Early-life trauma endophenotypes and brain circuit–gene expression relationships in functional neurological (conversion) disorder


Functional neurological (conversion) disorder (FND) is a neuropsychiatric condition whereby individuals present with sensorimotor symptoms incompatible with other neurological disorders. Early-life maltreatment (ELM) is a risk factor for developing FND, yet few studies have investigated brain network–trauma relationships in this population. In this neuroimaging–gene expression study, we used two graph theory approaches to elucidate ELM subtype effects on resting-state functional connectivity architecture in 30 patients with motor FND. Twenty-one individuals with comparable depression, anxiety, and ELM scores were used as psychiatric controls. Thereafter, we compared trauma endophenotypes in FND with regional differences in transcriptional gene expression as measured by the Allen Human Brain Atlas (AHBA). In FND patients only, we found that early-life physical abuse severity, and to a lesser extent physical neglect, correlated with corticolimbic weighted-degree functional connectivity. Connectivity profiles influenced by physical abuse occurred in limbic (amygdalar–hippocampal), paralimbic (cingulo-insular and ventromedial prefrontal), and cognitive control (ventrolateral prefrontal) areas, as well as in sensorimotor and visual cortices. These findings held adjusting for individual differences in depression/anxiety, PTSD, and motor phenotypes. In FND, physical abuse also correlated with amygdala and insula coupling to motor cortices. In exploratory analyses, physical abuse correlated connectivity maps overlapped with the AHBA spatial expression of three gene clusters: (i) neuronal morphogenesis and synaptic transmission genes in limbic/paralimbic areas; (ii) locomotory behavior and neuronal generation genes in left-lateralized structures; and (iii) nervous system development and cell motility genes in right-lateralized structures. These circuit-specific architectural profiles related to individual differences in childhood physical abuse burden advance our understanding of the pathophysiology of FND.

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Fig. 1: Physical abuse and physical neglect burden influence the corticolimbic architecture in patients with functional neurological disorder (FND).
Fig. 2: The magnitude of early-life physical abuse correlates with amygdala—precentral gyrus and insula—precentral gyrus functional connectivity strength in patients with functional neurological disorder.
Fig. 3: Clustering of gene expression profiles associated with physical abuse correlated weighted-degree functional connectivity maps in patients with functional neurological disorder.
Fig. 4: Spatial similarity between physical abuse correlated weighted-degree functional connectivity maps in patients with functional neurological disorder (FND) and regional brain-derived neurotrophic factor (BDNF) expression.


  1. 1.

    Espay AJ, Aybek S, Carson A, Edwards MJ, Goldstein LH, Hallett M, et al. Current concepts in diagnosis and treatment of functional neurological disorders. JAMA Neurol. 2018;75:1132–41.

  2. 2.

    Keynejad RC, Carson AJ, David AS, Nicholson TR. Functional neurological disorder: psychiatry’s blind spot. Lancet Psychiatry. 2017;4:e2–3.

  3. 3.

    Ludwig L, Pasman JA, Nicholson T, Aybek S, David AS, Tuck S, et al. Stressful life events and maltreatment in conversion (functional neurological) disorder: systematic review and meta-analysis of case-control studies. Lancet Psychiatry. 2018;5:307–20.

  4. 4.

    Kanaan RAA, Craig TKJ. Conversion disorder and the trouble with trauma. Psychol Med. 2019;49:1585–8.

  5. 5.

    Popkirov S, Wessely S, Nicholson TR, Carson AJ, Stone J. Different shell, same shock. BMJ. 2017;359:j5621.

  6. 6.

    American Psychiatric Association. Diagnostic and statistical manual of mental disorders (DSM-5). 5th ed. American Psychiatric Pub: Washington, DC; 2013. p. 947.

  7. 7.

    Keynejad RC, Frodl T, Kanaan R, Pariante C, Reuber M, Nicholson TR. Stress and functional neurological disorders: mechanistic insights. J Neurol Neurosurg Psychiatry. 2019;90:813–21.

  8. 8.

    Pick S, Goldstein LH, Perez DL, Nicholson TR. Emotional processing in functional neurological disorder: a review, biopsychosocial model and research agenda. J Neurol Neurosurg Psychiatry. 2019;90:704–11.

  9. 9.

