Alterations in Default Mode Network Connectivity During Pain Processing in Borderline Personality Disorder

Supplementary Online Content

Kluetsch RC, Schmahl C, Niedtfeld I, Densmore M, Calhoun VD, Daniels J, Kraus A, Ludaescher P, Bohus M, Lanius RA. Alterations in default mode network connectivity during pain processing in borderline personality disorder. Arch Gen Psychiatry. Published online June 4, 2012. doi:10.1001/archgenpsychiatry.2012.476.

eAppendix. Methods

eTable 1. Brain regions identified in each of the default mode subnetwork components

eTable 2. Brain regions identified in each of the default mode subnetwork components

eTable 3. Brain regions identified in each of the default mode subnetwork components

eTable 4. Areas showing connectivity with the two seed regions during “neutral” greater than “pain” – within-group results

eTable 5. Areas showing connectivity with the two seed regions during “pain” greater than “neutral” – within-group results

This supplementary material has been provided by the authors to give readers additional information about their work.

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Methods

Image Analysis

Component Identification The components related to the DMN were selected following visual inspection and methods previously described.1-3 First, we systematically excluded components that showed significant correlations (r ≥ 0.1) with a priori localized cerebral spinal fluid (CSF) and/or low correlations with a priori localized gray matter (r ≤ 0.1), as these are likely to be artifactual.4 The remaining component images were then correlated with a binary DMN mask derived from a previous study.5 This mask contained the PCC/PrC, mPFC, bilateral lateral parietal cortices, and bilateral temporal gyri. We selected those components that showed a significant correlation (r ≥ 0.25) with our template and included regions previously implicated in the DMN.3,5,6 _ENREF_54_ENREF_25 Statistical Comparison of Images For the selected components, the individual subject maps were entered into second-level analyses in SPM8 (http://www.fil.ion.ucl.ac.uk/spm/). First, separate one-sample t-tests were conducted for patients and controls to generate group-level maps of the selected components. Second, an overall component spatial map3,7_ENREF_53 was created for each sub-component by entering the maps of all subjects (collapsed across groups) into a one-sample t- test. Third, two-sample t-tests, masked with the respective overall component spatial map,53,55 were performed to test for between-group differences. p < 0.005 (uncorrected) at the voxel-level. Additionally, to correct for multiple comparisons across the whole brain, we used a cluster extent correction procedure to compute the number of expected voxels per cluster according to random field theory.8 Thus, only clusters exceeding the respective number of voxels are presented. _ENREF_58To control for differences in subjective pain intensity ratings

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during the fMRI acquisition, we entered each subject’s average rating for the five “pain” blocks as a covariate of no interest into the two-sample t-tests comparing the component images of BPD patients and HC. Statistical Comparison of Time Courses Multiple regression analysis, using the temporal sorting function in GIFT, was performed on the ICA time courses (considered the dependent variables) with the general linear model (GLM) design matrix taken from SPM8.9,10,11 The design matrix contained three regressors corresponding to the different types of thermal stimulation, namely (1) the individually adjusted temperature (subsequently referred to as “pain”), (2) the neutral temperature (subsequently referred to as “neutral”), and (3) a fixed temperature of 43°C that was of no interest to the current study. This procedure resulted in a set of beta-weights (= slopes of regressors) for every regressor, subject and component. These beta- weights were then entered into second-level analyses to draw inferences about the degree of task-relatedness.10,12 To account for our explicit baseline, we subtracted the beta-weights of “neutral” from “pain” and entered their difference scores into separate one-sample t-tests per group. Testing these difference scores against the null hypothesis of no change reveals whether a component exhibits significant pain-related signal change relative to “neutral”. Next, two- sample t-tests were performed for each component and its associated difference scores to test for group differences in task-modulation. The aforementioned group statistics on beta-weights were conducted in SPSS for Windows (Rel. 18.0.0. 2009. Chicago: SPSS Inc.), and thresholded at p < 0.05.10

