Functional connectivity and structural analysis of trial spinal cord stimulation responders in failed back surgery syndrome

Abstract

Background: Chronic pain has been associated with alterations in brain structure and function that appear dependent on pain phenotype. Functional connectivity (FC) data on chronic back pain (CBP) is limited and based on heterogeneous pain populations. We hypothesize that failed back surgery syndrome (FBSS) patients being considered for spinal cord stimulation (SCS) therapy have altered resting state (RS) FC cross-network patterns that 1) specifically involve emotion and reward/aversion functions and 2) are related to pain scores.

Methods: RS functional MRI (fMRI) scans were obtained for 10 FBSS patients who are being considered for but who have not yet undergone implantation of a permanent SCS device and 12 healthy age-matched controls. Seven RS networks were analyzed including the striatum (STM). The Wilcoxon signed-rank test evaluated differences in cross-network FC strength (FCS). Differences in periaqueductal grey (PAG) FC were assessed with seed-based analysis.

Results: Cross-network FCS was decreased (p<0.05) between the STM and all other networks in these FBSS patients. There was a negative linear relationship (R2 = 0.76, p<0.0022) between STMFCS index and pain scores. The PAG showed decreased FC with network elements and amygdala but increased FC with the sensorimotor cortex and cingulate gyrus.

Conclusions: Decreased FC between STM and other RS networks in FBSS has not been previously reported. This STMFCS index may represent a more objective measure of chronic pain specific to FBSS which may help guide patient selection for SCS and subsequent management.

Conflict of interest statement

Dr. Arocho-Quinones, MD has nothing to disclose. Dr. Pahapill MD PhD has nothing to disclose. Dr. Guangyu Chen, PhD has nothing to disclose. Dr. Andrew S. Nencka, PhD has nothing to disclose. Dr. Shi-Jiang Li PhD has financial relationships with Brain Symphonics and Bristol- Myer Squibb Company as a consultant. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1. Summary of methodology and data analysis.

A Regional FC within STM network for CN, FBSS. A two-sample t test is performed to analyze the difference in regional FC between CN and FBSS. B. Functional imaging cross-network analysis. Start from the pre-processed functional MRI imaging, using SPM to register the imaging into standard template with anatomical automatic labeling (AAL) maps. Each brain region’s BOLD signal is extracted and correlated with each other region’s BOLD signal to construct the whole brain regional FC network. The regions are then grouped into seven well known networks, i.e. MTN, DMN, SAN, STM, TEP, HIP and DAN. The FC across the seven networks (cross-network FC) is calculated for each individual. Two-sample Wilson-rank test is performed to characterize the difference between FBSS and control (CN) group. The STMFCS index is calculated individually based on the difference pattern and then correlated with the pain level scores. C. Seed-based PAG FC analysis. Each subject’s PAG whole brain FC is obtained by first extracting PAG ROI using MNI coordinates.[19, 20] This is followed by ROI co-registration to the functional data. The time series of all voxels within the co-registered region of interest (ROI) are averaged to obtain each subject’s PAG time series. Voxelwise Pearson cross-correlation coefficients (CC) between the seed region and the whole brain are calculated and then subjected to a Fisher transformation to improve normality. Finally, a two-sample student t-test is used to compare PAG FC between the CN and FBSS groups and results are corrected using the AlphaSim program.

Fig 2. Regional-based FC between each pair of brain regions for CN group and FBSS group.

A color bar (right) shows the color and associated value of FC (range from -0.2 to 1.0). Each red square contains the regions for each network.

Fig 3. Functional connectivity (FC) within each network for control and FBSS groups.

Box plots showing within network FC strength for control (CN, blue) and FBSS group (red) with individual overlaid data (black dots). Only the STM network shows significantly decreased within network FC (uncorrected) in FBSS group compared to CN group. * indicates p<0.05.

Fig 4. Regional FC within STM network for CN (A), FBSS (B) and the difference (C).

The values of FC between left caudate and left putamen, left caudate and left globus pallidus, left caudate and right globus pallidus, right caudate and left putamen, right caudate and right putamen, right caudate and right globus pallidus, left putamen and left globus pallidus significantly decreased in FBSS group compared to CN. After using the Bonferroni method, the only significant decrease in FC between CN and FBSS groups within STM was between right caudate-right globus pallidus (** indicates p

Fig 5. Cross-network FC among RSNs for CN group (A), FBSS group (B), and difference (C), respectively.

A color bar (left) shows the color and associated value of FC. D. Bar graph with mean and standard deviation values of FC between STM and MTN, DMN, TEP, HIP and DAN for the CN group (blue) and FBSS group (red).

Fig 6. Clinical significance of STMFCS.

A negative linear relationship was found between STMFCS and the corresponding pain scores in FBSS group (gray). STMFCS index is the mean FC between STM and all other 6 networks. Mean STMFCS index for control (CN, blue) group is 0.27, STD 0.13.

Fig 7. Altered PAG FC in FBSS.

PAG FC was significantly decreased (cold color) in L_MFG, L_INS, L_ITG, L_PHG, L_AMY, and R_ACC. FC was increased (warm color) between PAG and the R_PreCG, R_PoCG, and R_CG when compared with the CN group (p<0.05, AlphaSim correction). The color bar represents the corresponding Z scores. Legend: Periaqueductal gray (PAG), Left middle frontal gyrus (L_MFG), left insula (L_INS), left inferior temporal gyrus (L_ITG), left parahippocampal gyrus (L_PHG), left amygdala (L_AMY), right anterior cingulate cortex (R_ACC), right precentral gyrus (R_PreCG), right post central gyrus (R_PoCG), right cingulate gyrus (R_CG).

Fig 8. Conceptualization of changes in STMFCS and pain levels seen in ESCRPS FBSS patients.

In our study patients, back surgery represents the common inciting event that acutely increases pain levels (solid red) from baseline (dashed red). Subsequently, some patients (FBSS) go on to develop persistent pain (subacute/chronic phase) and enter the ESCRPS with sustained pain amplification (solid red) and associated decreased STMFCS index (solid blue) from normal baseline (dashed blue). Improvement in pain levels (dotted red) as well as normalization of STMFCS index (dotted blue) may be seen with successful SCS therapies.