    Teicher MH, Samson JA, Anderson CM, Ohashi K. The effects of childhood maltreatment on brain structure, function and connectivity. Nat Rev Neurosci. 2016;17:652–66.

  10. 10.

    Aybek S, Nicholson TR, Zelaya F, O’Daly OG, Craig TJ, David AS, et al. Neural correlates of recall of life events in conversion disorder. JAMA Psychiatry. 2014;71:52–60.

  11. 11.

    Aybek S, Nicholson TR, O’Daly O, Zelaya F, Kanaan RA, David AS. Emotion-motion interactions in conversion disorder: an FMRI study. PLoS ONE. 2015;10:e0123273.

  12. 12.

    Voon V, Brezing C, Gallea C, Ameli R, Roelofs K, LaFrance WC Jr, et al. Emotional stimuli and motor conversion disorder. Brain. 2010;133:1526–36.

  13. 13.

    Espay AJ, Maloney T, Vannest J, Norris MM, Eliassen JC, Neefus E, et al. Impaired emotion processing in functional (psychogenic) tremor: a functional magnetic resonance imaging study. Neuroimage Clin. 2018;17:179–87.

  14. 14.

    Hassa T, Sebastian A, Liepert J, Weiller C, Schmidt R, Tüscher O. Symptom-specific amygdala hyperactivity modulates motor control network in conversion disorder. Neuroimage Clin. 2017;15:143–50.

  15. 15.

    van der Kruijs SJ, Bodde NM, Vaessen MJ, Lazeron RH, Vonck K, Boon P, et al. Functional connectivity of dissociation in patients with psychogenic non-epileptic seizures. J Neurol Neurosurg Psychiatry. 2012;83:239–47.

  16. 16.

    Morris LS, To B, Baek K, Chang-Webb YC, Mitchell S, Strelchuk D, et al. Disrupted avoidance learning in functional neurological disorder: implications for harm avoidance theories. Neuroimage Clin. 2017;16:286–94.

  17. 17.

    Wegrzyk J, Kebets V, Richiardi J, Galli S, de Ville DV, Aybek S. Identifying motor functional neurological disorder using resting-state functional connectivity. Neuroimage Clin. 2018;17:163–8.

  18. 18.

    Li R, Liu K, Ma X, Li Z, Duan X, An D, et al. Altered functional connectivity patterns of the insular subregions in psychogenic nonepileptic seizures. Brain Topogr. 2015;28:636–45.

  19. 19.

    Diez I, Ortiz-Teran L, Williams B, Jalilianhasanpour R, Ospina JP, Dickerson BC, et al. Corticolimbic fast-tracking: enhanced multimodal integration in functional neurological disorder. J Neurol Neurosurg Psychiatry. 2019;90:929–38.

  20. 20.

    Voon V, Brezing C, Gallea C, Hallett M. Aberrant supplementary motor complex and limbic activity during motor preparation in motor conversion disorder. Mov Disord. 2011;26:2396–403.

  21. 21.

    Stone J, Zeman A, Simonotto E, Meyer M, Azuma R, Flett S, et al. FMRI in patients with motor conversion symptoms and controls with simulated weakness. Psychosom Med. 2007;69:961–9.

  22. 22.

    de Lange FP, Toni I, Roelofs K. Altered connectivity between prefrontal and sensorimotor cortex in conversion paralysis. Neuropsychologia. 2010;48:1782–8.

  23. 23.

    Voon V, Gallea C, Hattori N, Bruno M, Ekanayake V, Hallett M. The involuntary nature of conversion disorder. Neurology. 2010;74:223–8.

  24. 24.

    Baek K, Doñamayor N, Morris LS, Strelchuk D, Mitchell S, Mikheenko Y, et al. Impaired awareness of motor intention in functional neurological disorder: Implications for voluntary and functional movement. Psychol Med. 2017;47:1624–36.

  25. 25.

    Maurer CW, LaFaver K, Ameli R, Epstein SA, Hallett M, Horovitz SG. Impaired self-agency in functional movement disorders: a resting-state fMRI study. Neurology. 2016;87:564–70.

  26. 26.

    Dannlowski U, Stuhrmann A, Beutelmann V, Zwanzger P, Lenzen T, Grotegerd D, et al. Limbic scars: long-term consequences of childhood maltreatment revealed by functional and structural magnetic resonance imaging. Biol Psychiatry. 2012;71:286–93.

