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Altered Cerebellar Activity in Visceral Pain-Related Fear Conditioning in Irritable Bowel Syndrome

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Abstract

There is evidence to support a role of the cerebellum in emotional learning processes, which are demonstrably altered in patients with chronic pain. We tested if cerebellar activation is altered during visceral pain-related fear conditioning and extinction in irritable bowel syndrome (IBS). Cerebellar blood oxygenation level-dependent (BOLD) data from N = 17 IBS patients and N = 21 healthy controls, collected as part of a previous fMRI study, was reanalyzed utilizing an advanced normalizing method of the cerebellum. The differential fear conditioning paradigm consisted of acquisition, extinction, and reinstatement phases. During acquisition, two visual conditioned stimuli (CS) were presented either paired (CS+) or unpaired (CS−) with painful rectal distension as unconditioned stimulus (US). In the extinction phase, the CS+ and CS− were presented without US. For reinstatement, unpaired US presentations were followed by unpaired CS+ and CS− presentations. Group differences in cerebellar activation were analyzed for the contrasts CS+ > CS− and CS− > CS+. During acquisition, IBS patients revealed significantly enhanced cerebellar BOLD responses to pain-predictive (CS+) and safety (CS−) cues compared to controls (p < 0.05, family-wise error corrected). Increased activation was found in three main clusters, including the vermis (maximum in vermal lobule VI), intermediate cerebellum (maximum in lobule VIII), and the posterolateral cerebellar hemisphere (maximum in lobule VI). Areas overlapped for the contrasts CS+ > CS− and CS− > CS+. Group differences were most prominent in the contrast CS− > CS+. During extinction and reinstatement, no significant group differences were found. During visceral pain-related fear conditioning, IBS patients showed increased activations in circumscribed areas of the medial, intermediate, and lateral cerebellum. These areas are involved in autonomic, somatosensory, and cognitive functions and likely contribute to the different aspects of pain-related fear. The cerebellum contributes to altered pain-related fear learning in IBS.

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References

  1. Anand BK, Malhotra CL, Singh B, Dua S. Cerebellar projections to limbic system. J Neurophysiol. 1959;22:451–7.

    CAS  PubMed  Google Scholar 

  2. Borsook D, Erpelding N, Becerra L. Losses and gains: chronic pain and altered brain morphology. Expert Rev Neurother. 2013;13:1221–34.

    Article  CAS  PubMed  Google Scholar 

  3. Bracha V. Role of the cerebellum in eyeblink conditioning. Prog Brain Res. 2004;143:331–9.

    Article  PubMed  Google Scholar 

  4. Buckner RL. The cerebellum and cognitive function: 25 years of insight from anatomy and neuroimaging. Neuron. 2013;80:807–15.

    Article  CAS  PubMed  Google Scholar 

  5. Buckner RL, Krienen FM, Castellanos A, Diaz JC, Yeo BT. The organization of the human cerebellum estimated by intrinsic functional connectivity. J Neurophysiol. 2011;106:2322–45.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Cheng DT, Meintjes EM, Stanton ME, Desmond JE, Pienaar M, Dodge NC, Power JM, Molteno CD, Disterhoft JF, Jacobson JL, Jacobson SW. Functional MRI of cerebellar activity during eyeblink classical conditioning in children and adults. Hum Brain Mapp. 2014;35:1390–403.

    Article  PubMed  Google Scholar 

  7. De Zeeuw CI, Yeo CH. Time and tide in cerebellar memory formation. Curr Opin Neurobiol. 2005;15:667–74.

    Article  CAS  PubMed  Google Scholar 

  8. Diedrichsen J, Balsters JH, Flavell J, Cussans E, Ramnani N. A probabilistic MR atlas of the human cerebellum. NeuroImage. 2009;46:39–46.

    Article  PubMed  Google Scholar 

  9. Dimitrova A, Weber J, Maschke M, Elles HG, Kolb FP, Forsting M, Diener HC, Timmann D. Eyeblink-related areas in human cerebellum as shown by fMRI. Hum Brain Mapp. 2002;17:100–15.

    Article  PubMed  Google Scholar 

  10. Fischer H, Andersson JL, Furmark T, Fredrikson M. Fear conditioning and brain activity: a positron emission tomography study in humans. Behav Neurosci. 2000;114:671–80.

