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. 2023 May 19;38:103440. doi: 10.1016/j.nicl.2023.103440

Disturbed insular functional connectivity and its clinical implication in patients with complex regional pain syndrome

Jinsol Kim a,1, Eun Namgung b,1, Suji Lee a, Eunji Ha a, Haejin Hong a, Yumi Song a,c, Hyangwon Lee a,c, Sohyun Oh a,c, In Kyoon Lyoo a,c,d, Sujung Yoon a,c,⁎, Hyeonseok Jeong e,⁎
PMCID: PMC10220260  PMID: 37224606

Highlights

  • •

    We examined insular functional connectivity (FC) in patients with CRPS.

  • •

    CRPS patients exhibited lower FC within the bilateral anterior insulae.

  • •

    CRPS patients showed decreased FC between the insular and cognitive control regions.

  • •

    Our findings suggest pivotal roles of the insula in impaired pain processing of CRPS.

Keywords: Complex regional pain syndrome; Insula, functional connectivity; Magnetic resonance imaging

Abstract

Background

Complex regional pain syndrome (CRPS) is characterized by continued amplification of pain intensity. Given the pivotal roles of the insula in the perception and interpretation of pain, we examined insular functional connectivity and its associations with clinical characteristics in patients with CRPS.

Methods

Twenty-one patients with CRPS and 49 healthy controls underwent resting-state functional magnetic resonance imaging. The seed-to-seed functional connectivity analysis was performed for the bilateral insulae and cognitive control regions including the dorsal anterior cingulate cortex (dACC) and bilateral dorsolateral prefrontal cortex (DLPFC) between the two groups. Correlations between altered functional connectivity and clinical characteristics were assessed in CRPS patients.

Results

CRPS patients exhibited lower functional connectivity within the bilateral anterior insulae, between the insular and cognitive control regions (the bilateral anterior/posterior insulae-dACC; the right posterior insula-left DLPFC), as compared with healthy controls at false discovery rate-corrected p < 0.05. In CRPS patients, pain severity was associated negatively with the left–right anterior insular functional connectivity (r = −0.49, p = 0.03), yet positively with the left anterior insula-dACC functional connectivity (r = 0.51, p = 0.02).

Conclusions

CRPS patients showed lower functional connectivity both within the bilateral anterior insulae and between the insular and cognitive control regions. The current findings may suggest pivotal roles of the insula in dysfunctional pain processing of CRPS patients.

1. Introduction

Complex regional pain syndrome (CRPS) is characterized by continued amplification and rumination of pain that is disproportionate and greater to the inciting event (Bruehl, 2015, Bruehl and Warner, 2010). In addition, CRPS critically influences the physical and mental quality of life and overall functioning of those affected (Breivik et al., 2006, Galer et al., 2000). Given its underlying mechanisms related to central hyper-sensitization (Woolf, 2011), it is important to elucidate the brain pathophysiological mechanisms underlying CRPS to develop the prevention and intervention of the disease (Bolwerk et al., 2013, Kim et al., 2018, Otti et al., 2013). Along with growing interest in the brain functional mechanisms, intrinsic functional alterations within and between the somatosensory, salience, attention, and default mode networks have been increasingly reported in neuropathic disorders including CRPS (Bolwerk et al., 2013, Kim et al., 2018, Otti et al., 2013). As such, functional balance between sensory perception, affective-motivational processing, and cognitive control is suggested as the key brain correlates underlying the pathophysiology of CRPS (Bolwerk et al., 2013, Kim et al., 2018, Otti et al., 2013).

Critically, accumulating evidence suggests the pivotal role of the insula in perception and interpretation of chronic pain including CRPS (Baliki et al., 2012, Baliki et al., 2011, Barad et al., 2014, Kim et al., 2017). As an integral hub, the insula is involved in sensory, affective, and cognitive processing of pain by interconnecting to the prefronto-limbic regions (Menon and Uddin, 2010, Namkung et al., 2017). In other words, the insula integrates visceral and somatic pain along with motivational and affective signals, and cognitively guides behavioural actions according to prioritized salient signals (Menon and Uddin, 2010, Namkung et al., 2017). For these functions, the posterior insula engages in discriminating pain sensations (Bushnell et al., 2013, Tan and Kuner, 2021), and afterwards the anterior insula involves in affective-motivational processing of perceived pain sensation (Bastuji et al., 2018).