  27. 27.

    Dannlowski U, Kugel H, Huber F, Stuhrmann A, Redlich R, Grotegerd D, et al. Childhood maltreatment is associated with an automatic negative emotion processing bias in the amygdala. Hum Brain Mapp. 2013;34:2899–909.

  28. 28.

    Jedd K, Hunt RH, Cicchetti D, Hunt E, Cowell RA, Rogosch FA, et al. Long-term consequences of childhood maltreatment: altered amygdala functional connectivity. Dev Psychopathol. 2015;27:1577–89.

  29. 29.

    Herringa RJ, Birn RM, Ruttle PL, Burghy CA, Stodola DE, Davidson RJ, et al. Childhood maltreatment is associated with altered fear circuitry and increased internalizing symptoms by late adolescence. Proc Natl Acad Sci USA. 2013;110:19119–24.

  30. 30.

    van der Werff SJ, Pannekoek JN, Veer IM, van Tol MJ, Aleman A, Veltman DJ, et al. Resting-state functional connectivity in adults with childhood emotional maltreatment. Psychol Med. 2013;43:1825–36.

  31. 31.

    Ohashi K, Anderson CM, Bolger EA, Khan A, McGreenery CE, Teicher MH. Susceptibility or resilience to maltreatment can be explained by specific differences in brain network architecture. Biol Psychiatry. 2019;85:690–702.

  32. 32.

    Kaiser RH, Clegg R, Goer F, Pechtel P, Beltzer M, Vitaliano G, et al. Childhood stress, grown-up brain networks: corticolimbic correlates of threat-related early life stress and adult stress response. Psychol Med. 2018;48:1157–66.

  33. 33.

    Teicher MH, Anderson CM, Ohashi K, Polcari A. Childhood maltreatment: altered network centrality of cingulate, precuneus, temporal pole and insula. Biol Psychiatry. 2014;76:297–305.

  34. 34.

    Selkirk M, Duncan R, Oto M, Pelosi A. Clinical differences between patients with nonepileptic seizures who report antecedent sexual abuse and those who do not. Epilepsia. 2008;49:1446–50.

  35. 35.

    Spinhoven P, Roelofs K, Moene F, Kuyk J, Nijenhuis E, Hoogduin K, et al. Trauma and dissociation in conversion disorder and chronic pelvic pain. Int J Psychiatry Med. 2004;34:305–18.

  36. 36.

    Sepulcre J. Functional streams and cortical integration in the human brain. Neuroscientist. 2014;20:499–508.

  37. 37.

    Fornito A, Arnatkeviciute A, Fulcher BD. Bridging the gap between connectome and transcriptome. Trends Cogn Sci. 2019;23:34–50.

  38. 38.

    Arnatkevic Iute A, Fulcher BD, Fornito A. A practical guide to linking brain-wide gene expression and neuroimaging data. Neuroimage. 2019;189:353–67.

  39. 39.

    Ortiz-Teran L, Diez I, Ortiz T, Perez DL, Aragon JI, Costumero V, et al. Brain circuit-gene expression relationships and neuroplasticity of multisensory cortices in blind children. Proc Natl Acad Sci USA. 2017;114:6830–5.

  40. 40.

    Xin Q, Ortiz-Teran L, Diez I, Perez DL, Ginsburg J, El Fakhri G, et al. Sequence alterations of cortical genes linked to individual connectivity of the human brain. Cereb Cortex. 2019;29:3828–35.

  41. 41.

    Heim C, Binder EB. Current research trends in early life stress and depression: review of human studies on sensitive periods, gene-environment interactions, and epigenetics. Exp Neurol. 2012;233:102–11.

  42. 42.

    Seeley WW, Menon V, Schatzberg AF, Keller J, Glover GH, Kenna H, et al. Dissociable intrinsic connectivity networks for salience processing and executive control. J Neurosci. 2007;27:2349–56.

  43. 43.

    Perez DL, Dworetzky BA, Dickerson BC, Leung L, Cohn R, Baslet G, et al. An integrative neurocircuit perspective on psychogenic nonepileptic seizures and functional movement disorders: neural functional unawareness. Clin EEG Neurosci. 2015;46:4–15.

  44. 44.