References

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3. Assaf M, Jagannathan K, Calhoun VD, Miller L, Stevens MC, Sahl R, O'Boyle JG, Schultz RT, Pearlson GD. Abnormal functional connectivity of default mode sub‐networks in autism spectrum disorder patients. Neuroimage. Oct 15 2010;53(1):247‐256. 4. Maldjian JA, Laurienti PJ, Kraft RA, Burdette JH. An automated method for neuroanatomic and cytoarchitectonic atlas‐based interrogation of fMRI data sets. Neuroimage. Jul 2003;19(3):1233‐1239. 5. Bluhm RL, Osuch EA, Lanius RA, Boksman K, Neufeld RW, Théberge J, Williamson P. Default mode network connectivity: effects of age, sex, and analytic approach. Neuroreport. May 28 2008;19(8):887‐891. 6. Buckner RL, Andrews‐Hanna JR, Schacter DL. The brain's default network: anatomy, function, and relevance to disease. Ann N Y Acad Sci. Mar 2008;1124:1‐38. 7. Garrity AG, Pearlson GD, McKiernan K, Lloyd D, Kiehl KA, Calhoun VD. Aberrant "default mode" functional connectivity in schizophrenia. Am J Psychiatry. Mar 2007;164(3):450‐457. 8. Hayasaka S, Nichols TE. Combining voxel intensity and cluster extent with permutation test framework. Neuroimage. Sep 2004;23(1):54‐63. 9. Calhoun VD, Liu J, Adali T. A review of group ICA for fMRI data and ICA for joint inference of imaging, genetic, and ERP data. Neuroimage. Mar 2009;45(1 Suppl):S163‐ 172. 10. Otti A, Guendel H, Laer L, Wohlschlaeger AM, Lane RD, Decety J, Zimmer C, Henningsen P, Noll‐Hussong M. I know the pain you feel‐how the human brain's default mode predicts our resonance to another's suffering. Neuroscience. Aug 11 2010;169(1):143‐148. 11. Kim DI, Mathalon DH, Ford JM, Mannell M, Turner JA, Brown GG, Belger A, Gollub R, Lauriello J, Wible C, O'Leary D, Lim K, Toga A, Potkin SG, Birn F, Calhoun VD. Auditory oddball deficits in schizophrenia: an independent component analysis of the fMRI multisite function BIRN study. Schizophr Bull. Jan 2009;35(1):67‐81. 12. Kim DI, Manoach DS, Mathalon DH, Turner JA, Mannell M, Brown GG, Ford JM, Gollub RL, White T, Wible C, Belger A, Bockholt HJ, Clark VP, Lauriello J, O'Leary D, Mueller BA, Lim KO, Andreasen N, Potkin SG, Calhoun VD. Dysregulation of working memory and default‐mode networks in schizophrenia using independent component analysis, an fBIRN and MCIC study. Hum Brain Mapp. Nov 2009;30(11):3795‐3811.

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eTable 1: Brain regions identified in each of the default mode subnetwork components All participants (n = 47) Brain region* MNI coordinates z Score

Component 28 Bilateral posterior cingulate/precuneus (BA 23, 29, 30, 31) -6, -57, 21 Inf Right superior/middle temporal gyrus, angular gyrus (BA 19, 39) 48, -72, 24 Inf Left superior/middle temporal gyrus, angular gyrus (BA 19, 39) -45, -69, 18 Inf Bilateral medial frontal gyrus (BA 10, 11) -3, 48, -15 Inf Left superior/middle frontal gyrus (BA 6, 8) -27, 33, 48 7.68 Right superior/middle frontal gyrus (BA 6, 8) 27, 30, 54 7.34 Right insula 36, -9, 6 7.05 Cerebellum 36, -69, -51 6.95

Component 27 Bilateral posterior cingulate/precuneus (BA 23, 30, 31) -3, -54, 24 Inf Bilateral superior/medial frontal gyrus (BA 6, 8, 9, 10) -6, 54, 36 Inf Left superior/middle temporal gyrus, angular gyrus (BA 39, 40) -51, -66, 27 Inf Left inferior parietal lobule (BA 40) -54, -60, 42 Inf Right cerebellum 30, -84, -33 Inf Right insula 36, -15, 12 Inf Right inferior temporal gyrus (BA 19, 37) 48, -72, -9 7.78 Right superior/middle temporal gyrus, angular gyrus (BA 39, 40) 57, -60, 30 Inf Right precentral/postcentral gyrus (BA 3, 4) 33, -21, 51 Inf Left inferior/middle/superior temporal gyrus (BA 20, 21, 38) -54, -6, -30 Inf Right inferior/middle/superior temporal gyrus (BA 20, 21, 38) 63, -6, -27 Inf Left inferior frontal gyrus (BA 45, 47) -33, 27, -21 Inf Bilateral anterior cingulate gyrus (BA 24) 0, -15, 42 7.80