The insula is also known to be interconnectd with the cognitive control brain regions including the dorsal anterior cingulate cortex (dACC) (Bolwerk et al., 2013, Maihöfner et al., 2005), and dorsolateral prefrontal cortex (DLPFC) (Bolwerk et al., 2013, Bushnell et al., 2013), both of which are critically involved in affective-cognitive processing of pain-related signals. Specifically, the dACC engages in salience detection and attentional monitoring of pain sensation (Heilbronner and Hayden, 2016, Shenhav et al., 2017, Goulden et al., 2014, Seeley et al., 2007), while the DLPFC plays an important role in executive cognitive control (Kim et al., 2018, Smith et al., 2009).

Structural and functional alterations in each of the insula, dACC, and DLPFC have been observed in relation to chronic pain conditions (Maihöfner et al., 2005, Baliki et al., 2011, Barad et al., 2014, Kim et al., 2017). However, altered functional connectivity between the insula and cognitive control regions has not yet been examined in relation to CPRS, necessitating further investigations.

We previously reported functional alterations of the pain-related resting-state networks in CRPS patients using independent component analysis of resting-state functional magnetic resonance imaging (rs-fMRI) data: altered intra-network functional connectivity of the salience and attention networks as well as enhanced functional coupling between the salience and attention networks in CRPS patients (Kim et al., 2018). Given these previous findings, the current study re-analyzed this dataset to focus on the insula involved in autonomic modulation including pain processing (Kim et al., 2017, Bushnell et al., 2013) and the interconnected cognitive control regions including the dACC and DLPFC (Bushnell et al., 2013, Tan and Kuner, 2021) using a different methodological approach such as seed-based functional connectivity analysis. Functional connectivity among these regions-of-interest (ROIs) was compared between the CRPS patients and healthy controls, and its associations with the clinical characteristics were examined in the patient group.

2. Material and methods

2.1. Participants and clinical assessments

The study participants are from the previously published study (Kim et al., 2018, Im et al., 2021). The participants included 21 patients diagnosed as CRPS based on the International Association for the Study of Pain criteria (Harden et al., 2010) (16 men, 5 women; mean age ± standard deviation [SD] = 37.7 ± 10.9 years), and 49 demographically matched healthy subjects (39 men, 10 women; mean age ± SD = 36.8 ± 9.4 years). All patients with CRPS in the current study were categorized into the type 1.1 Exclusion criteria were any contraindication to brain MRI, a current diagnosis of axis 1 psychiatric disorders other than major depressive disorder, a history of traumatic brain injury with loss of consciousness, or the presence of major medical or neurological disorders.

The short-form of the McGill Pain Questionnaire (MPQ) was used to assess the current intensity of sensory and affective dimensions of the pain experiences in patients with CRPS. The MPQ is a 15-item report measuring affective (4 items) and sensory (11 items) properties of pain using a 4-point Likert scale (0–3) and the total scores ranged from 0 to 45, with the higher scores indicating greater pain severity (Melzack, 1987).

The use of prescribed pain-relieving medications was quantified using the Medication Quantification Scale (MQS) in consideration of the three relevant aspects including the medication class, dosage, and detriment (risk) (Harden et al., 2005).

All participants provided written informed consent before the study participation. The study protocol was approved by the Institutional Review Board of the Catholic University of Korea College of Medicine.

2.2. Brain magnetic resonance imaging

Using a 3.0 Tesla Magnetic Resonance scanner (Skyra, Siemens, Erlangen, Germany), rs-fMRI and high-resolution T1-weighted images were acquired. The parameters for the rs-fMRI data were as follows: a T2*-weighted echo planar imaging sequence; repetition time (TR)/echo time (TE), 3,000/20 ms; flip angle (FA), 90°; field of view (FOV), 192 × 192 mm2; slice thickness, 3 mm; volumes, 120; slices, 48. T1-weighted structural images were obtained with the following parameters: TR/TE, 1,900/2.49 ms, FA, 9°; FOV, 230 × 230 mm2; slice thickness, 0.9 mm; slices, 208.

The participants were explicitly instructed not to fall asleep and keep their eyes closed, while thinking of nothing in particular during the rs-fMRI scan. The presence of wakefulness during the rs-fMRI scan was assessed and confirmed by the visual analogue scale applied immediately after the MRI scan.

None of the participants took medications for reducing MRI scanning-related anxiety.

2.3. Functional connectivity analysis

Processing of rs-fMRI data was performed using the CONN toolbox version 21a (https://web.conn-toolbox.org) (Whitfield-Gabrieli and Nieto-Castanon, 2012) and Statistical Parametric Mapping 12 (SPM12; https://www.fil.ion.ucl.ac.uk/spm).

