Pain-free resting-state functional brain connectivity predicts individual pain sensitivity

Individual differences in pain perception are of key interest in basic and clinical research as altered pain sensitivity is both a characteristic and a risk factor for many pain conditions. It is, however, unclear how individual susceptibility to pain is reflected in the pain-free resting-state brain activity and functional connectivity. Here, we identified and validated a network pattern in the pain-free resting-state functional brain connectome that is predictive of interindividual differences in pain sensitivity. Our predictive network signature (https://spisakt.github.io/RPN-signature) allows assessing the individual susceptibility to pain without applying any painful stimulation, as might be valuable in patients where reliable behavioural pain reports cannot be obtained. Additionally, as a direct, non-invasive readout of the supraspinal neural contribution to pain sensitivity, it may have broad implications for translational research and the development and assessment of analgesic treatment strategies.

[1]  Stefan Knecht,et al.  Pain sensitivity can be assessed by self-rating: Development and validation of the Pain Sensitivity Questionnaire , 2009, PAIN.

[2]  Abraham Z. Snyder,et al.  Steps toward optimizing motion artifact removal in functional connectivity MRI; a reply to Carp , 2013, NeuroImage.

[3]  K. Sandberg,et al.  Is whole-brain functional connectivity a neuromarker of sustained attention? Comment on Rosenberg & al. (2016) , 2017, bioRxiv.

[4]  D. Lehr,et al.  Screening depressiver Störungen mittels Allgemeiner Depressions- Skala (ADS-K) und State-Trait Depressions Scales (STDS-T) Eine vergleichende Evaluation von Cut-Off-Werten , 2008 .

[5]  Miklós Emri,et al.  Voxel-Wise Motion Artifacts in Population-Level Whole-Brain Connectivity Analysis of Resting-State fMRI , 2014, PloS one.

[6]  K. Wiech,et al.  Neurocognitive aspects of pain perception , 2008, Trends in Cognitive Sciences.

[7]  Christos Davatzikos,et al.  Benchmarking of participant-level confound regression strategies for the control of motion artifact in studies of functional connectivity , 2017, NeuroImage.

[8]  Irene Tracey,et al.  The influence of negative emotions on pain: Behavioral effects and neural mechanisms , 2009, NeuroImage.

[9]  K. Wiech,et al.  Differential structural and resting state connectivity between insular subdivisions and other pain-related brain regions , 2014, PAIN®.

[10]  Christian Büchel,et al.  The parietal operculum preferentially encodes heat pain and not salience , 2019 .

[11]  Richard E. Harris,et al.  Combined glutamate and glutamine levels in pain-processing brain regions are associated with individual pain sensitivity , 2016, Pain.

[12]  Stephen M Smith,et al.  Correspondence of the brain's functional architecture during activation and rest , 2009, Proceedings of the National Academy of Sciences.

[13]  Donald M. Steinwachs,et al.  Promises and pitfalls of the , 1997 .

[14]  A. Pollard,et al.  Limb proportions show developmental plasticity in response to embryo movement , 2017, Scientific Reports.

[15]  N. Crone,et al.  Analysis of synchrony demonstrates that the presence of “pain networks” prior to a noxious stimulus can enable the perception of pain in response to that stimulus , 2008, Experimental Brain Research.

[16]  Chris Leptak,et al.  What evidence do we need for biomarker qualification? , 2017, Science Translational Medicine.

[17]  Nikolaus Kriegeskorte,et al.  How does an fMRI voxel sample the neuronal activity pattern: Compact-kernel or complex spatiotemporal filter? , 2010, NeuroImage.

[18]  NeuroData,et al.  Towards Automated Analysis of Connectomes: The Configurable Pipeline for the Analysis of Connectomes , 2015 .

[19]  Ishtiaq Mawla,et al.  The relationship between catastrophizing and altered pain sensitivity in patients with chronic low-back pain , 2018, Pain.

