Abstract
The brain contains both generalized and stimulus-type-specific representations of aversive events, but models of how these are integrated and related to subjective experience are lacking. We combined functional magnetic resonance imaging with predictive modeling to identify representations of generalized (common) and stimulus-type-specific negative affect across mechanical pain, thermal pain, aversive sounds and aversive images of four intensity levels each. This allowed us to examine how generalized and stimulus-specific representations jointly contribute to aversive experience. Stimulus-type-specific negative affect was largely encoded in early sensory pathways, whereas generalized negative affect was encoded in a distributed set of midline, forebrain, insular and somatosensory regions. All models specifically predicted negative affect rather than general salience or arousal and accurately predicted negative affect in independent samples, demonstrating robustness and generalizability. Common and stimulus-type-specific models were jointly important for predicting subjective experience. Together, these findings offer an integrated account of how negative affect is constructed in the brain and provide predictive neuromarkers for future studies.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 per month
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$189.00 per year
only $15.75 per issue
Rent or buy this article
Get just this article for as long as you need it
$39.95
Prices may be subject to local taxes which are calculated during checkout






Data availability
Brain patterns generated and analyzed during the current study, as well as source data for figures are freely available via . The dataset used in study 6 is available at https://github.com/cocoanlab/interpret_ml_neuroimaging/.
Code availability
Code for analysis and for generating figures is openly shared at https://github.com/canlab/2021_Ceko_MPA2_Aversive/. Analyses reported in this paper were performed using code release v1.0.1 (https://doi.org/10.5281/zenodo.6452244).
References
Berridge, K. C. & Kringelbach, M. L. Neuroscience of affect: brain mechanisms of pleasure and displeasure. Curr. Opin. Neurobiol. 23, 294–303 (2013).
Tye, K. M. Neural circuit motifs in valence processing. Neuron 100, 436–452 (2018).
Russell, J. A. A circumplex model of affect. J. Pers. Soc. Psychol. 39, 1161–1178 (1980).
Russell, J. A. & Barrett, L. F. Core affect, prototypical emotional episodes, and other things called emotion: dissecting the elephant. J. Pers. Soc. Psychol. 76, 805–819 (1999).
Gray, J. A. The Psychology of Fear and Stress. (CUP Archive, 1987).
Montague, P. R. & Berns, G. S. Neural economics and the biological substrates of valuation. Neuron 36, 265–284 (2002).
Padoa-Schioppa, C. & Assad, J. A. Neurons in the orbitofrontal cortex encode economic value. Nature 441, 223–226 (2006).
Hariri, A. R. et al. A susceptibility gene for affective disorders and the response of the human amygdala. Arch. Gen. Psychiatry 62, 146–152 (2005).
Bishop, S., Duncan, J., Brett, M. & Lawrence, A. D. Prefrontal cortical function and anxiety: controlling attention to threat-related stimuli. Nat. Neurosci. 7, 184–188 (2004).
Duerden, E. G. & Albanese, M.-C. Localization of pain-related brain activation: a meta-analysis of neuroimaging data. Hum. Brain Mapp. 34, 109–149 (2013).
Insel, T. et al. Research domain criteria (RDoC): toward a new classification framework for research on mental disorders. Am. J. Psychiatry 167, 748–751 (2010).
Hayden, B. Y. & Niv, Y. The case against economic values in the orbitofrontal cortex (or anywhere else in the brain). Behav. Neurosci. 135, 192–201 (2021).
Gehrlach, D. A. et al. Aversive state processing in the posterior insular cortex. Nat. Neurosci. 22, 1424–1437 (2019).
Corradi-Dell’Acqua, C., Tusche, A., Vuilleumier, P. & Singer, T. Cross-modal representations of first-hand and vicarious pain, disgust and fairness in insular and cingulate cortex. Nat. Commun. 7, 10904 (2016).
Kragel, P. A. et al. Generalizable representations of pain, cognitive control, and negative emotion in medial frontal cortex. Nat. Neurosci. 21, 283–289 (2018).