Component 13 Bilateral posterior cingulate gyrus/ precuneus (BA 7, 23, 31) 6, -45, 36 Inf Right superior temporal gyrus, angular gyrus, inferior parietal 42, -66, 39 Inf Left angular gyrus, inferior parietal lobule (BA 19, 39) -36, -69, 39 Inf Bilateral mid-cingulate gyrus (BA 24) -3, 12, 36 7.73

Abbreviations: BA = Brodmann area; BPD = Borderline Personality Disorder; MNI = Montreal Neurological Institute. * Peak activation voxels are thresholded at p < 0.005 (uncorrected) at the voxel-level, in addition to multiple comparisons correction using a cluster extent correction procedure based on random field theory.58_ENREF_57

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eTable 2: Brain regions identified in each of the default mode subnetwork components Controls (n = 22) Brain region* MNI coordinates z Score

Component 28 Bilateral posterior cingulate/precuneus (BA 23, 29, 30, 31) 15, -60, 12 Inf Right superior/middle temporal gyrus, angular gyrus (BA 19, 39) 45, -69, 18 7.79 Left superior/middle temporal gyrus, angular gyrus (BA 19, 39) -48, -69, 18 7.01 Bilateral medial frontal gyrus (BA 10, 11) 0, 51, -9 6.79 Left superior/middle frontal gyrus (BA 6, 8) -24, 33, 51 6.44 Right superior/middle frontal gyrus (BA 6, 8) 30, 24, 57 5.51 Right insula 36, -9, 6 6.09 Cerebellum 42, -69, -45 5.59

Component 27 Bilateral posterior cingulate/precuneus (BA 23, 30, 31) -6, -54, 21 7.55 Bilateral superior/medial frontal gyrus (BA 6, 8, 9, 10) -6, 54, 30 Inf Left superior/middle temporal gyrus, angular gyrus (BA 39, 40) -48, -63, 27 7.65 Left inferior parietal lobule (BA 40) -54, -60, 42 5.71 Right cerebellum 30, -84, -33 6.17 Right insula 36, -15, 12 6.56 Right inferior temporal gyrus (BA 19, 37) 48, -75, -6 6.36 Right superior/middle temporal gyrus, angular gyrus (BA 39, 40) 54, -63, 33 6.43 Right precentral/postcentral gyrus (BA 3, 4) 30, -24, 54 5.70 Left inferior/middle/superior temporal gyrus (BA 20, 21, 38) -57, -6, -27 6.11 Right inferior/middle/superior temporal gyrus (BA 20, 21, 38) 54, -9, -33 5.68 Left inferior frontal gyrus (BA 45, 47) -36, 36, -15 6.32 Bilateral anterior cingulate gyrus (BA 24) 3, -12, 42 6.23

Component 13 Bilateral posterior cingulate gyrus/ precuneus (BA 7, 23, 31) 6, -45, 36 Inf Right superior temporal gyrus, angular gyrus, inferior parietal lobule 42, -66, 36 6.91 (BA 39, 40) Left angular gyrus, inferior parietal lobule (BA 19, 39) -36, -69, 33 5.98 Bilateral mid-cingulate gyrus (BA 24) -3, 12, 39 6.73

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eTable 3: Brain regions identified in each of the default mode subnetwork components Patients (n = 25) Brain region* MNI coordinates z Score

Component 28 Bilateral posterior cingulate/precuneus (BA 23, 29, 30, 31) -6, -63, 21 Inf Right superior/middle temporal gyrus, angular gyrus (BA 19, 39) 51, -60, 12 7.74 Left superior/middle temporal gyrus, angular gyrus (BA 19, 39) -42, -75, 24 7.43 Bilateral medial frontal gyrus (BA 10, 11) 0, 48, -15 5.66 Left superior/middle frontal gyrus (BA 6, 8) Right superior/middle frontal gyrus (BA 6, 8) 24, 42, 45 5.43 Right insula 33, -21, 9 6.53 Cerebellum -9, -51, -39 5.49