    Bernstein DP, Fink L, Handelsman L, Foote J, Lovejoy M, Wenzel K, et al. Initial reliability and validity of a new retrospective measure of child abuse and neglect. Am J Psychiatry. 1994;151:1132–6.

  45. 45.

    Blevins CA, Weathers FW, Davis MT, Witte TK, Domino JL. The posttraumatic stress disorder checklist for DSM-5 (PCL-5): development and initial psychometric evaluation. J Trauma Stress. 2015;28:489–98.

  46. 46.

    Qian J, Diez I, Ortiz-Teran L, Bonadio C, Liddell T, Goni J, et al. Positive connectivity predicts the dynamic intrinsic topology of the human brain network. Front Syst Neurosci. 2018;12:38.

  47. 47.

    Hawrylycz MJ, Lein ES, Guillozet-Bongaarts AL, Shen EH, Ng L, Miller JA, et al. An anatomically comprehensive atlas of the adult human brain transcriptome. Nature. 2012;489:391–9.

  48. 48.

    Desikan RS, Ségonne F, Fischl B, Quinn BT, Dickerson BC, Blacker D, et al. An automated labeling system for subdividing the human cerebral cortex on MRI scans into gyral based regions of interest. Neuroimage. 2006;31:968–80.

  49. 49.

    Keuken MC, Bazin PL, Crown L, Hootsmans J, Laufer A, Muller-Axt C, et al. Quantifying inter-individual anatomical variability in the subcortex using 7 T structural MRI. Neuroimage. 2014;94:40–6.

  50. 50.

    Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM, et al. Gene ontology: tool for the unification of biology. The Gene Ontology Consortium. Nat Genet. 2000;25:25–9.

  51. 51.

    Bakvis P, Roelofs K, Kuyk J, Edelbroek PM, Swinkels WA, Spinhoven P. Trauma, stress, and preconscious threat processing in patients with psychogenic nonepileptic seizures. Epilepsia. 2009;50:1001–11.

  52. 52.

    Apazoglou K, Mazzola V, Wegrzyk J, Polara GF, Aybek S. Biological and perceived stress in motor functional neurological disorders. Psychoneuroendocrinology. 2017;85:142–50.

  53. 53.

    Ghaziri J, Tucholka A, Girard G, Houde JC, Boucher O, Gilbert G, et al. The corticocortical structural connectivity of the human insula. Cereb Cortex. 2017;27:1216–28.

  54. 54.

    Espay AJ, Maloney T, Vannest J, Norris MM, Eliassen JC, Neefus E, et al. Dysfunction in emotion processing underlies functional (psychogenic) dystonia. Mov Disord. 2018;33:136–45.

  55. 55.

    Craig AD. How do you feel-now? The anterior insula and human awareness. Nat Rev Neurosci. 2009;10:59–70.

  56. 56.

    Sepulcre J, Sabuncu MR, Yeo TB, Liu H, Johnson KA. Stepwise connectivity of the modal cortex reveals the multimodal organization of the human brain. J Neurosci. 2012;32:10649–61.

  57. 57.

    Ricciardi L, Demartini B, Crucianelli L, Krahé C, Edwards MJ, Fotopoulou A. Interoceptive awareness in patients with functional neurological symptoms. Biol Psychol. 2016;113:68–74.

  58. 58.

    Boulle F, van den Hove DL, Jakob SB, Rutten BP, Hamon M, van Os J, et al. Epigenetic regulation of the BDNF gene: implications for psychiatric disorders. Mol Psychiatry. 2012;17:584–96.

  59. 59.

    Pollak DD, Monje FJ, Zuckerman L, Denny CA, Drew MR, Kandel ER. An animal model of a behavioral intervention for depression. Neuron. 2008;60:149–61.

  60. 60.

    LaFrance WC Jr, Leaver K, Stopa EG, Papandonatos GD, Blum AS. Decreased serum BDNF levels in patients with epileptic and psychogenic nonepileptic seizures. Neurology. 2010;75:1285–91.

  61. 61.

    Deveci A, Aydemir O, Taskin O, Taneli F, Esen-Danaci A. Serum brain-derived neurotrophic factor levels in conversion disorder: comparative study with depression. Psychiatry Clin Neurosci. 2007;61:571–3.

  62. 62.