In the preprocessing steps, T1-weighted images were segmented into grey matter, white matter, and cerebrospinal fluid. The resultant images were then normalized into the Montreal Neurological Institute (MNI) space and resampled to into 1 mm isotropic voxels. The rs-fMRI images were estimated and corrected for subject-level motion and slice timing. The Artifact Detection Tools (ART; https://www.nitrc.org/projects/artifact_detect) was used for detection and scrubbing of outlier volumes, after calculation and z-transformation of the average signal across the entire time series. Outlier volumes were defined when fulfilling either of the following conditions: >5 SD of average intensity deviation from the mean intensity of the session; >0.9 mm framewise displacement. Mean values of head motion were assessed for each subject by CONN. The resultant functional images were then spatially normalized into the MNI space, resampled into 2 mm isotropic voxels, and were finally smoothed with an 8 mm full-width at half-maximum Gaussian kernel.

The anatomical component-based noise correction method (aCompCor) was employed to remove signals from white matter and cerebrospinal fluid as physiological sources of noise (Behzadi et al., 2007). The head motion parameters from motion correction and head motion outlier volumes were regressed out. Then, the residual time series underwent a temporal band pass filtering (0.008–0.09 Hz) to remove other spurious sources of noise.

The seed ROIs for the insular regions were defined as 6 mm radius spheres centered on the anterior and posterior insular regions using the following coordinates based on previous fMRI studies (Cottam et al., 2018, Ichesco et al., 2012, Ichesco et al., 2014, Nicholson et al., 2016, Zhang et al., 2014): left anterior insula (–32, 16, 6), right anterior insula (32, 16, 6), left posterior insula (-39, −15, 1), and right posterior insula (39, −15, 8). The seed ROIs for the cognitive control regions were placed within the dACC and bilateral DLPFC regions centered on the following coordinates based on the previous fMRI study (Dosenbach et al., 2006): dACC (−1, 10, 46), left DLPFC (-43, 22, 34), and right DLPFC (43, 22, 34). Detailed information on the coordinates and locations of the seed ROIs is provided in Fig. 1 and Supplementary Table 1. After averaging the time series of all voxels within each of the ROIs were averaged, and the bivariate correlation coefficients between each pair of ROIs were calculated and converted as z-scores using Fisher’s transformation. Seed-to-seed analysis among all 7 seed ROIs was performed.

Fig. 1.

Fig. 1

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Seed regions-of-interest for functional connectivity analysis. The four seed areas are overlaid on the brain template colored as orange for the insular regions (bilateral anterior insulae and bilateral posterior insulae) and green as the cognitive control regions (dorsal anterior cingulate cortex and bilateral dorsolateral prefrontal cortex).

As auxiliary analyses, seed-to-voxel analyses were performed to explore the whole-brain wise functional connectivity of the insular regions. These auxiliary analyses include four seeds including the left anterior insula, right anterior insula, left posterior insula, and right posterior insula.

The four seed areas are overlaid on the brain template colored as orange for the insular regions (bilateral anterior insulae and bilateral posterior insulae) and green as the cognitive control regions (dorsal anterior cingulate cortex and bilateral dorsolateral prefrontal cortex).

2.4. Statistical analysis

Differences in continuous and categorical demographic variables between the two groups were examined using an independent t-test or chi-squared test, respectively.

For seed-to-seed and seed-to-voxel analyses, analysis of covariance models with age and sex as covariates were used to assess between-group differences in functional connectivity. The statistical threshold for seed-to-seed analysis was p < 0.05 after the false discovery rate (FDR) corrections at the connection level. The statistical threshold for seed-to-voxel analysis was set at a voxel-level p value of <0.001 and at an FDR-corrected cluster-level p value of <0.05.

As subgroup analyses to examine whether the findings may differ according to the affected side, between-group comparisons in the functional connectivity values of seed-to-seed analyses were repeated in the right-affected patients (n = 13) vs. controls (n = 49) as well as the left-affected patients (n = 8) vs. controls (n = 49).

Pearson correlation analysis was used to examine whether altered functional connectivity from seed-to-seed analysis is associated with the MPQ scores or duration of illness in CRPS patients.

A two-tailed p value of <0.05 was considered statistically significant. All statistical analyses were conducted using Stata version 16 (StataCorp., College Station, USA).