Chikazoe, J., Lee, D. H., Kriegeskorte, N. & Anderson, A. K. Population coding of affect across stimuli, modalities and individuals. Nat. Neurosci. 17, 1114–1122 (2014).
Kober, H. et al. Functional grouping and cortical-subcortical interactions in emotion: a meta-analysis of neuroimaging studies. Neuroimage 42, 998–1031 (2008).
Satpute, A. B. et al. Involvement of sensory regions in affective experience: a meta-analysis. Front. Psychol. 6, 1860 (2015).
Ekman, P. An argument for basic emotions. Cognition Emot. 6, 169–200 (1992).
Friedman, B. H. Feelings and the body: the Jamesian perspective on autonomic specificity of emotion. Biol. Psychol. 84, 383–393 (2010).
Barrett, L. F. Solving the emotion paradox: categorization and the experience of emotion. Pers. Soc. Psychol. Rev. 10, 20–46 (2006).
Saarimäki, H. et al. Discrete neural signatures of basic emotions. Cereb. Cortex 26, 2563–2573 (2016).
Kragel, P. A. & LaBar, K. S. Multivariate neural biomarkers of emotional states are categorically distinct. Soc. Cogn. Affect. Neurosci. 10, 1437–1448 (2015).
Stephens, C. L., Christie, I. C. & Friedman, B. H. Autonomic specificity of basic emotions: evidence from pattern classification and cluster analysis. Biol. Psychol. 84, 463–473 (2010).
Horing, B., Sprenger, C. & Büchel, C. The parietal operculum preferentially encodes heat pain and not salience. PLoS Biol. 17, e3000205 (2019).
Wager, T. D. et al. A Bayesian model of category-specific emotional brain responses. PLoS Comput. Biol. 11, e1004066 (2015).
Kragel, P. A., Reddan, M. C., LaBar, K. S. & Wager, T. D. Emotion schemas are embedded in the human visual system. Sci. Adv. 5, eaaw4358 (2019).
Corder, G. et al. An amygdalar neural ensemble that encodes the unpleasantness of pain. Science 363, 276–281 (2019).
Hua, T. et al. General anesthetics activate a potent central pain-suppression circuit in the amygdala. Nat. Neurosci. 23, 854–868 (2020).
Chiang, M. C. et al. Divergent neural pathways emanating from the lateral parabrachial nucleus mediate distinct components of the pain response. Neuron 106, 927–939 (2020).
Allen, W. E. et al. Thirst-associated preoptic neurons encode an aversive motivational drive. Science 357, 1149–1155 (2017).
Allen, W. E. et al. Thirst regulates motivated behavior through modulation of brainwide neural population dynamics. Science 364, 253 (2019).
Pool, A.-H. et al. The cellular basis of distinct thirst modalities. Nature 588, 112–117 (2020).
McIntosh, A. R. & Lobaugh, N. J. Partial least squares analysis of neuroimaging data: applications and advances. Neuroimage 23, 250–263 (2004).
Wold, S., Sjöström, M. & Eriksson, L. PLS-regression: a basic tool of chemometrics. Chemom. Intell. Lab. Syst. 58, 109–130 (2001).
Woo, C.-W., Chang, L. J., Lindquist, M. A. & Wager, T. D. Building better biomarkers: brain models in translational neuroimaging. Nat. Neurosci. 20, 365–377 (2017).
Poldrack, R. A., Huckins, G. & Varoquaux, G. Establishment of best practices for evidence for prediction: a review. JAMA Psychiatry 77, 534–540 (2020).
Nimon, K., Lewis, M., Kane, R. & Haynes, R. M. An R package to compute commonality coefficients in the multiple regression case: an introduction to the package and a practical example. Behav. Res. Methods 40, 457–466 (2008).
Haufe, S. et al. On the interpretation of weight vectors of linear models in multivariate neuroimaging. Neuroimage 87, 96–110 (2014).
Hayes, D. J. & Northoff, G. Identifying a network of brain regions involved in aversion-related processing: a cross-species translational investigation. Front. Integr. Neurosci. 5, 49 (2011).