    Article  CAS  PubMed  Google Scholar 

  11. Freeman JH, Steinmetz AB. Neural circuitry and plasticity mechanisms underlying delay eyeblink conditioning. Learn Mem. 2011;18:666–77.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Frings M, Maschke M, Erichsen M, Jentzen W, Müller SP, Kolb FP, Diener HC, Timmann D. Involvement of the human cerebellum in fear-conditioned potentiation of the acoustic startle response: a PET study. Neuroreport. 2002;13:1275–8.

    Article  PubMed  Google Scholar 

  13. Fullana MA, Harrison BJ, Soriano-Mas C, Vervliet B, Cardoner N, Avila-Parcet A, Radua J. Neural signatures of human fear conditioning: an updated and extended meta-analysis of fMRI studies. Mol Psychiatry. 2015; doi:10.1038/mp.2015.88.

    PubMed  Google Scholar 

  14. Gerwig M, Kolb FP, Timmann D. The involvement of the human cerebellum in eyeblink conditioning. Cerebellum. 2007;6:38–57.

    Article  CAS  PubMed  Google Scholar 

  15. Gramsch C, Kattoor J, Icenhour A, Forsting M, Schedlowski M, Gizewski ER, Elsenbruch S. Learning pain-related fear: neural mechanisms mediating rapid differential conditioning, extinction and reinstatement processes in human visceral pain. Neurobiol Learn Mem. 2014;116C:36–45.

    Article  Google Scholar 

  16. Helmchen C, Mohr C, Erdmann C, Petersen D, Nitschke MF. Differential cerebellar activation related to perceived pain intensity during noxious thermal stimulation in humans: a functional magnetic resonance imaging study. Neurosci Lett. 2003;335:202–6.

    Article  CAS  PubMed  Google Scholar 

  17. Hermann-Lingen C, Buss U, Snaith R. Hospital Anxiety and Depression Scale (HADS-D)—Deutsche version. Bern: Huber; 2005.

    Google Scholar 

  18. Icenhour A, Langhorst J, Benson S, Schlamann M, Hampel S, Engler H, Forsting M, Elsenbruch S. Neural circuitry of abdominal pain-related fear learning and reinstatement in irritable bowel syndrome. Neurogastroenterol Motil. 2015;27:114–27.

    Article  CAS  PubMed  Google Scholar 

  19. Ito M. Mechanisms of motor learning in the cerebellum. Brain Res. 2000;886:237–45.

    Article  CAS  PubMed  Google Scholar 

  20. Jiang D, Edwards MG, Mullins P, Callow N. The neural substrates for the different modalities of movement imagery. Brain Cogn. 2015;97:22–31.

    Article  PubMed  Google Scholar 

  21. Kattoor J, Gizewski ER, Kotsis V, Benson S, Gramsch C, Theysohn N, Maderwald S, Forsting M, Schedlowski M, Elsenbruch S. Fear conditioning in an abdominal pain model: neural responses during associative learning and extinction in healthy subjects. PLoS One. 2013;8(2):e51149.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Kattoor J, Thürling M, Gizewski ER, Forsting M, Timmann D, Elsenbruch S. Cerebellar contributions to different phases of visceral aversive extinction learning. Cerebellum. 2014;13:1–8.

    Article  PubMed  Google Scholar 

  23. Koziol LF, Budding D, Andreasen N, D’Arrigo S, Bulgheroni S, Imamizu H, Ito M, Manto M, Marvel C, Parker K, Pezzulo G, Ramnani N, Riva D, Schmahmann J, Vandervert L, Yamazaki T. Consensus paper: the cerebellum’s role in movement and cognition. Cerebellum. 2014;13:151–77.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Labrenz F, Icenhour A, Thürling M, Schlamann M, Forsting M, Timmann D, Elsenbruch S. Sex differences in cerebellar mechanisms involved in pain-related safety learning. Neurobiol Learn Mem. 2015a;123:92–9.

    Article  PubMed  Google Scholar 

  25. Labrenz F, Icenhour A, Benson B, Elsenbruch S. Contingency awareness shapes acquisition and extinction of emotional responses in a conditioning model of pain-related fear. Front Behav Neurosci. 2015b;9:318.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Labus JS, Gupta A, Coveleskie K, Tillisch K, Kilpatrick L, Jarcho J, Feier N, Bueller J, Stains J, Smith S, Suyenobu B, Naliboff B, Mayer EA. Sex differences in emotion-related cognitive processes in irritable bowel syndrome and healthy control subjects. Pain. 2013a;154:2088–99.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Labus JS, Hubbard CS, Bueller J, Ebrat B, Tillisch K, Chen M, Stains J, Dukes GE, Kelleher DL, Naliboff BD, Fanselow M, Mayer EA. Impaired emotional learning and involvement of the corticotropin-releasing factor signaling system in patients with irritable bowel syndrome. Gastroenterology. 2013b;145:1253–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Lange I, Kasanova Z, Goossens L, Leibold N, De Zeeuw CI, van Amelsvoort T, Schruers K. The anatomy of fear learning in the cerebellum: a systematic meta-analysis. Neurosci Biobehav Rev. 2015;59:83–91.

