Editor’s note: Laura Sirucek is a PhD student of Petra Schweinhardt in the Integrative Spinal Research Group, University of Zurich, Switzerland, where she investigates chronic pain using brain imaging methods and psychophysical assessments. Recently, Schweinhardt’s group held a journal club discussion about recent research by Kim and colleagues published in the July 2019 issue of PAIN. PRF thanks Laura for submitting the following summary of the conversation. Please consider continuing the discussion by logging in and leaving a comment below.
A large body of research links chronic pain to altered functional brain connectivity. Still, very little is known about whether these functional connectivity changes relate to clinical pain characteristics, and if so, how. Recently, Kim and colleagues (Kim et al., 2019) presented new evidence for an encoding of clinical pain intensity via functional cross-network connectivity changes, using a novel methodological approach.
In their study, the authors focused on the cross-network connectivity between the salience network (SN), default mode network (DMN), and sensorimotor network in chronic low back pain patients. While the SN and DMN were identified using a common dual-regression independent component analysis, Kim and colleagues used an innovative approach to define the somatosensory region of interest.
Briefly, in addition to a resting-state functional magnetic resonance imaging (fMRI) session to investigate functional connectivity patterns, participants underwent a different session with task fMRI, during which experimental pain was provoked. The task fMRI session served to localize the representation in the primary somatosensory cortex (S1) for the body area related to the pain pathology, the lower back. Painful and non-painful electrical stimuli were applied to the lower back and two control locations (finger and face; the face location was drawn from a previous fMRI study [Moulton et al., 2009]) and the difference maps were used to localize S1 representations for nociceptive afferents. The hereby-identified regions were used as seeds for subsequent connectivity analyses with the SN and DMN.
The main findings were that the back-specific S1 region showed increased connectivity to the SN and to the DMN compared to healthy controls. Furthermore, within the chronic low back pain cohort, pain exacerbation exercises led to increased back-specific S1 connectivity to the SN, but decreased connectivity to the DMN. Importantly, these changes in connectivity patterns were greater for patients with larger changes in pain intensity after the exercises. The two control S1 regions (finger and face) were investigated regarding their connectivity to the SN and showed no differences between chronic low back pain patients and healthy controls.
Nociceptive signals ascend to the cortical targets of the spinothalamic tract such as the insular cortex, medial operculum, anterior cingulate cortex, and S1, subsequently spreading to higher-order brain regions. It is conceivable that if functional changes occur in the brain of chronic pain patients, they might happen between the nodes that are permanently activated by ascending noxious input. Therefore, the idea of Kim and colleagues to investigate the connectivity of S1 as an important target of somatotopically specific nociceptive input to other brain areas or networks is a novel and interesting approach.
Considering the promising methodological approach by Kim and colleagues, a few points merit discussion.
One aspect concerns the choice of S1 as a seed area. Based on tract-tracing evidence in non-human primates (Dum et al., 2009), only a small percentage of spinothalamic fibers ascends to the S1, while the majority projects to the posterior insula, the medial operculum, and the cingulate cortex. Further, the operculo-insular region has other potentially important characteristics such as the generation of pain upon electrical stimulation (Mazzola et al., 2012), which S1 lacks. Nevertheless, functional and structural plasticity in S1 is consistently reported in chronic pain patients (reviewed in Kim et al., 2017), implying an involvement of both the operculo-insular region and S1 in chronic pain. Whether alterations in the operculo-insular region or the S1 are more important for the development and/or maintenance of chronic pain remains unclear and is a subject for further investigation. In fact, it is currently unknown to what extent observed alterations in the operculo-insular region as well as S1 are causally related to chronic pain or whether they constitute epiphenomena.
Another aspect is the question of how well the identified back-specific S1 area fits the assumption of representing somatotopically the patients’ clinical pain. First, the applied electrical stimulus activates superficial nociceptive afferents. In chronic low back pain, however, deep somatic afferents are likely to play a more important role compared to superficial afferents. Little is known about the somatosensory cortical representations of deep somatic fibers compared to superficial fibers, but they are not necessarily identical, as observed in differences between somatosensory-evoked potentials from deep and superficial radial nerves in monkeys (Yamada et al., 2016).
Second, the electrical stimulus was administered at the right erector spinae muscles for all patients. Of course, the stimulus location needs to be standardized in order to perform group-level analyses. Nevertheless, it would have been interesting to see whether the patients did indeed have clinical pain in the stimulated area. Further, more detailed information regarding the stimulated spinal segment would be of interest to the reader. Since the original work by Penfield and Rasmussen (The Cerebral Cortex of Man, The Macmillan Company, New York, NY, 1950) and the resulting somatosensory homunculus, the whole trunk between the shoulder and the hips became associated with one single region in the S1, without any further somatotopic subdivisions. Despite this historically grown assumption, it is possible that different spinal segments of the low back are represented at different subregions in the trunk-specific S1 area, similar to the hand with its individual digits (Roux et al., 2018) but on a smaller scale.
Admittedly, the spatial resolution of fMRI may not be sufficient to detect minor variations in cortical localization. Still, if the intent is to link the investigated brain area to the patients’ pain, this aspect needs to be considered for appropriate interpretation of the results.
Last, the identified positive association between the change in back-specific S1-SN connectivity and change in pain intensity after pain exacerbation is very interesting. However, there seems to be a great portion of variance left over that is not accounted for by the exercise-induced change in back pain intensity. Is it possible that clinical pain characteristics other than pain intensity would help to explain the observed variability? In the end, clinical pain presentations are multifaceted, and research should start accounting for this diversity. Thorough pain characterization should be implemented in upcoming studies and analyses. This way, exploratory studies can pave the way to directed hypothesis-driven follow-up studies, slowly disentangling the effects of different clinical pain characteristics on functional connectivity patterns.
Laura Sirucek is a PhD student in the Integrative Spinal Research Group, University of Zurich, Switzerland.
Leave a comment below.