Lindquist, K. A., Satpute, A. B., Wager, T. D., Weber, J. & Barrett, L. F. The brain basis of positive and negative affect: evidence from a meta-analysis of the human neuroimaging literature. Cereb. Cortex 26, 1910–1922 (2016).
Panzeri, S., Macke, J. H., Gross, J. & Kayser, C. Neural population coding: combining insights from microscopic and mass signals. Trends Cogn. Sci. 19, 162–172 (2015).
Mouraux, A., Diukova, A., Lee, M. C., Wise, R. G. & Iannetti, G. D. A multisensory investigation of the functional significance of the ‘pain matrix’. Neuroimage 54, 2237–2249 (2011).
Liang, M., Mouraux, A., Hu, L. & Iannetti, G. D. Primary sensory cortices contain distinguishable spatial patterns of activity for each sense. Nat. Commun. 4, 1979 (2013).
Shuler, M. G. & Bear, M. F. Reward timing in the primary visual cortex. Science 311, 1606–1609 (2006).
Kragel, P. A. et al. A human colliculus-pulvinar-amygdala pathway encodes negative emotion. Neuron https://doi.org/10.1016/j.neuron.2021.06.001 (2021).
Pessoa, L. & Adolphs, R. Emotion processing and the amygdala: from a ‘low road’ to ‘many roads’ of evaluating biological significance. Nat. Rev. Neurosci. 11, 773–783 (2010).
Chen, C., Cheng, M., Ito, T. & Song, S. Neuronal organization in the inferior colliculus revisited with cell-type-dependent monosynaptic tracing. J. Neurosci. 38, 3318–3332 (2018).
Tan, L. L. & Kuner, R. Neocortical circuits in pain and pain relief. Nat. Rev. Neurosci. 22, 458–471 (2021).
Mogil, J. S. The genetic mediation of individual differences in sensitivity to pain and its inhibition. Proc. Natl Acad. Sci. USA 96, 7744–7751 (1999).
Baron, R. et al. Peripheral neuropathic pain: a mechanism-related organizing principle based on sensory profiles. Pain 158, 261–272 (2017).
Price, D. D. Psychological and neural mechanisms of the affective dimension of pain. Science 288, 1769–1772 (2000).
Satpute, A. B. et al. Identification of discrete functional subregions of the human periaqueductal gray. Proc. Natl Acad. Sci. USA 110, 17101–17106 (2013).
Craig, A. D., Bushnell, M. C., Zhang, E. T. & Blomqvist, A. A thalamic nucleus specific for pain and temperature sensation. Nature 372, 770–773 (1994).
Woo, C.-W. et al. Quantifying cerebral contributions to pain beyond nociception. Nat. Commun. 8, 14211 (2017).
Anderson, A. K. & Sobel, N. Dissociating intensity from valence as sensory inputs to emotion. Neuron 39, 581–583 (2003).
Wehrum, S. et al. Gender commonalities and differences in the neural processing of visual sexual stimuli. J. Sex. Med. 10, 1328–1342 (2013).
Neugebauer, V. Amygdala pain mechanisms. Handb. Exp. Pharmacol. 227, 261–284 (2015).
Kim, J., Shinkareva, S. V. & Wedell, D. H. Representations of modality-general valence for videos and music derived from fMRI data. Neuroimage 148, 42–54 (2017).
Li, J., Schiller, D., Schoenbaum, G., Phelps, E. A. & Daw, N. D. Differential roles of human striatum and amygdala in associative learning. Nat. Neurosci. 14, 1250–1252 (2011).
Belova, M. A., Paton, J. J. & Salzman, C. D. Moment-to-moment tracking of state value in the amygdala. J. Neurosci. 28, 10023–10030 (2008).
Hayes, D. J. & Northoff, G. Common brain activations for painful and non-painful aversive stimuli. BMC Neurosci. 13, 60 (2012).
Villemure, C. & Bushnell, M. C. Mood influences supraspinal pain processing separately from attention. J. Neurosci. 29, 705–715 (2009).
