Psychotherapy With Somatosensory Stimulation for Endometriosis-Associated Pain: The Role of the Anterior Hippocampus

  • Author Footnotes
    1 FB and CP contributed equally to this work.
    Florian Beissner
    Address correspondence to Florian Beissner, Dr. phil. nat., Somatosensory and Autonomic Therapy Research, Institute for Neuroradiology, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany; .
    1 FB and CP contributed equally to this work.
    Somatosensory and Autonomic Therapy Research, Institute for Neuroradiology, Hannover Medical School, Hannover
    Search for articles by this author
  • Author Footnotes
    1 FB and CP contributed equally to this work.
    Christine Preibisch
    1 FB and CP contributed equally to this work.
    Clinic for Neurology, Technische Universität München, Munich

    Department of Neuroradiology, Technische Universität München, Munich
    Search for articles by this author
  • Annemarie Schweizer-Arau
    Practice for Psychotherapeutic Medicine, Diessen
    Search for articles by this author
  • Roxana M. Popovici
    Department of Gynecologic Endocrinology and Fertility Disorders, Heidelberg University Women’s Hospital, Heidelberg
    Search for articles by this author
  • Karin Meissner
    Institute of Medical Psychology, Ludwig-Maximilians-Universität München, Munich

    Division Integrative Health Promotion, University of Applied Sciences, Coburg, Germany
    Search for articles by this author
  • Author Footnotes
    1 FB and CP contributed equally to this work.



      Endometriosis is a gynecological disorder affecting 6%–10% of all women in their reproductive age. There is an emerging view in the literature that psychological trauma plays a central role in the pathogenesis of pelvic pain, one of the core symptoms of endometriosis. Here we report central nervous system mechanisms of a novel combination of psychotherapy and somatosensory stimulation that has recently shown remarkable effects in reducing pain, anxiety, and depressive symptoms in these patients.


      We conducted a randomized controlled trial; 67 patients with severe endometriosis-associated pain (maximum pain: 7.6 ± 2.0, average pain: 4.5 ± 2.0 on a 10-point numeric rating scale) were included in the study and randomly allocated to intervention (35 patients) or waitlist control (32 patients) groups. Resting-state functional magnetic resonance imaging was used to assess brain connectivity of these patients at baseline, after 3 months of therapy, and after 6 months. The analysis focused on the hippocampus.


      We identified a cortical network comprising the right anterolateral hippocampus—a region modulating the hypothalamic-pituitary-adrenal axis—and somatosensory, viscerosensory, and interoceptive brain regions. Regression analysis showed that reduction in connectivity predicted therapy-induced improvement in patients׳ anxiety.


      We have identified a putative neurobiological mechanism underlying the potent combination of psychotherapy and somatic stimulation in treating symptoms of endometriosis.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Biological Psychiatry
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