Component 27 Bilateral posterior cingulate/precuneus (BA 23, 30, 31) 0, -57, 21 7.70 Bilateral superior/medial frontal gyrus (BA 6, 8, 9, 10) -6, 57, 33 7.76 Left superior/middle temporal gyrus, angular gyrus (BA 39, 40) -51, -69, 36 7.44 Left inferior parietal lobule (BA 40) -48, -63, 51 5.86 Right cerebellum 27, -84, -33 7.43 Right insula 36, -18, 9 6.20 Right inferior temporal gyrus (BA 19, 37) 48, -69, -6 5.10 Right superior/middle temporal gyrus, angular gyrus (BA 39, 40) 57.-60, 30 6.38 Right precentral/postcentral gyrus (BA 3, 4) 33, -21, 54 6.23 Left inferior/middle/superior temporal gyrus (BA 20, 21, 38) -54, 3, -27 6.73 Right inferior/middle/superior temporal gyrus (BA 20, 21, 38) 63, -6, -27 6.64 Left inferior frontal gyrus (BA 45, 47) -33, 27, -21 6.46 Bilateral anterior cingulate gyrus (BA 24) 9, -9, 45 5.31

Component 13 Bilateral posterior cingulate gyrus/ precuneus (BA 7, 23, 31) 9, -51, 33 Inf Right superior temporal gyrus, angular gyrus, inferior parietal lobule 54, -54, 36 5.52 (BA 39, 40) Left angular gyrus, inferior parietal lobule (BA 19, 39) -36, -66, 39 6.54 Bilateral mid-cingulate gyrus (BA 24) -6, 12, 33 5.05

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eTable 4: Areas showing connectivity with the two seed regions during “neutral” greater “pain” – within-group results Brain region* MNI coordinates z Score Controls Connectivity with mPFC Bilateral posterior cingulate/precuneus (BA 7, 23, 29, 30, 31) -3 -57 21 4.94 Right fusiform/parahippocampal gyrus (BA 20, 36, 37) 30 -33 -24 4.72 Right inferior/middle occipital gyrus (BA 17, 18) 33 -93 -12 4.16 Left parahippocampal gyrus (BA 35, 36) -30 -24 -27 3.84 Bilateral medial frontal gyrus (BA 10) -3 54 -3 4.68 Right superior/middle frontal gyrus (BA 8) 21 36 57 4.65 Left superior/middle frontal gyrus (BA 8) -27 39 48 4.58 Left inferior/middle occipital gyrus (BA 17, 18, 19) -24 -96 -15 4.14 Left inferior frontal gyrus (BA 47) -42 30 -18 4.10 Right inferior/middle temporal gyrus (BA 20, 21) 57 0 -30 4.01 Right superior/middle temporal gyrus (BA 38) 30 -6 -42 3.26 Left inferior/middle temporal gyrus (BA 21, 38) -60 -12 -27 3.92 Right inferior frontal gyrus (BA 47) 39 33 -21 3.91 Left middle/superior temporal gyrus, angular gyrus/precuneus (BA -45 -63 24 3.76 19, 39) Right cerebellum 15 -87 -45 3.73 Right middle/superior temporal gyrus (BA 39) 51 -63 21 3.64 Right superior/middle occipital gyrus (BA 19) 39 -81 21 3.38 Right precentral/middle frontal gyrus (BA 4, 6) 42 -15 57 3.20

Connectivity with PCC Bilateral posterior cingulate/precuneus (BA 7, 23, 29, 30, 31), cuneus -3 -54 27 4.88 (BA 30) Bilateral medial frontal gyrus, anterior cingulate (BA 10, 11, 32) -6 54 -9 4.63 Left cerebellum, parahippocampal/fusiform gyrus (BA 35, 36) -27 -27 -30 4.56 Left precuneus, middle temporal/angular gyrus (BA 19, 39) -42 -75 45 4.40 Left superior/middle frontal gyrus (BA 6, 8) -24 36 48 4.14 Right superior/middle temporal gyrus, angular gyrus (BA 39) 51 -66 24 4.13 Left inferior/middle temporal gyrus, fusiform gyrus (BA 20, 21) -63 -12 -27 4.00 Right inferior/middle temporal gyrus, fusiform gyrus (BA 20, 21) 57, -9, -36 3.66 Right superior/middle frontal gyrus (BA 6, 8) 27 33 57 3.60 Right parahippocampal/fusiform gyrus (BA 20, 28, 35, 36) 27 -21 -30 3.54 Patients with BPD Connectivity with mPFC Bilateral posterior cingulate/precuneus (BA 23, 29, 30, 31) 3 -48 21 5.62 Bilateral medial frontal gyrus (BA 10, 11) -6 51 -12 5.58 Left middle/superior frontal gyrus (BA 8) -36 27 51 4.99