Roy, M., Piché, M., Chen, J.-I., Peretz, I. & Rainville, P. Cerebral and spinal modulation of pain by emotions. Proc. Natl Acad. Sci. USA 106, 20900–20905 (2009).
Anders, S., Eippert, F., Weiskopf, N. & Veit, R. The human amygdala is sensitive to the valence of pictures and sounds irrespective of arousal: an fMRI study. Soc. Cogn. Affect. Neurosci. 3, 233–243 (2008).
Woo, C.-W. et al. Separate neural representations for physical pain and social rejection. Nat. Commun. 5, 5380 (2014).
Peelen, M. V. & Downing, P. E. Using multi-voxel pattern analysis of fMRI data to interpret overlapping functional activations. Trends Cogn. Sci. 11, 4–5 (2007).
Tomova, L. et al. Acute social isolation evokes midbrain craving responses similar to hunger. Nat. Neurosci. 23, 1597–1605 (2020).
Woolf, C. J. Central sensitization: implications for the diagnosis and treatment of pain. Pain 152, S2–S15 (2011).
Ceko, M., Bushnell, M. C., Fitzcharles, M.-A. & Schweinhardt, P. Fibromyalgia interacts with age to change the brain. Neuroimage Clin. 3, 249–260 (2013).
López-Solà, M. et al. Towards a neurophysiological signature for fibromyalgia. Pain 158, 34–47 (2017).
Grothusen, J. R., Alexander, G., Erwin, K. & Schwartzman, R. Thermal pain in complex regional pain syndrome type I. Pain Physician 17, 71–79 (2014).
Eippert, F. et al. Activation of the opioidergic descending pain control system underlies placebo analgesia. Neuron 63, 533–543 (2009).
Wager, T. D. et al. An fMRI-based neurologic signature of physical pain. N. Engl. J. Med. 368, 1388–1397 (2013).
Bartoshuk, L. M. et al. Valid across-group comparisons with labeled scales: the gLMS versus magnitude matching. Physiol. Behav. 82, 109–114 (2004).
Hayes, J. E., Allen, A. L. & Bennett, S. M. Direct comparison of the generalized visual analog scale and general labeled magnitude scale. Food Qual. Prefer. 28, 36–44 (2013).
Kumar, S., Forster, H. M., Bailey, P. & Griffiths, T. D. Mapping unpleasantness of sounds to their auditory representation. J. Acoust. Soc. Am. 124, 3810–3817 (2008).
Kumar, S., von Kriegstein, K., Friston, K. & Griffiths, T. D. Features versus feelings: dissociable representations of the acoustic features and valence of aversive sounds. J. Neurosci. 32, 14184–14192 (2012).
Lang, P. J., Bradley, M. M. & Cuthbert, B. N. International affective picture system (IAPS): affective ratings of pictures and instruction manual. Technical Report A-8. University of Florida, Gainesville (2008).
Op de Beeck, H. P. Against hyperacuity in brain reading: spatial smoothing does not hurt multivariate fMRI analyses? Neuroimage 49, 1943–1948 (2010).
Genovese, C. R., Lazar, N. A. & Nichols, T. Thresholding of statistical maps in functional neuroimaging using the false discovery rate. Neuroimage 15, 870–878 (2002).
Thompson, B. & Borrello, G. M. The importance of structure coefficients in regression research. Educ. Psychol. Meas. 45, 203–209 (1985).
Parra, L. C., Spence, C. D., Gerson, A. D. & Sajda, P. Recipes for the linear analysis of EEG. Neuroimage 28, 326–341 (2005).
Kohoutová, L. et al. Toward a unified framework for interpreting machine-learning models in neuroimaging. Nat. Protoc. https://doi.org/10.1038/s41596-019-0289-5 (2020).
Mumford, J. A. & Nichols, T. Simple group fMRI modeling and inference. Neuroimage 47, 1469–1475 (2009).
Bota, M. & Swanson, L. W. BAMS Neuroanatomical Ontology: design and implementation. Front. Neuroinformatics 2, 2 (2008).