      1. Giudice LC. Clinical practice. Endometriosis. N Engl J Med 362:2389–2398.

        • Rogers P.A.
        • D’Hooghe T.M.
        • Fazleabas A.
        • Giudice L.C.
        • Montgomery G.W.
        • Petraglia F.
        • Taylor R.N.
        Defining future directions for endometriosis research: Workshop report from the 2011 World Congress of Endometriosis In Montpellier, France.
        Reprod Sci. 2013; 20: 483-499
        • Soliman A.M.
        • Yang H.
        • Du E.X.
        • Kelley C.
        • Winkel C.
        The direct and indirect costs associated with endometriosis: A systematic literature review.
        Hum Reprod. 2016; 31: 712-722
        • Vercellini P.
        • Fedele L.
        • Aimi G.
        • Pietropaolo G.
        • Consonni D.
        • Crosignani P.G.
        Association between endometriosis stage, lesion type, patient characteristics and severity of pelvic pain symptoms: A multivariate analysis of over 1000 patients.
        Hum Reprod. 2007; 22: 266-271
        • Allen C.
        • Hopewell S.
        • Prentice A.
        • Gregory D.
        Nonsteroidal anti-inflammatory drugs for pain in women with endometriosis.
        Cochrane Database Syst Rev. 2009; 2: CD004753
        • Triolo O.
        • Lagana A.S.
        • Sturlese E.
        Chronic pelvic pain in endometriosis: An overview.
        J Clin Med Res. 2013; 5: 153-163
        • Latthe P.
        • Mignini L.
        • Gray R.
        • Hills E.
        • Khan K.
        Factors predisposing women to chronic pelvic pain: Systematic review.
        BMJ. 2006; 332: 749
        • As-Sanie S.
        • Clevenger L.A.
        • Geisser M.E.
        • Williams D.A.
        • Roth R.S.
        History of abuse and its relationship to pain experience and depression in women with CPP.
        Am J Obstet Gynecol. 2014; 210 (e1–8): 317
        • Seth A.
        • Teichman J.M.
        Differences in the clinical presentation of interstitial cystitis/painful bladder syndrome in patients with or without sexual abuse history.
        J Urol. 2008; 180: 2029-2033
        • Pope C.J.
        • Sharma V.
        • Sharma S.
        • Mazmanian D.
        A systematic review of the association between psychiatric disturbances and endometriosis.
        J Obstet Gynaecol Can. 2015; 37: 1006-1015
        • Bajaj P.
        • Bajaj P.
        • Madsen H.
        • Arendt-Nielsen L.
        Endometriosis is associated with central sensitization: a psychophysical controlled study.
        J Pain. 2003; 4: 372-380
        • Iacovides S.
        • Baker F.C.
        • Avidon I.
        • Bentley A.
        Women with dysmenorrhea are hypersensitive to experimental deep muscle pain across the menstrual cycle.
        J Pain. 2013; 14: 1066-1076
        • As-Sanie S.
        • Kim J.
        • Schmidt-Wilcke T.
        • Sundgren P.C.
        • Clauw D.J.
        • Napadow V.
        • Harris R.E.
        Functional connectivity is associated with altered brain chemistry in women with endometriosis-associated chronic pelvic pain.
        J Pain. 2016; 17: 1-13
        • Brawn J.
        • Morotti M.
        • Zondervan K.T.
        • Becker C.M.
        • Vincent K.
        Central changes associated with chronic pelvic pain and endometriosis.
        Hum Reprod Update. 2014; 20: 737-747
        • As-Sanie S.
        • Harris R.E.
        • Napadow V.
        • Kim J.
        • Neshewat G.
        • Kairys A.
        • et al.
        Changes in regional gray matter volume in women with chronic pelvic pain: A voxel-based morphometry study.
        Pain. 2012; 153: 1006-1014
        • Meissner K.
        • Schweizer-Arau A.
        • Limmer A.
        • Preibisch C.
        • Popovici R.M.
        • Lange I.
        • et al.
        Psychotherapy with somatosensory stimulation for endometriosis-associated pain: A randomized controlled trial.
        Obstet Gynecol. 2016; 128: 1134-1142
        • Meissner K.
        • Bohling B.
        • Schweizer-Arau A.
        Long-term effects of traditional Chinese medicine and hypnotherapy in patients with severe endometriosis--A retrospective evaluation.
        Forsch Komplementmed. 2010; 17: 314-320
        • LaBar K.S.
        • Cabeza R.
        Cognitive neuroscience of emotional memory.
        Nat Rev Neurosci. 2006; 7: 54-64
        • LeDoux J.E.
        Emotional memory systems in the brain.
        Behav Brain Res. 1993; 58: 69-79
        • Levy-Gigi E.
        • Szabó C.
        • Kelemen O.
        • Kéri S.
        Association among clinical response, hippocampal volume, and FKBP5 gene expression in individuals with posttraumatic stress disorder receiving cognitive behavioral therapy.
        Biol Psychiatry. 2013; 74: 793-800
        • Lindauer R.J.
        • Vlieger E.J.
        • Jalink M.
        • Olff M.
        • Carlier I.V.
        • Majoie C.B.
        • et al.
        Effects of psychotherapy on hippocampal volume in out-patients with post-traumatic stress disorder: A MRI investigation.