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Brain region MNI coordinates z Score Right middle temporal/angular gyrus (BA 19, 39, 40) 54 -60 33 5.02 Left parahippocampal/fusiform gyrus (BA 20, 35, 36, 37) -39 -30 -24 4.64 Left middle temporal/angular gyrus (BA 39) -48 -72 33 4.61 Left superior occipital gyrus/precuneus (BA 19) -36 -87 33 3.81 Right cerebellum 30 -33 -27 4.41 Left inferior frontal gyrus (BA 47) -42 30 -18 3.98 Left paracentral lobule/medial frontal gyrus (BA 4, 5, 6) -3 -36 66 3.79 Right paracentral lobule/medial frontal gyrus (BA 4, 6) 9 -33 72 3.56 Left cerebellum -24 -90 -36 3.67 Left thalamus -18 -27 15 3.64 Left inferior/middle occipital gyrus (BA 18, 19) -45 -81 -12 3.61 Left precentral gyrus (BA 3, 4) -36 -30 63 3.55 Right middle occipital gyrus/cuneus (BA 17, 18, 19) 18 -99 12 3.45 Left claustrum, insula (BA 13), putamen -36 -24 0 3.45 Left postcentral gyrus (BA 43), transverse temporal gyrus (BA 41) -51 -12 15 3.34 Left cuneus (BA 17, 18) -21 -102 -6 3.43 Right thalamus 21 -27 15 3.35 Left inferior/middle temporal gyrus (BA 20, 21) -60 -9 -21 3.34 Right fusiform/inferior temporal gyrus (BA 20) 63 -12 -30 3.20 Right precentral gyrus (BA 4) 33 -21 54 3.09

Connectivity with PCC Bilateral posterior cingulate/precuneus (BA 23, 29, 30, 31) -3 -57 24 6.51 Right superior/middle temporal gyrus, angular gyrus (BA 39) 54 -63 24 5.07 Left middle temporal/angular gyrus (BA 39) -48 -72 33 4.95 Left medial frontal gyrus, anterior cingulate (BA 10, 11, 32) -6 48 -12 4.54 Right medial frontal gyrus, anterior cingulate (BA 9, 10, 32) 6 54 18 4.01 Right parahippocampal/fusiform gyrus (BA 20, 27, 36, 37) 30, -30, -18 4.07 right superior/middle frontal gyrus (BA 8, 9) 27 30 51 3.68 Left superior/middle frontal gyrus (BA 8, 9) -18 36 45 3.15 Left inferior frontal gyrus (BA 47) -30 33 -15 3.08

Abbreviations: BA = Brodmann area; BPD = Borderline Personality Disorder; MNI = Montreal Neurological Institute; mPFC = medial prefrontal cortex; PCC = posterior cingulate cortex. * Peak activation voxels are thresholded at p < 0.005 (uncorrected) at the voxel-level, in addition to multiple comparisons correction using a cluster extent correction procedure based on random field theory.58_ENREF_57

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eTable 5: Areas showing connectivity with the two seed regions during “pain” greater than “neutral” – within-group results Brain region MNI coordinates z Score Controls Connectivity with mPFC -

Connectivity with PCC Left inferior frontal/superior temporal gyrus, insula (BA 13, 38, 47) -48 15 -15 3.15

Patients with BPD Connectivity with mPFC Right inferior parietal lobule (BA 40) 66 -36 30 3.28

Connectivity with PCC Right inferior parietal lobule/supramarginal gyrus (BA 40) 66 -39 30 4.77 Left inferior parietal lobule/supramarginal gyrus (BA 40) -63 -42 36 4.34 Right inferior frontal/superior temporal gyrus, insula (BA 13, 44, 45) 54 21 6 4.06 Left inferior frontal gyrus -51 6 18 3.96 Left mid-cingulate gyrus (BA 24) 0 15 24 3.28 Left cerebellum -27 -66 -30 2.91

Abbreviations: BA = Brodmann area; MNI = Montreal Neurological Institute; mPFC = medial prefrontal cortex; PCC = posterior cingulate cortex. * Peak activation voxels are thresholded at p < 0.005 (uncorrected) at the voxel-level, in addition to multiple comparisons correction using a cluster extent correction procedure based on random field theory.58_ENREF_57

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