[20]  Katja Wiech,et al.  Prestimulus functional connectivity determines pain perception in humans , 2009, Proceedings of the National Academy of Sciences.

[21]  K. Davis,et al.  Mind wandering away from pain dynamically engages antinociceptive and default mode brain networks , 2013, Proceedings of the National Academy of Sciences.

[22]  B. Rosen,et al.  Functional connectivity of the frontoparietal network predicts cognitive modulation of pain , 2013, PAIN®.

[23]  Pierre Bellec,et al.  MIST: A multi-resolution parcellation of functional brain networks , 2017, MNI Open Research.

[24]  S. Evans,et al.  What Has Replication Ever Done for Us? Insights from Neuroimaging of Speech Perception , 2017, Front. Hum. Neurosci..

[25]  Christoph S. Herrmann,et al.  Transcranial Alternating Current Stimulation (tACS) Enhances Mental Rotation Performance during and after Stimulation , 2017, Front. Hum. Neurosci..

[26]  Martin A Lindquist,et al.  Quantifying cerebral contributions to pain beyond nociception , 2017, Nature Communications.

[27]  Thomas J. Schnitzer,et al.  Corticostriatal functional connectivity predicts transition to chronic back pain , 2012, Nature Neuroscience.

[28]  Steven C. Cramer,et al.  Resting-state cortical connectivity predicts motor skill acquisition , 2014, NeuroImage.

[29]  P. Haggard,et al.  Linking Pain and the Body: Neural Correlates of Visually Induced Analgesia , 2012, The Journal of Neuroscience.

[30]  Garret A. FitzGerald,et al.  Measure for Measure: Biomarker standards and transparency , 2016, Science Translational Medicine.

[31]  C Büchel,et al.  Somatotopic representation of nociceptive information in the putamen: an event-related fMRI study. , 2004, Cerebral cortex.

[32]  H. Merskey,et al.  Classification of chronic pain. Descriptions of chronic pain syndromes and definitions of pain terms. Prepared by the International Association for the Study of Pain, Subcommittee on Taxonomy. , 1994, Pain. Supplement.

[33]  Miroslav Backonja,et al.  Usefulness and limitations of quantitative sensory testing: Clinical and research application in neuropathic pain states , 2007, PAIN.

[34]  Lao Juan,et al.  Development and Validation of a Scale for Measuring Instructors' Attitudes toward Concept-Based or Reform-Oriented Teaching of Introductory Statistics in the Health and Behavioral Sciences , 2010, 1007.3219.

[35]  Christopher. Simons,et al.  Machine learning with Python , 2017 .

[36]  F. Birklein,et al.  Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): Standardized protocol and reference values , 2006, PAIN.

[37]  Karl J. Friston,et al.  Movement‐Related effects in fMRI time‐series , 1996, Magnetic resonance in medicine.

[38]  Satrajit S. Ghosh,et al.  Nipype: A Flexible, Lightweight and Extensible Neuroimaging Data Processing Framework in Python , 2011, Front. Neuroinform..

[39]  Ninon Burgos,et al.  New advances in the Clinica software platform for clinical neuroimaging studies , 2019 .

[40]  Elisabeth Gerver,et al.  Promises and Pitfalls , 1986 .

[41]  Julia M. Huntenburg,et al.  Loading and plotting of cortical surface representations in Nilearn , 2017 .

[42]  Naomi B. Pitskel,et al.  Three Systems of Insular Functional Connectivity Identified with Cluster Analysis , 2010, Cerebral cortex.

[43]  Abraham Z. Snyder,et al.  Spurious but systematic correlations in functional connectivity MRI networks arise from subject motion , 2012, NeuroImage.

[44]  Vince D. Calhoun,et al.  Single subject prediction of brain disorders in neuroimaging: Promises and pitfalls , 2017, NeuroImage.

[45]  Mark W. Woolrich,et al.  FSL , 2012, NeuroImage.