3. Results

3.1. Demographic and clinical characteristics

There were no significant differences in age (t = −0.33, p = 0.74) and sex (χ2 = 0.10, p = 0.75) between the CRPS and control groups. With respect to the CRPS-related clinical characteristics, the mean disease duration since diagnosis of CRPS (SD) was 27.5 (25.3) months. The affected side of CRPS was mostly the right side (61.9%) than the left side (38.1%). Fracture (33.3%) was most common inciting event, followed by contusion (14.3%), disc protrusion (14.3%), and spontaneous (14.3%) inciting events. The MPQ total scores was 31.1 ± 9.3 (mean ± SD). The demographic and clinical characteristics of the study participants are indicated in Table 1.

Table 1.

Demographic and clinical characteristics of the study participants.

Characteristics CRPS
(n = 21)		 Control
(n = 49)
Demographic characteristicsa
 Age, years 37.7 ± 10.9 36.8 ± 9.4
 Sex, men 16 (76.2) 39 (79.6)



Clinical characteristics related to CRPS
 Disease duration, months 27.5 ± 25.3 —
 Affected side
  Right side 13 (61.9) —
  Left side 8 (38.1) —
 Inciting event
  Fracture 7 (33.3) —
  Contusion 3 (14.3) —
  Disc protrusion 3 (14.3) —
  Spontaneous 3 (14.3) —
  Ligament injury 2 (9.5) —
  Operation 1 (4.8) —
  Strain 1 (4.8) —
  Burn 1 (4.8) —
 MPQ score 31.1 ± 9.3 —
 MQS score 28.4 ± 11.6 —
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Data are presented as mean ± standard deviation or number (percentage).

Abbreviations: CRPS, complex regional pain syndrome; MPQ, Short-Form McGill Pain Questionnaire; MQS, Medication Quantification Scale.

a

There were no significant differences in age and sex between the groups.

3.2. Seed-to-seed analysis of functional connectivity

All possible seed-to-seed connections between ROIs were compared between CPRS patients and healthy controls.

With respect to insular functional connectivity, CRPS patients showed lower functional connectivity between the left and right anterior insulae as compared to healthy controls. Bilateral insular connectivity with the dACC was lower in CRPS patients relative to healthy controls. Moreover, functional connectivity between the right posterior insula and left DLPFC was lower in CRPS patients as compared with healthy controls. In contrast, CRPS patients exhibited higher functional connectivity between the dACC and the right DLPFC than healthy controls. There were no between-group differences in functional connectivity between other ROIs. The results and detailed statistical values for seed-to-seed analyses are provided in Table 2 and Fig. 2.

Table 2.

Differences in seed-to-seed functional connectivity between CRPS patients and healthy controls.

Functional connectivity t Uncorrected p FDR-corrected p
CRPS < Control
Left anterior insula - Right anterior insula −3.94 <0.001 0.002
Left anterior insula - dACC −3.46 0.001 0.003
Right anterior insula - dACC −2.51 0.02 0.03
Left posterior insula - dACC −3.55 0.001 0.003
Right posterior insula - dACC −2.73 0.01 0.02
Right posterior insula - Left DLPFC −2.67 0.01 0.02
CRPS > Control
dACC - Right DLPFC 3.07 0.003 0.03
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The FDR threshold was applied at the connection level.

Abbreviations: CRPS, complex regional pain syndrome; dACC, dorsal anterior cingulate cortex; DLPFC, dorsolateral prefrontal cortex; FDR, false discovery rate.

Fig. 2.

Fig. 2

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Group comparisons of seed-to-seed functional connectivity between CRPS patients and healthy controls. The seeds include the insulae (left anterior insula, right anterior insula, left posterior insula, right posterior insula), the dACC, and DLPFC (left DLPFC, right DLPFC). The red line indicates higher functional connectivity in CRPS than controls, while the blue line indicates lower functional connectivity in CRPS than controls (FDR-corrected p < 0.05 at the connection level). The gray line represents no significant difference in functional connectivity between the groups. Abbreviations: CRPS, complex regional pain syndrome; dACC, dorsal anterior cingulate cortex; DLPFC, dorsolateral prefrontal cortex; FDR, false discovery rate.

Subgroup analyses were performed to examine the potential influence of affected side. The results from the subgroup analyses for the right-affected patients vs. controls were similar to those of the left-affected patients vs. controls (Supplementary Table 2). Although the sample size for each subgroup analysis was not enough to provide confirmatory findings, these findings may suggest that there is no discrepancy in findings according to the affected side.