    Aas M, Haukvik UK, Djurovic S, Tesli M, Athanasiu L, Bjella T, et al. Interplay between childhood trauma and BDNF val66met variants on blood BDNF mRNA levels and on hippocampus subfields volumes in schizophrenia spectrum and bipolar disorders. J Psychiatr Res. 2014;59:14–21.

  63. 63.

    Gutierrez B, Bellon JA, Rivera M, Molina E, King M, Marston L, et al. The risk for major depression conferred by childhood maltreatment is multiplied by BDNF and SERT genetic vulnerability: a replication study. J Psychiatry Neurosci. 2015;40:187–96.

  64. 64.

    Mukherjee P, Whalley HC, McKirdy JW, McIntosh AM, Johnstone EC, Lawrie SM, et al. Effects of the BDNF Val66Met polymorphism on neural responses to facial emotion. Psychiatry Res. 2011;191:182–8.

  65. 65.

    Li A, Jing D, Dellarco DV, Hall BS, Yang R, Heilberg RT, et al. Role of BDNF in the development of an OFC-amygdala circuit regulating sociability in mouse and human. Mol Psychiatry. 2019. https://doi.org/10.1038/s41380-019-0422-4 [Epub ahead of print].

  66. 66.

    Perez-Rodriguez MM, New AS, Goldstein KE, Rosell D, Yuan Q, Zhou Z, et al. Brain-derived neurotrophic factor Val66Met genotype modulates amygdala habituation. Psychiatry Res Neuroimaging. 2017;263:85–92.

  67. 67.

    Young DA, Neylan TC, O’Donovan A, Metzler T, Richards A, Ross JA, et al. The interaction of BDNF Val66Met, PTSD, and child abuse on psychophysiological reactivity and HPA axis function in a sample of Gulf War Veterans. J Affect Disord. 2018;235:52–60.

  68. 68.

    Roth TL, Sweatt JD. Epigenetic marking of the BDNF gene by early-life adverse experiences. Horm Behav. 2011;59:315–20.

  69. 69.

    Wilkinson AV, Gabriel KP, Wang J, Bondy ML, Dong Q, Wu X, et al. Sensation-seeking genes and physical activity in youth. Genes Brain Behav. 2013;12:181–8.

  70. 70.

    Perez DL, Matin N, Barsky A, Costumero-Ramos V, Makaretz SJ, Young SS, et al. Cingulo-insular structural alterations associated with psychogenic symptoms, childhood abuse and PTSD in functional neurological disorders. J Neurol Neurosurg Psychiatry. 2017;88:491–7.

  71. 71.

    Nicholson TR, Aybek S, Craig T, Harris T, Wojcik W, David AS, et al. Life events and escape in conversion disorder. Psychol Med. 2016;46:2617–26.

  72. 72.

    Tomic A, Agosta F, Sarasso E, Petrovic I, Basaia S, Pesic D, et al. Are there two different forms of functional dystonia? A multimodal brain structural MRI study. Mol Psychiatry. 2018. https://doi.org/10.1038/s41380-018-0222-2 [Epub ahead of print].

  73. 73.

    Dunn EC, Nishimi K, Powers A, Bradley B. Is developmental timing of trauma exposure associated with depressive and post-traumatic stress disorder symptoms in adulthood? J Psychiatr Res. 2017;84:119–27.

  74. 74.

    Andreano JM, Touroutoglou A, Dickerson B, Barrett LF. Hormonal cycles, brain network connectivity, and windows of vulnerability to affective disorder. Trends Neurosci. 2018;41:660–76.

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ID was supported by postdoctoral fellowship program from the Basque Country Government. DLP was funded by the National Institute of Mental Health Grant K23MH111983-03, Massachusetts General Hospital Physician-Scientist Development Award and the Sidney R. Baer Jr. Foundation. This study was also supported by the NIH shared instrument grant S10RR023043.

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Correspondence to David L. Perez.

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TRN is funded by a UK National Institute for Health Research (NIHR) Clinician Scientist Fellowship. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health and Social Care. DLP has received honoraria for continuing medical education lectures in functional neurological disorder.

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Diez, I., Larson, A.G., Nakhate, V. et al. Early-life trauma endophenotypes and brain circuit–gene expression relationships in functional neurological (conversion) disorder. Mol Psychiatry (2020). https://doi.org/10.1038/s41380-020-0665-0

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