attentional circuitry.62–64
The intralaminar and medial nuclear complexes are involved mainly in the mediation of long term information about the state of the viscera and of emotional components of viscerosensory impact, including pain.36
Both lateral and medial thalamic nuclei possess neurones encoding pain intensity and most functional imaging studies of acute pain in healthy subjects have demonstrated significant activation in these regions.40,62,63,65
Thalamic activation differences from controls imply aberrant sensory encoding or feedback regulation from cortical and limbic centres in IBS.
Potential weaknesses of this study include, firstly, the small patient numbers due to splitting of the IBS patients into subgroups. However, pooling of the data was deemed inappropriate due to the marked differences between the groups. Highly significant and consistent effects were demonstrated but minor effects may have been insignificant due to inadequate statistical power. The current data need to be confirmed in larger groups of patients. Secondly, manual volume based distensions rather than barostat pressure controlled inflations were used due to difficulties with the use of a barostat in the MRI scanner room. This is unlikely to affect the results as titrations to individual perception levels were performed using a rapid phasic inflation paradigm. Pain threshold volumes were significantly higher in IBS-C than in IBS-D, as has previously been demonstrated for pressure thresholds.66
However, small numbers and the relative insensitivity of volume versus pressure thresholds preclude further speculation. Thirdly, because of the coexistence of inhibitory and excitatory neurones in many of the involved centres, a causal correlation between visualised activations and function is currently not possible using fMRI techniques.
In summary, activation of inhibitory noxious controls by counterirritation in healthy controls activated extensive supraspinal pathways, probably including the PAG-RVM pathways. Constipated and diarrhoeic IBS patients differed significantly from each other and healthy controls in their inappropriate brain activation responses to rectal pain without and with counterirritation. The centres affected were part of the matrix controlling emotional, autonomic, and descending modulatory responses to pain.