[46]  D. Seminowicz,et al.  Partial recovery of abnormal insula and dorsolateral prefrontal connectivity to cognitive networks in chronic low back pain after treatment , 2015, Human brain mapping.

[47]  Satrajit S. Ghosh,et al.  FMRIPrep: a robust preprocessing pipeline for functional MRI , 2018, bioRxiv.

[48]  Szabolcs David,et al.  Central sensitization-related changes of effective and functional connectivity in the rat inflammatory trigeminal pain model , 2017, Neuroscience.

[49]  Luke J. Chang,et al.  Building better biomarkers: brain models in translational neuroimaging , 2017, Nature Neuroscience.

[50]  Danielle S Bassett,et al.  Mitigating head motion artifact in functional connectivity MRI , 2018, Nature Protocols.

[51]  Joshua Carp,et al.  Optimizing the order of operations for movement scrubbing: Comment on Power et al. , 2013, NeuroImage.

[52]  Michael Eickenberg,et al.  Machine learning for neuroimaging with scikit-learn , 2014, Front. Neuroinform..

[53]  S. Powers,et al.  Increased pain sensitivity but normal pain modulation in adolescents with migraine , 2019, Pain.

[54]  Correction for Coghill et al., Neural correlates of interindividual differences in the subjective experience of pain , 2017, Proceedings of the National Academy of Sciences.

[55]  Simon B. Eickhoff,et al.  An improved framework for confound regression and filtering for control of motion artifact in the preprocessing of resting-state functional connectivity data , 2013, NeuroImage.

[56]  J. Farrar,et al.  The dorsal posterior insula subserves a fundamental role in human pain , 2015, Nature Neuroscience.

[57]  M. Boly,et al.  Baseline brain activity fluctuations predict somatosensory perception in humans , 2007, Proceedings of the National Academy of Sciences.

[58]  Hadley Wickham,et al.  ggplot2 - Elegant Graphics for Data Analysis (2nd Edition) , 2017 .

[59]  I. Tracey Finding the Hurt in Pain , 2016, Cerebrum : the Dana forum on brain science.

[60]  S. Levenstein,et al.  Development of the Perceived Stress Questionnaire: a new tool for psychosomatic research. , 1993, Journal of psychosomatic research.

[61]  Roland Staud,et al.  Individual differences in pain sensitivity: measurement, causation, and consequences. , 2009, The journal of pain : official journal of the American Pain Society.

[62]  Stephen M. Smith,et al.  fMRI resting state networks define distinct modes of long-distance interactions in the human brain , 2006, NeuroImage.

[63]  A. Crawley,et al.  Regional brain signal variability: a novel indicator of pain sensitivity and coping , 2016, Pain.

[64]  C. Spielberger State‐Trait Anxiety Inventory , 2010 .

[65]  Nicola Filippini,et al.  Structural Connectivity Variances Underlie Functional and Behavioral Changes During Pain Relief Induced by Neuromodulation , 2017, Scientific Reports.

[66]  Daniel J Buysse,et al.  The Pittsburgh sleep quality index: A new instrument for psychiatric practice and research , 1989, Psychiatry Research.

[67]  Arno Klein,et al.  A reproducible evaluation of ANTs similarity metric performance in brain image registration , 2011, NeuroImage.

[68]  Roland Eils,et al.  circlize implements and enhances circular visualization in R , 2014, Bioinform..

[69]  Jacob Cohen Statistical Power Analysis for the Behavioral Sciences , 1969, The SAGE Encyclopedia of Research Design.

[70]  Kevin Murphy,et al.  Towards a consensus regarding global signal regression for resting state functional connectivity MRI , 2017, NeuroImage.

[71]  Tor D Wager,et al.  Predicting Individual Differences in Placebo Analgesia: Contributions of Brain Activity during Anticipation and Pain Experience , 2011, The Journal of Neuroscience.

[72]  N. Prins Psychophysics: A Practical Introduction , 2009 .