    Article  PubMed  Google Scholar 

  29. Magal A, Mintz M. Inhibition of the amygdala central nucleus by stimulation of cerebellar output in rats: a putative mechanism for extinction of the conditioned fear response. Eur J Neurosci. 2014;40:3548–55.

    Article  PubMed  Google Scholar 

  30. Maillet D, Rajah MN. Age-related differences in brain activity in the subsequent memory paradigm: a meta-analysis. Neurosci Biobehav Rev. 2014;45:246–57.

    Article  PubMed  Google Scholar 

  31. Maschke M, Drepper J, Kindsvater K, Kolb FP, Diener HC, Timmann D. Fear conditioned potentiation of the acoustic blink reflex in patients with cerebellar lesions. J Neurol Neurosurg Psychiatry. 2000;68:358–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Maschke M, Schugens M, Kindsvater K, Drepper J, Kolb FP, Diener HC, Daum I, Timmann D. Fear conditioned changes of heart rate in patients with medial cerebellar lesions. J Neurol Neurosurg Psychiatry. 2002;72:116–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Milad MR, Pitman RK, Ellis CB, Gold AL, Shin LM, Lasko NB, Zeidan MA, Handwerger K, Orr SP, Rauch SL. Neurobiological basis of failure to recall extinction memory in posttraumatic stress disorder. Biol Psychiatry. 2009;66:1075–82.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Milad MR, Rosenbaum BL, Simon NM. Neuroscience of fear extinction: implications for assessment and treatment of fear-based and anxiety related disorders. Behav Res Ther. 2014;62:17–23.

    Article  PubMed  Google Scholar 

  35. Morton SM, Bastian AJ. Cerebellar control of balance and locomotion. Neuroscientist. 2004;10:247–59.

    Article  PubMed  Google Scholar 

  36. Moulton EA, Schmahmann JD, Becerra L, Borsook D. The cerebellum and pain: passive integrator or active participator? Brain Res Rev. 2010;65:14–27.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Moulton EA, Elman I, Pendse G, Schmahmann J, Becerra L, Borsook D. Aversion-related circuitry in the cerebellum: responses to noxious heat and unpleasant images. J Neurosci. 2011;31:3795–804.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Poser BA, Versluis MJ, Hoogduin JM, Norris DG. BOLD contrast sensitivity enhancement and artifact reduction with multiecho EPI: parallel-acquired inhomogeneity-desensitized fMRI. Magn Reson Med. 2006;55:1227–35.

    Article  PubMed  Google Scholar 

  39. Raz N, Gunning-Dixon F, Head D, Williamson A, Acker JD. Age and sex differences in the cerebellum and the ventral pons: a prospective MR study of healthy adults. AJNR Am J Neuroradiol. 2001;22:1161–7.

    CAS  PubMed  Google Scholar 

  40. Robleto K, Poulos AM, Thompson RF. Brain mechanisms of extinction of the classically conditioned eyeblink response. Learn Mem. 2004;11:517–24.

    Article  PubMed  Google Scholar 

  41. Rosenberger C, Thürling M, Forsting M, Elsenbruch S, Timmann D, Gizewski ER. Contributions of the cerebellum to disturbed central processing of visceral stimuli in irritable bowel syndrome. Cerebellum. 2013;12:194–8.

    Article  PubMed  Google Scholar 

  42. Ruscheweyh R, Kühnel M, Filippopulos F, Blum B, Eggert T, Straube A. Altered experimental pain perception after cerebellar infarction. Pain. 2014;155:1303–12.

    Article  PubMed  Google Scholar 

  43. Sacchetti B, Baldi E, Lorenzini CA, Bucherelli C. Cerebellar role in fear-conditioning consolidation. Proc Natl Acad Sci U S A. 2002;99:8406–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Sacchetti B, Scelfo B, Strata P. The cerebellum: synaptic changes and fear conditioning. Neuroscientist. 2005;11:217–27.