There was significant difference in the extent of head motion between CRPS patients and healthy controls (t = -2.89, p = 0.005). Analyses for comparisons of seed-to-seed functional connectivity between the two groups were repeated after adjusting for the mean head motion (Supplementary Table 3). Although the exact statistical values changed, the trend and direction of results from these repeated analyses were similar to the original findings.

3.3. Associations between altered functional connectivity and clinical characteristics

In CRPS patients, lower functional connectivity between the bilateral anterior insulae was associated with higher total scores of the MPQ, indicating greater pain severity (r = −0.488, p = 0.025; Fig. 3A). In contrast, lower functional connectivity between the left anterior insula and dACC was associated with lower total scores of the MPQ, indicative of lower pain severity (r = 0.505, p = 0.020; Fig. 3B). The results remained unchanged after adjusting for the total scores of MQS (bilateral insulae vs. MPQ, r = −0.467, p = 0.038; left anterior insula-dACC vs. MPQ, r = 0.518, p = 0.019) as well as for the mean values of head motion (bilateral insulae vs. MPQ, r = −0.489, p = 0.029; left anterior insula-dACC vs. MPQ, r = 0.504, p = 0.023).

Fig. 3.

Fig. 3

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Relationships between the severity of pain and the insular functional connectivity in CRPS patients (A) The significant negative association between the total MPQ score and functional connectivity of the left anterior insula-right anterior insula in CRPS patients. (B) The significant positive association between the total MPQ score and functional connectivity of the left anterior insula-dACC in CRPS patients. The solid lines indicate the line of best fit, and the short-dashed lines represent 95% confidence level. The CRPS patients with the left-affected side and right-affected side are indicated as red and blue dots, respectively.Abbreviations: AI, anterior insula; dACC, dorsal anterior cingulate cortex; CRPS, complex regional pain syndrome; MPQ, Short-Form McGill Pain Questionnaire.

There were no significant relationships between connections of other ROI pairs and the MPQ scores in CRPS patients (Right anterior insula-dACC, r = −0.10, p = 0.67; Left posterior insula-dACC, r = 0.10, p = 0.68; Right posterior insula-dACC, r = −0.27, p = 0.25; Right posterior insula-Left DLPFC, r = −0.14, p = 0.54; dACC-Right DLPFC, r = −0.28, p = 0.22).

Next, we examined whether altered functional connectivity in CPRS patients may be associated with disease chronicity. No significant correlations were found between altered functional connectivity in relation to CPRS and disease duration (Left anterior insula-Right anterior insula, r = −0.099, p = 0.668; Left anterior insula-dACC, r = 0.128, p = 0.581; Right anterior insula-dACC, r = 0.254, p = 0.266; Left posterior insula-dACC, r = 0.066, p = 0.777; Right posterior insula-dACC, r = 0.136, p = 0.557; Right posterior insula-Left DLPFC, r = −0.028, p = 0.906; dACC-Right DLPFC, r = 0.027, p = 0.909).

3.4. Auxiliary seed-to-voxel analysis of functional connectivity

With the left anterior insula as the seed, lower functional connectivity with the bilateral ACC, right anterior insula, right supramarginal cortex, posterior cingulate cortex, and right DLPFC was demonstrated in CRPS patients than relative to healthy controls (Fig. 4A). In contrast, higher functional connectivity of the left anterior insult with the left superior frontal cortex was found in CRPS patients than in healthy controls (Fig. 4A).

Fig. 4.

Fig. 4

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Voxel-wise results on between-group comparisons of insular functional connectivity Using the bilateral anterior and posterior insulae as the four relevant seeds, seed-to-voxel analysis in functional connectivity was performed between CRPS patients and controls. The statistical threshold for significant group difference is voxel-level p < 0.001 and cluster-level FDR-corrected p < 0.05. The color bar denotes voxel-level t values. The red-to-yellow bar indicates higher insular functional connectivity in patients with CRPS than in healthy controls, while blue-to-green line indicates lower insular functional connectivity in CRPS. The numbers below the brain slices stand for z coordinates of the Montreal Neurological Institute coordinates system.Abbreviations: CRPS, complex regional pain syndrome; FDR, false discovery rate; L, left; R, right.

The functional connectivity of the right anterior insula was lower with the left anterior insula and the right middle cingulate cortex in CRPS patients than in healthy controls (Fig. 4B).

The functional connectivity of the left posterior insula was lower with the left ACC in CRPS patients in healthy controls (Fig. 4C).

Moreover, lower functional connectivity of the right posterior insula was found with the left postcentral cortex, right precentral cortex, and bilateral ACC in CRPS patients relative to healthy controls (Fig. 4D).