[73]  H. Kugel,et al.  Gray matter correlates of pressure pain thresholds and self-rated pain sensitivity: a voxel-based morphometry study , 2018, Pain.

[74]  A. Dickenson,et al.  Morphine effects within the rodent anterior cingulate cortex and rostral ventromedial medulla reveal separable modulation of affective and sensory qualities of acute or chronic pain , 2018, Pain.

[75]  Thomas T. Liu,et al.  A component based noise correction method (CompCor) for BOLD and perfusion based fMRI , 2007, NeuroImage.

[76]  S. Bruehl,et al.  The relationship between pain sensitivity and blood pressure in normotensives , 1992, Pain.

[77]  C. Spielberger,et al.  Manual for the State-Trait Anxiety Inventory , 1970 .

[78]  H. Zou,et al.  Regularization and variable selection via the elastic net , 2005 .

[79]  David Cella,et al.  Interpreting the clinical importance of treatment outcomes in chronic pain clinical trials: IMMPACT recommendations. , 2008, The journal of pain : official journal of the American Pain Society.

[80]  R. Treede,et al.  Human brain mechanisms of pain perception and regulation in health and disease , 2005, European journal of pain.

[81]  Clifford J. Woolf,et al.  Composite Pain Biomarker Signatures for Objective Assessment and Effective Treatment , 2019, Neuron.

[82]  Juri D. Kropotov,et al.  Functional Neuromarkers in Diseased Brain , 2016 .

[83]  Satrajit S. Ghosh,et al.  The brain imaging data structure, a format for organizing and describing outputs of neuroimaging experiments , 2016, Scientific Data.

[84]  Ming Li,et al.  Impact of global signal regression on characterizing dynamic functional connectivity and brain states , 2018, NeuroImage.

[85]  B. Vogt Pain and emotion interactions in subregions of the cingulate gyrus , 2005, Nature Reviews Neuroscience.

[86]  Ben D. Fulcher,et al.  An evaluation of the efficacy, reliability, and sensitivity of motion correction strategies for resting-state functional MRI , 2017, NeuroImage.

[87]  R W Cox,et al.  AFNI: software for analysis and visualization of functional magnetic resonance neuroimages. , 1996, Computers and biomedical research, an international journal.

[88]  Li Qingyang,et al.  Towards Automated Analysis of Connectomes: The Configurable Pipeline for the Analysis of Connectomes (C-PAC) , 2013 .

[89]  Robert C. Coghill,et al.  Neural correlates of interindividual differences in the subjective experience of pain , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[90]  Evian Gordon,et al.  Integrating genomics and neuromarkers for the era of brain-related personalized medicine. , 2007, Personalized medicine.

[91]  Scott R. Bishop,et al.  The Pain Catastrophizing Scale: Development and validation. , 1995 .

[92]  Mark W. Woolrich,et al.  Network modelling methods for FMRI , 2011, NeuroImage.

[93]  A. Straube,et al.  Altered experimental pain perception after cerebellar infarction , 2014, PAIN®.

[94]  Gaël Varoquaux,et al.  Cross-validation failure: Small sample sizes lead to large error bars , 2017, NeuroImage.

[95]  Gian Domenico Iannetti,et al.  Alpha and gamma oscillation amplitudes synergistically predict the perception of forthcoming nociceptive stimuli , 2015, Human brain mapping.

[96]  M. Lindquist,et al.  An fMRI-based neurologic signature of physical pain. , 2013, The New England journal of medicine.

[97]  Heidi Johansen-Berg,et al.  Model-free characterization of brain functional networks for motor sequence learning using fMRI , 2008, NeuroImage.

[98]  Gaël Varoquaux,et al.  Benchmarking functional connectome-based predictive models for resting-state fMRI , 2019, NeuroImage.

[99]  L. Becerra,et al.  Mapping pain activation and connectivity of the human habenula. , 2012, Journal of neurophysiology.

[100]  Ravi S. Menon,et al.  Dissociating pain from its anticipation in the human brain. , 1999, Science.