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Research paper
Corticolimbic fast-tracking: enhanced multimodal integration in functional neurological disorder
  1. Ibai Diez1,2,3,4,
  2. Laura Ortiz-Terán1,4,
  3. Benjamin Williams1,
  4. Rozita Jalilianhasanpour1,
  5. Juan Pablo Ospina1,
  6. Bradford C Dickerson1,
  7. Matcheri S Keshavan5,
  8. W Curt LaFrance Jr6,
  9. Jorge Sepulcre4,
  10. David L Perez2,7
  1. 1 Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
  2. 2 Radiology, Athinoula A Martinos Center for Biomedical Imaging, Charlestown, Massachusetts, USA
  3. 3 Neurotechnology Laboratory, Tecnalia Health, Derio, Bizkai, Spain
  4. 4 Radiology and Nuclear Medicine, Gordon Center for Medical Imaging, Harvard Medical School, Boston, Massachusetts, USA
  5. 5 Psychiatry, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
  6. 6 Psychiatry and Neurology, Rhode Island Hospital, Brown Medical School, Providence, Rhode Island, USA
  7. 7 Neurology and Psychiatry, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA
  1. Correspondence to Dr David L Perez, Neurology and Psychiatry, Massachusetts General Hospital, Charlestown, MA 02129, USA; dlperez{at}


Objective Some individuals with functional neurological disorder (FND) exhibit motor and affective disturbances, along with limbic hyper-reactivity and enhanced motor-limbic connectivity. Given that the multimodal integration network (insula, dorsal cingulate, temporoparietal junction (TPJ)) is implicated in convergent sensorimotor, affective and interoceptive processing, we hypothesised that patients with FND would exhibit altered motor and amygdalar resting-state propagation to this network. Patient-reported symptom severity and clinical outcome were also hypothesised to map onto multimodal integration areas.

Methods Between-group differences in primary motor and amygdalar nuclei (laterobasal, centromedial) were examined using graph-theory stepwise functional connectivity (SFC) in 30 patients with motor FND compared with 30 healthy controls. Within-group analyses correlated functional propagation profiles with symptom severity and prospectively collected 6-month outcomes as measured by the Screening for Somatoform Symptoms Conversion Disorder subscale and Patient Health Questionnaire-15 composite score. Findings were clusterwise corrected for multiple comparisons.

Results Compared with controls, patients with FND exhibited increased SFC from motor regions to the bilateral posterior insula, TPJ, middle cingulate cortex and putamen. From the right laterobasal amygdala, the FND cohort showed enhanced connectivity to the left anterior insula, periaqueductal grey and hypothalamus among other areas. In within-group analyses, symptom severity correlated with enhanced SFC from the left anterior insula to the right anterior insula and TPJ; increased SFC from the left centromedial amygdala to the right anterior insula correlated with clinical improvement. Within-group associations held controlling for depression, anxiety and antidepressant use.

Conclusions These neuroimaging findings suggest potential candidate neurocircuit pathways in the pathophysiology of FND.

  • conversion disorder
  • somatisation
  • psychogenic nonepileptic seizures
  • functional movement disorders
  • fMRI

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  • JS and DLP contributed equally.

  • Contributors ID, LOT, JS and DLP designed the study. BW, RJ, JPO and DLP collected the data. ID performed all statistical analyses supervised by JS and DLP. All authors critically interpreted the results and discussed potential post hoc analyses. ID and DLP wrote the manuscript, and all authors critically reviewed, edited and approved the manuscript.

  • Funding DLP was funded by the National Institute of Mental Health Grant K23MH111983-02, Massachusetts General Hospital Physician-Scientist Development Award and the Sidney R Baer Jr Foundation. ID was supported by postdoctoral fellowship programme from the Basque Country Government. This study was also supported by the NIH shared instrument grant S10RR023043.

  • Competing interests BCD is a consultant at Merck, Med Learning Group and Haymarket; royalties from Oxford University Press and Cambridge University Press; on the editorial board of Neuroimage: Clinical, Cortex, Hippocampus, Neurodegenerative Disease Management. WCL has served on the editorial boards of Epilepsia and Epilepsy, receives editor’s royalties from the publication of Gates and Rowan’s Nonepileptic Seizures, 3rd ed (Cambridge University Press, 2010) and 4th ed (2018); author’s royalties for Taking Control of Your Seizures: Workbook and Therapist Guide (Oxford University Press, 2015); has received research support from the NIH (NINDS 5K23NS45902 (PI)), Rhode Island Hospital, the American Epilepsy Society (AES), the Epilepsy Foundation (EF), Brown University, the Siravo Foundation and the DoD (W81XWH-17-0169 (PI)); serves on the Epilepsy Foundation New England Professional Advisory Board; has received honoraria for the American Academy of Neurology Annual Meeting Annual Course; has served as a clinic development consultant at University of Colorado Denver, Cleveland Clinic, Spectrum Health and Emory University; and has provided medicolegal expert testimony. MSK is a one-time consultant at Forum Pharmaceuticals; editor for Schizophrenia Research. DLP received honoraria from Harvard Medical School, the American Academy of Neurology and the Movement Disorder Society.

  • Patient consent for publication Not required.

  • Ethics approval The Partners Human Research Committee approved the study.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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