Detailed information on clusters of significant between-group differences obtained from seed-to-voxel analysis results is provided in Supplementary Table 4.

4. Discussion

The current findings critically suggest that CRPS-related insular functional alterations may be involved in maladaptive pain processing. Specifically, CRPS patients showed lower interconnections within the anterior and posterior insulae. In addition, insular functional connections with the cognitive control regions including the dACC and DLPFC were lower in CRPS patients, as compared with healthy controls. Importantly, lower functional connectivity within the bilateral anterior insulae was associated with more severe pain, while higher functional connectivity between the left anterior insula and dACC was related to more severe perceived pain in patients with CRPS.

We found lower insular functional connectivity in relation to CRPS, which may indicate functional decoupling within the bilateral anterior insulae. Interestingly, functional decoupling of the anterior insula in patients with CRPS was associated with greater pain severity. The anterior insula has been known to be heavily involved in autonomic-visceral processing (Rolls, 2016, Craig, 2002, Critchley et al., 2004, Critchley, 2005, Critchley and Harrison, 2013). Specifically, the anterior insula along with the anterior cingulate cortex plays an important role in autonomic-visceral functions that can be activated in response to salient stimuli (Menon and Uddin, 2010, Rolls, 2016). Therefore, lower anterior insular functional connectivity in CRPS may relate to exaggerated pain perception by its impaired modulatory role in autonomic symptoms. Furthermore, the anterior insula coordinates motivational and affective pain responses by integrating sensory, emotional, physiological information from the posterior insula, amygdala, and sympathetic system, respectively (Bastuji et al., 2018). The current finding may suggest that the altered interconnections of the anterior insula may play an important role in dysfunctional motivational and affective processing of excessive pain sensations in CRPS patients (Cole and Schneider, 2007, Kulkarni et al., 2005, Ploner et al., 2002). As such, these functional alterations in the anterior insula may result in the mismatch between external pain sensations and interoceptive signals, leading to fixation and magnification of pain in CRPS. A previous meta-analysis for chronic pain conditions may support the current findings of the dysfunctional anterior insular role in misinterpretation of CRPS-related pain (Ferraro et al., 2022). A similar finding of dysregulated anterior insula has also been reported in CRPS (Geha et al., 2008) and other chronic pain conditions such as fibromyalgia (Hsu et al., 2009) and dysmenorrhea (Dun et al., 2017).

In the current study, functional connectivity between the anterior insula and dACC was lower in CRPS patients relative to controls. Interestingly, correlation analysis demonstrated that increased functional connectivity between these two regions was related to severe pain in CRPS patients. Considering these regions as part of the salience network, functional decoupling between the dACC and anterior insula in CRPS may be explained by cognitive dysregulation by the dACC over hypersensitive pain signals related to the dysfunctional anterior insula (Cole and Schneider, 2007, Kulkarni et al., 2005, Ploner et al., 2002). Given the positive functional connectivity values in both healthy controls (mean ± SD, 0.32 ± 0.22) and CPRS patients (mean ± SD, 0.12 ± 0.04), the extent of positive functional control of the dACC over the anterior insula may be diminished in CRPS patients below the normal range. This finding may be supported by previous findings that reported functional decoupling as well as structural atrophy of the anterior insula and dACC in chronic pain conditions such as CRPS (Kim et al., 2017), ankylosing spondylitis (Wu et al., 2013), and irritable bowel syndrome (Kwan et al., 2005).

On the other hand, relatively higher functional coupling between the dACC and anterior insula may represent enhanced cognitive monitoring or directed attention of increased pain perception in CRPS patients (Bushnell et al., 2013, Penfield and Boldrey, 1937). Accordingly, previous neuroimaging studies revealed that the dACC engages in pain unpleasantness and anterior insula is involved in subjective pain perception (Bushnell et al., 2013, Rainville et al., 1997). This is further supported by the heightened functional connectivity within the salience network reported in relation to higher pain catastrophizing of CRPS (Kim et al., 2018). However, the exact role of functional connection between the dACC and anterior insula in the pathophysiology of CRPS needs further clarifications through future longitudinal studies.