Acknowledgements
We thank D. Ott, J. Griffin, E. Biringen and T. Wilkes for assistance with data collection; P. Gianaros for sharing data included in study 4 and R. Stark for sharing data included in study 6; and R. Botvinik-Nezer, K. Zorina-Lichtenwalter and B. Petre for helpful comments on earlier versions of the manuscript. This work was funded by NIH R01DA035484 (to T.D.W.). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.
Author information
Authors and Affiliations
Contributions
M.C., C.-W.W., M.L.-S. and T.D.W. conceived and designed the experiment for studies 1 and 2, and P.A.K. and T.D.W. conceived and designed the experiment for study 3. M.C. and C.-W.W. collected and preprocessed the data for studies 1 and 2, and P.A.K. collected and preprocessed the data for study 3. M.C., P.A.K. and T.D.W. analyzed the data and interpreted the results. M.C. created the figures, with intellectual input from all other authors. M.C. and T.D.W. wrote the manuscript. All authors edited the manuscript.
Corresponding authors
Ethics declarations
Competing interests
The authors declare no competing interests.
Peer review
Peer review information
Nature Neuroscience thanks Junichi Chikazoe and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Extended data
Extended Data Fig. 1 PLS-R models trained to predict normative ratings to negative (aversive) and positive (pleasant) IAPS images.
(a) PLS-R procedure to estimate brain patterns for ‘arousal’ (common across stimuli) and for stimulus type-specific outcomes (IAPS norm ratings) simultaneously (b) Behavior plots. Left: normative ratings shown for each individual stimulus (that is, IAPS image); original IAPS scales (1–9 scales for Valence (higher score = less negative / more positive; 0 is neutral) and Arousal (higher score = more arousing). Right: norm ratings averaged per bin (‘stimulus intensity level’, used for PLS-R training) and shown on a 0–4 split scale (higher score = more negative / more positive; 0 is neutral); Pattern response plots. Relationship between observed and predicted ratings. Circles reflect mean values across participants for each stimulus type, error bars reflect within-participant SEM. ‘Arousal’ model (panel 1), trained on all stimuli, significantly predicted ratings across stimulus types. Stimulus type-specific models (panels 2–3) significantly predicted ratings to target (color-matched), but not off-target stimulus type. r, mean within-participant Pearson correlation between predicted and observed ratings; two-sided P-values based on a 10,000 samples bootstrap test of within-participant r values. (c) Left: PLS-R model weight maps showing which brain areas make a reliable contribution to each model’s prediction (based on bootstrapping with 10,000 samples and displayed here at t > 3, retaining positive values). Right: Model encoding maps showing where in the brain voxel-wise activity correlates with PLS model outcomes, corrected for multiple comparisons using q < 0.05 FDR and thresholded at t > 3, retaining positive values. (d) Violin plots showing average BOLD response per stimulus intensity (x-axis) in bilateral ventral striatum (vStr) and amygdala ROIs (Supplementary Table 7), * p = 0.047, ** p = 0.002, * p < 0.001 (left panels); Mean structure coefficient values for each model, averaged across in-ROI voxels across both hemispheres, * p < 0.001, only p-values associated with positive t-values are marked and interpreted, each dot is a participant (right panels); one-sample t-test on n = 55 participants, treating participant as random effect, bars reflect mean values across participants for each stimulus type, error bars reflect within-participant SEM.(e) 3D surface maps of vStr and amy are displaying FDR-corrected model encoding maps for PLS ‘norm’ models of positive and negative images, and for the PLS model trained on participants’ ratings of negative images (Analysis 1).
Supplementary information
Supplementary Information
Supplementary Methods, Figs. 1–4 and Tables 1–10
Rights and permissions
About this article
Cite this article
Čeko, M., Kragel, P.A., Woo, CW. et al. Common and stimulus-type-specific brain representations of negative affect. Nat Neurosci 25, 760–770 (2022). https://doi.org/10.1038/s41593-022-01082-w
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41593-022-01082-w
This article is cited by
-
A neuromarker for drug and food craving distinguishes drug users from non-users
Nature Neuroscience (2023)
-
Refining the negative into general and specific
Nature Neuroscience (2022)