        Psychol Med. 2005; 35: 1421-1431
        • Zeidman P.
        • Maguire E.A.
        Anterior hippocampus: the anatomy of perception, imagination and episodic memory.
        Nat Rev Neurosci. 2016; 17: 173-182
        • Bannerman D.M.
        • Rawlins J.N.
        • McHugh S.B.
        • Deacon R.M.
        • Yee B.K.
        • Bast T.
        • et al.
        Regional dissociations within the hippocampus--Memory and anxiety.
        Neurosci Biobehav Rev. 2004; 28: 273-283
        • Shackman A.J.
        • Fox A.S.
        • Oler J.A.
        • Shelton S.E.
        • Davidson R.J.
        • Kalin N.H.
        Neural mechanisms underlying heterogeneity in the presentation of anxious temperament.
        Proc Natl Acad Sci U S A. 2013; 110: 6145-6150
        • Mutso A.A.
        • Petre B.
        • Huang L.
        • Baliki M.N.
        • Torbey S.
        • Herrmann K.M.
        • et al.
        Reorganization of hippocampal functional connectivity with transition to chronic back pain.
        J Neurophysiol. 2014; 111: 1065-1076
        • Moher Alsady T.
        • Blessing E.
        • Beissner F.
        MICA-A toolbox for masked independent component analysis of fMRI data.
        Hum Brain Mapp 2016. 2016; 37: 3544-3556
        • Blessing E.M.
        • Beissner F.
        • Schumann A.
        • Brünner F.
        • Bär K.J.
        A data-driven approach to mapping cortical and subcortical intrinsic functional connectivity along the longitudinal hippocampal axis.
        Hum Brain Mapp. 2016; 37: 462-476
        • Protopopescu X.
        • Butler T.
        • Pan H.
        • Root J.
        • Altemus M.
        • Polanecsky M.
        • et al.
        Hippocampal structural changes across the menstrual cycle.
        Hippocampus. 2008; 18: 985-988
        • van Wingen G.A.
        • van Broekhoven F.
        • Verkes R.J.
        • Petersson K.M.
        • Bäckström T.
        • Buitelaar J.K.
        • Fernández G.
        Progesterone selectively increases amygdala reactivity in women.
        Mol Psychiatry. 2008; 13: 325-331
        • Zigmond A.S.
        • Snaith R.P.
        The hospital anxiety and depression scale.
        Acta Psychiatr Scand. 1983; 67: 361-370
        • Spielberger C.
        • Gorsuch R.
        • Lushene R.
        • Vagg P.
        • Jacobs G.
        Manual for the State-Trait Anxiety Inventory (Form Y).
        Consulting Psychologists Press, Palo Alto, CA1983
        • Ware J.E.
        • Kosinski M.
        • Keller S.D.
        A 12-Item Short-Form Health Survey: Construction of scales and preliminary tests of reliability and validity.
        Med Care. 1996; 34: 220-233
        • Erickson M.H.
        • Rossi E.L.
        Hypnotherapy, an Exploratory Casebook. North Stratford.
        Irvington, NH1979
        • Kabat-Zinn J.
        An outpatient program in behavioral medicine for chronic pain patients based on the practice of mindfulness meditation: Theoretical considerations and preliminary results.
        Gen Hosp Psychiatry. 1982; 4: 33-47
        • Butler A.C.
        • Chapman J.E.
        • Forman E.M.
        • Beck A.T.
        The empirical status of cognitive-behavioral therapy: A review of meta-analyses.
        Clin Psychol Rev. 2006; 26: 17-31
        • Haley J.
        Problem-Solving Therapy.
        Jossey-Bass, San Francisco1987
        • Kaptchuk T.J.
        The Web That Has No Weaver.
        Congdon and Weed, Inc, New York1983: 1983
        • Salimi-Khorshidi G.
        • Douaud G.
        • Beckmann C.F.
        • Glasser M.F.
        • Griffanti L.
        • Smith S.M.
        Automatic denoising of functional MRI data: Combining independent component analysis and hierarchical fusion of classifiers.
        Neuroimage. 2014; 90: 449-468
        • Greve D.N.
        • Fischl B.
        Accurate and robust brain image alignment using boundary-based registration.
        Neuroimage. 2009; 48: 63-72
        • Beckmann C.F.
        • Smith S.M.
        Probabilistic independent component analysis for functional magnetic resonance imaging.
        IEEE Trans Med Imaging. 2004; 23: 137-152
        • Hyvarinen A.
        Fast and robust fixed-point algorithms for independent component analysis.
        IEEE Trans Neural Netw. 1999; 10: 626-634
        • Filippini N.
        • MacIntosh B.J.
        • Hough M.G.
        • Goodwin G.M.
        • Frisoni G.B.
        • Smith S.M.
        • et al.
        Distinct patterns of brain activity in young carriers of the APOE-ε4 allele.
        Proc Natl Acad Sci U S A. 2009; 106: 7209-7214
        • Eklund A.
        • Nichols T.E.
        • Knutsson H.
        Cluster failure: Why fMRI inferences for spatial extent have inflated false-positive rates.
        Proc Natl Acad Sci U S A. 2016; 113: 7900-7905
        • Grady C.L.
        • McIntosh A.R.
        • Craik F.I.M.
        Age-related differences in the functional connectivity of the hippocampus during memory encoding.