Lower functional connectivity between the bilateral posterior insulae and dACC and between the right posterior insula and the left DLPFC in CRPS patients relative to healthy controls may be interpreted as dysfunctional sensory processing of the posterior insula in CRPS (Kuehn et al., 2016, Lin et al., 2017, Rance et al., 2014). This may be attributed by maladaptive cognitive modulation through the left DLPFC and the dACC over hypersensitive interoceptive pain signals involved in the posterior insula (Kuehn et al., 2016, Lin et al., 2017, Rance et al., 2014). This rationale is further supported by the previously reported co-activation of the posterior insula and dACC in response to unanticipated painful stimuli (Sawamoto et al., 2000). The suggested pivotal role of the posterior insula in preferentially discriminating pain sensations through the spino-thalamic-cortical pathway also supports this notion (Bushnell et al., 2013, Tan and Kuner, 2021). In line with this speculation, the attentional control of the dACC and DLPFC over hypersensitive pain sensations involved in the posterior insula is suggested to play critical role in magnified pain intensity of chronic pain (Kuehn et al., 2016, Lin et al., 2017, Rance et al., 2014). As such, lower functional connectivity between the posterior insula, dACC, and left DLPFC may potentially reflect the dysfunctional adaptive modulation, attentional control, and sensory processing of excessive and sustained pain-related interoceptive signals underlying CRPS (Bushnell et al., 2013, Tan and Kuner, 2021).

It is noteworthy that CRPS patients showed higher functional connectivity between the dACC and the right DLPFC as compared to healthy controls. Our previous study has reported similar increased functional connectivity between the attention and salience networks in CRPS patients (Kim et al., 2018). As the part of the right frontoparietal attention networks, the right-lateralized role of the DLPFC is well known in somesthetic and pain processing (Kim et al., 2018, Smith et al., 2009). Moreover, the dACC plays a key role in attentional monitoring as well as salience detection (Heilbronner and Hayden, 2016, Shenhav et al., 2017, Goulden et al., 2014, Seeley et al., 2007). Given these roles of the dACC and right DLPFC, it could be assumed that higher functional connectivity between these brain regions may represent altered executive control over excessive and unregulated CRPS-related pain as a compensatory effort. In alignment with this assumption, functional activation of the DLPFC has been observed in relation to self-control and regulatory attempts for chronic pain and pain-related aversive emotion (Lorenz et al., 2003, Wager et al., 2004, Wiech et al., 2008). Furthermore, patients with fibromyalgia demonstrated higher functional connectivity between the ACC and DLPFC as inhibitory attempts to regulate chronic pain (Kong et al., 2019).

The auxiliary seed-to-voxel analysis replicated the main results of seed-to-seed analysis and also found altered insular functional connectivity with other brain areas. Functional decoupling of the bilateral anterior insulae with the cingulate cortices involved in motivational processing and the supramarginal cortex as part of the somatosensory association cortex was additionally reported from the seed-to-voxel analysis. The functional decoupling between the anterior insulae and supramarginal cortex may suggest dysfunctional processing of somatosensory perception in relation to magnified pain in patients with CRPS (Kim et al., 2017, Bushnell et al., 2013, Tan and Kuner, 2021). Considering the posterior cingulate cortex as part of the default mode network (DMN) related to interoceptive processing, insula-DMN functional decoupling may also suggest dysfunctional pain modulation of CRPS as reported in chronic pain conditions of CRPS and fibromyalgia (Penfield and Boldrey, 1937, Hsiao et al., 2017).

Functional decoupling of the right posterior insula with the precentral and postcentral cortices were additionally demonstrated from the auxiliary analysis. Accordingly, the pre/post-central cortices related to localization and discrimination of pain showed co-activations with the insular, somatosensory, and posterior cingulate regions during motor performance of the affected limb in CRPS (Maihofner et al., 2006). The functional decoupling of the posterior insula with the somatosensory and motor cortices may indicate dysfunctional sensory-discriminatory processing over encoded location and degree of exteroceptive pain signals (Kim et al., 2017, Bushnell et al., 2013, Tan and Kuner, 2021).

Unlike the previous study of insular functional connectivity in CRPS (Kim et al., 2017), we did not find lower functional connectivity between the anterior insula and DLPFC in the current seed-to-seed functional connectivity analysis. This discrepancy may be partly attributed to the methodological differences such as the sample characteristics, seed definitions, and statistical analyses. First, our seed-to-seed analysis included the separate insular seeds for each hemisphere that were defined as spheres based on the literature (Cottam et al., 2018, Ichesco et al., 2012, Ichesco et al., 2014, Nicholson et al., 2016, Zhang et al., 2014, Dosenbach et al., 2006), while the previous study performed seed-to-voxel analysis using the insular seeds that were manually delineated and combined for both hemispheres (Kim et al., 2017). However, it is noteworthy that our supplementary seed-to-voxel analysis demonstrated similar findings to those from Kim et al. (Kim et al., 2017) such as lower functional connectivity between the left anterior insula and right DLPFC in CRPS patients (Fig. 4 and Supplementary Table 4). Second, sex distribution and exclusion criteria for psychiatric comorbidities were different between the two studies. Third, the two studies used different covariates and significance thresholds for statistical analyses. Since replication and generalization are critical issues in neuroimaging research (Fletcher and Grafton, 2013), further studies are necessary to draw more definite conclusions regarding the functional connectivity alterations between the insula and DLPFC in CRPS.