    Article  PubMed  Google Scholar 

  45. Schmahmann JD, Doyon J, McDonald D, Holmes C, Lavoie K, Hurwitz AS, Kabani N, Toga A, Evans A, Petrides M. Three-dimensional MRI atlas of the human cerebellum in proportional stereotaxic space. NeuroImage. 1999;10:233–60.

  46. Senkowski D, Höfle M, Engel AK. Crossmodal shaping of pain: a multisensory approach to nociception. Trends Cogn Sci. 2014;18:319–27.

    Article  PubMed  Google Scholar 

  47. Stoodley CJ, Schmahmann JD. Evidence for topographic organization in the cerebellum of motor control versus cognitive and affective processing. Cortex. 2010;46:831–44.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Stoodley CJ, Valera EM, Schmahmann JD. Functional topography of the cerebellum for motor and cognitive tasks: an fMRI study. NeuroImage. 2012;59:1560–70.

    Article  PubMed  Google Scholar 

  49. Strata P. The emotional cerebellum. Cerebellum. 2015;14:570–7.

    Article  PubMed  Google Scholar 

  50. Strick PL, Dum RP, Fiez JA. Cerebellum and nonmotor function. Annu Rev Neurosci. 2009;32:413–34.

    Article  CAS  PubMed  Google Scholar 

  51. Thach WT. A role for the cerebellum in learning movement coordination. Neurobiol Learn Mem. 1998;70:177–88.

    Article  CAS  PubMed  Google Scholar 

  52. Thompson RF, Steinmetz JE. The role of the cerebellum in classical conditioning of discrete behavioral responses. Neuroscience. 2009;162:732–55.

    Article  CAS  PubMed  Google Scholar 

  53. Timmann D, Drepper J, Frings M, Maschke M, Richter S, Gerwig M, Kolb FP. The human cerebellum contributes to motor, emotional and cognitive associative learning. A review Cortex. 2010;46:845–57.

    Article  CAS  PubMed  Google Scholar 

  54. Utz A, Thürling M, Ernst TM, Hermann A, Stark R, Wolf OT, Timmann D, Merz CJ. Cerebellar vermis contributes to the extinction of conditioned fear. Neurosci Lett. 2015;604:173–7.

    Article  CAS  PubMed  Google Scholar 

  55. Vlaeyen JW. Learning to predict and control harmful events: chronic pain and conditioning. Pain. 2015;156:S86–93.

    Article  PubMed  Google Scholar 

  56. Zaman J, Vlaeyen JW, Van Oudenhove L, Wiech K, Van Diest I. Associative fear learning and perceptual discrimination: a perceptual pathway in the development of chronic pain. Neurosci Biobehav Rev. 2015;51:118–25.

    Article  PubMed  Google Scholar 

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Acknowledgments

Funded by the German Research Foundation (Deutsche Forschungsgemeinschaft, DFG) within the Research Unit FOR 1581 “Extinction learning: Neural Mechanisms, Behavioral Manifestations and Clinical Implications” (TI 239/10-1; TI 239/10-2; EL 236/9-1; 236/9-2). The funding agency had no role in the conception, analysis, or interpretation of the data. The authors thank Dr. Benedikt Poser and the Donders Institute for providing the multi-echo EPI sequence used in this study as well as Alex Luft, Sarah Hampel, and Joswin Kattoor for the excellent technical and logistical support during data acquisition.

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Authors and Affiliations

  1. Department of Neurology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany

    J. Claassen, T.M. Ernst & D. Timmann

  2. Institute of Medical Psychology and Behavioral Immunobiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany

    F. Labrenz, A. Icenhour & S. Elsenbruch

  3. Integrative Gastroenterology, Clinic for Internal and Integrative Medicine, Kliniken Essen-Mitte, Essen, Germany

    J. Langhorst

  4. Institute of Diagnostic and Interventional Radiology and Neuroradiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany

    M. Forsting

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  1. J. Claassen
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  3. T.M. Ernst
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Correspondence to S. Elsenbruch.

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Ethical Approval and Informed Consent Statement

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study.

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J. Claassen and F. Labrenz shared first authorship.

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Claassen, J., Labrenz, F., Ernst, T. et al. Altered Cerebellar Activity in Visceral Pain-Related Fear Conditioning in Irritable Bowel Syndrome. Cerebellum 16, 508–517 (2017). https://doi.org/10.1007/s12311-016-0832-7

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