        Hippocampus. 2003; 3: 572-586
        • Bannerman D.M.
        • Grubb M.
        • Deacon R.M.J.
        • Yee B.K.
        • Feldon J.
        • Rawlins J.N.P.
        Ventral hippocampal lesions affect anxiety but not spatial learning.
        Behav Brain Res. 2003; 139: 197-213
        • Tang J.
        • Gibson S.J.
        A psychophysical evaluation of the relationship between trait anxiety, pain perception, and induced state anxiety.
        J Pain. 2005; 6: 612-619
        • Moix J.
        • Kovacs F.M.
        • Martín A.
        • Plana M.N.
        • Royuela A.
        • Spanish Back Pain Research Network
        Catastrophizing, state anxiety, anger, and depressive symptoms do not correlate with disability when variations of trait anxiety are taken into account. A study of chronic low back pain patients treated in Spanish pain units [NCT00360802].
        Pain Med. 2011; 12: 1008-1017
        • Ploghaus A.
        • Narain C.
        • Beckmann C.F.
        • Clare S.
        • Bantick S.
        • Wise R.
        • et al.
        Exacerbation of pain by anxiety is associated with activity in a hippocampal network.
        J Neurosci. 2001; 21: 9896-9903
        • McCracken L.M.
        • Gross R.T.
        The role of pain-related anxiety reduction in the outcome of multidisciplinary treatment for chronic low back pain: Preliminary results.
        J Occupat Rehabil. 1998; 8: 179-189
        • McWilliams L.A.
        • Cox B.J.
        • Enns M.W.
        Mood and anxiety disorders associated with chronic pain: An examination in a nationally representative sample.
        Pain. 2003; 106: 127-133
        • Jacobson L.
        • Sapolsky R.
        The role of the hippocampus in feedback regulation of the hypothalamic-pituitary-adrenocortical axis.
        Endocr Rev. 1991; 12: 118-134
        • Heim C.
        • Ehlert U.
        • Hellhammer D.H.
        The potential role of hypocortisolism in the pathophysiology of stress-related bodily disorders.
        Psychoneuroendocrinology. 2000; 25: 1-35
        • Petrelluzzi K.F.
        • Garcia M.C.
        • Petta C.A.
        • Grassi-Kassisse D.M.
        • Spadari-Bratfisch R.C.
        Salivary cortisol concentrations, stress and quality of life in women with endometriosis and chronic pelvic pain.
        Stress. 2008; 11: 390-397
        • Quiñones M.
        • Urrutia R.
        • Torres-Reverón A.
        • Vincent K.
        • Flores I.
        Anxiety, coping skills and hypothalamus-pituitary-adrenal (HPA) axis in patients with endometriosis.
        J Reprod Biol Health. 2015; 3: 2
        • Heim C.
        • Ehlert U.
        • Hanker J.P.
        • Hellhammer D.H.
        Abuse-related posttraumatic stress disorder and alterations of the hypothalamic-pituitary-adrenal axis in women with chronic pelvic pain.
        Psychosom Med. 1998; 60: 309-318
        • Gray J.A.
        • McNaughton N.
        The Neuropsychology of Anxiety: An Enquiry into the Functions of the Septo-Hippocampal System. 2nd ed. Oxford University Press, Oxford, UK2000
        • Bannerman D.M.
        • Sprengel R.
        • Sanderson D.J.
        • McHugh S.B.
        • Rawlins J.N.P.
        • Monyer H.
        • Seeburg P.H.
        Hippocampal synaptic plasticity, spatial memory and anxiety.
        Nat Rev Neurosci. 2014; 15: 181-192
        • Hui K.K.
        • Liu J.
        • Makris N.
        • Gollub R.L.
        • Chen A.J.
        • Moore C.I.
        • et al.
        Acupuncture modulates the limbic system and subcortical gray structures of the human brain: Evidence from fMRI studies in normal subjects.
        Hum Brain Mapp. 2000; 9: 13-25
        • Napadow V.
        • Dhond R.
        • Park K.
        • Kim J.
        • Makris N.
        • Kwong K.K.
        • Harris R.E.
        • Purdon P.L.
        • Kettner N.
        • Hui K.K.
        Time-variant fMRI activity in the brainstem and higher structures in response to acupuncture.
        Neuroimage. 2009; 47: 289-301
        • Napadow V.
        • Kettner N.
        • Liu J.
        • Li M.
        • Kwong K.K.
        • Vangel M.
        • et al.
        Hypothalamus and amygdala response to acupuncture stimuli in carpal tunnel syndrome.
        Pain. 2007; 130: 254-266
        • Beissner F.
        • Deichmann R.
        • Henke C.
        • Bär K.J.
        Acupuncture - Deep pain with an autonomic dimension?.
        Neuroimage. 2012; 60: 653-660
        • Payne K.A.
        • Binik Y.M.
        • Amsel R.
        • Khalifé S.
        When sex hurts, anxiety and fear orient attention toward pain.
        Eur J Pain. 2005; 9: 427-436
        • Davis K.D.
        • Moayedi M.
        Central mechanisms of pain revealed through functional and structural MRI.
        J Neuroimmune Pharmacol. 2013; 8: 518-534
        • Hrobjartsson A.
        • Kaptchuk T.J.
        • Miller F.G.
        Placebo effect studies are susceptible to response bias and to other types of biases.
        J Clin Epidemiol. 2011; 64: 1223-1229