The current findings from correlation analysis suggested that functional connectivity alterations in CRPS patients may not be attributed to disease chronicity. However, considering a wide range of disease duration (1.8–74.5 months) and a relatively small sample size, the future longitudinal studies with a larger sample size are warranted to explore whether insular functional connectivity is progressively altered as CPRS develops.

The following limitations should be considered in interpreting the current study findings. Although the repeated analyses in both right- and left-affected patient subgroups demonstrated similar findings, a possible uncontrolled effect of the affected side should be taken into account for interpreting the results given a relatively small sample size of the current subgroup analysis. Furthermore, it should be noted that the potential influences of immediate factors such as the current resting pain during the rs-fMRI scan should be considered in interpreting the results since the pain severity in CRPS may be fluctuating and the MPQ could not exactly assess the fluctuating pain. In the current study, there was a significant between-group difference in head motion and all CPRS patients were prescribed several pain-relieving medications, both of which may influence the rs-fMRI results. Although the outlier volumes with suprathreshold head motion were excluded from the estimation of functional connectivity and the repeated analyses adjusting for the use of pain-relieving medications or the amount of head motion produced similar results, these factors may act as the potential source of confounders for the current findings. Seed selection may potentially influence the results of seed-based functional connectivity analysis. Although the seed ROIs in the current study were selected based on previously published fMRI studies focusing the insula, dACC, and DLPFC regions as an attempt to reduce potential bias in seed selection (Supplementary Table 1), the current findings should be replicated in the future studies using the more robust coordinates reported in meta-analysis of chronic pain disorders. In the current study, all study subjects were instructed to stay awake during the rs-fMRI scan and none of them reported to fall asleep during the rs-fMRI scan. However, it should be noted that the influence of transient and involuntary intrusions of sleep during the scan cannot be ruled out. All of the CRPS patients in the current study were classified as type 1. In addition, there was no available information regarding the other subtypes such as “warm” vs. “cold” or “sympathetically maintained pain” vs. “sympathetically independent pain” for the current study subjects. Given the clinical importance of these subtypes in CRPS (Bruehl, 2015, Feliu and Edwards, 2010), the future studies including the different subtypes of CRPS are warranted. Finally, the causality of CRPS-related brain functional alterations and generalizability of the findings may be limited in the current cross-sectional design that included the relatively small number of CRPS patients. Future larger longitudinal studies may provide further insights regarding a casual relation between brain functional alterations and pain severity in relation to CRPS and other pre-existing vulnerability factors such as baseline participant characteristics.

5. Conclusion

The functional decoupling of the insular regions as well as dysfunctional insular connections with cognitive control regions such as dACC and DLPFC was reported in relation to magnified pain intensity of CRPS patients. Our findings highlight that the insula may be of significance in future research on pathophysiology of CPRS. Further multi-modal neuroimaging studies may provide additional insight into the pathophysiological roles of the insula in CRPS. In addition, the insula could be a potential target for CRPS treatment such as non-invasive brain stimulation, by modulating altered functional connectivity and abnormal pain processing.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgments

Acknowledgements

The authors thank all the study participants.

Funding

This research was supported by the Bio & Medical Technology Development Program of the National Research Foundation funded by Ministry of Science and ICT (NRF-2020M3E5D9080555) and Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education (NRF-2020R1A6A1A03043528).

Footnotes

Appendix A

Supplementary data to this article can be found online at https://doi.org/10.1016/j.nicl.2023.103440.

Contributor Information

Sujung Yoon, Email: sujungjyoon@ewha.ac.kr.

Hyeonseok Jeong, Email: hsjeong@catholic.ac.kr.

Appendix A. Supplementary data

The following are the Supplementary data to this article:

Supplementary data 1
mmc1.docx (1.7MB, docx)

Data availability

Data will be made available on request.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplementary data 1
mmc1.docx (1.7MB, docx)

Data Availability Statement

Data will be made available on request.

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