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Anterior hippocampal grey matter predicts mental health outcome in functional neurological disorders: an exploratory pilot study
  1. David L Perez1,2,3,
  2. Benjamin Williams1,
  3. Nassim Matin1,
  4. Julie Mello4,
  5. Bradford C Dickerson3,5,
  6. W Curt LaFrance Jr6,7,
  7. Matcheri S Keshavan8
  1. 1 Department of Neurology, Functional Neurology Research Group, Cognitive Behavioral Neurology Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
  2. 2 Department of Psychiatry, Neuropsychiatry Unit, Massachusetts General Hospital, Boston, Massachusetts, USA
  3. 3 Athinoula A Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, Massachusetts, USA
  4. 4 Department of Physical Therapy, Massachusetts General Hospital, Boston, Massachusetts, USA
  5. 5 Department of Neurology, Frontotemporal Disorders Unit, Massachusetts General Hospital, Boston, Massachusetts, USA
  6. 6 Neuropsychiatry and Behavioral Neurology Division, Rhode Island Hospital, Providence, Rhode Island, USA
  7. 7 Departments of Psychiatry and Neurology, Brown University, Alpert Medical School, Providence, Rhode Island, USA
  8. 8 Department of Psychiatry, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
  1. Correspondence to Dr David L Perez, Departments of Neurology and Psychiatry, Massachusetts General Hospital, Boston, MA 02129, USA; dlperez{at}

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Advancements in the management of FND emphasise a ‘rule-in’ diagnosis and roles for cognitive behavioural therapy (CBT)1 and physical therapy (PT).2 Neuroimaging studies have also started delineating the neuropathophysiology of FND.3 In the same cohort as this present study, we previously identified that impaired mental health and increased trait anxiety correlated with individual differences in amygdalar volume in patients with FND, while diminished physical functioning was associated with reduced anterior insular volume.4 In FND, the magnitude of adverse life event burden also correlated with decreased insular and hippocampal volumes.5

This pilot voxel-based morphometry (VBM) study used a within-group design to investigate the relationship between baseline volumetric profiles and prospectively collected 6-month outcome data in 22 patients with FND. Stratified comparative analyses with 27 controls were performed to contextualise statistically significant within-group findings. Based on the outcome literature6 and previously described corticolimbic associations with health status and adverse life events,4 5 we hypothesised that baseline amygdalar–hippocampal and cingulo-insular volumes would predict clinical outcomes in FND.


Methods were adapted from Perez et al.4


Twenty-two subjects with FND (19 women, 3 men; age=41.7±11.0 years; illness duration=3.9±4.6 years) were recruited from the Massachusetts General Hospital (MGH) FND Clinic with baseline (MRI+psychometric data) and follow-up (psychometric only) data collected at 6.4±1.1 months; 4 of 26 initial patients were lost to follow-up. Twenty-seven healthy controls (22 women, 5 men; age=40.5±10.8 years) were also recruited through local advertisements.

Patients met criteria for clinically established functional movement disorders (n=12), documented (n=8) or clinically established (n=1) psychogenic non-epileptic seizures and/or exhibited signs of functional weakness (n=9). Eight had mixed symptoms. Inclusion/exclusion criteria were as previously described.4 Psychiatric comorbidities were assessed through the Structured Clinical Interview for DSM-IV-TR. Nineteen patients were on psychotropic medications at baseline (online supplementary table 1).

Supplementary file 1

Prior to enrolment, patients were diagnosed with FND. The term ‘Functional Neurological Disorder’ was communicated, as well as the pertinent motor subtype. FND was presented as common, real and treatable. Patients were introduced to the website and given printed educational materials. Treatments were individualised, emphasising CBT and PT. Fifteen individuals were in psychotherapy at baseline and eight were newly referred (including one who remained in supportive psychotherapy while also starting CBT). In CBT, patients were encouraged to explore the relationships between functional symptoms, thoughts, behaviours, emotions and psychosocial factors.1 Nine were in PT at baseline, and seven were newly referred. Physical therapists were recommended to use the Nielsen et al guidelines.2 Six were started on selective serotonin reuptake inhibitors/serotonin–norepinephrine reuptake inhibitors. Patients did not exclusively receive care at MGH which limited compliance information. Subjects signed informed consent, and the Partners Human Research Committee approved this study.

Patients completed the Short Form Health Survey-36 (SF-36) at baseline and follow-up. A mental health composite score (the average of four mental health related subscores) and a physical health composite score (the average of four physical health related subscores) were calculated per subject so that higher post-treatment versus baseline scores reflected greater improvement. Baseline Spielberger Trait Anxiety Inventory (STAI-T), Beck Depression Inventory-II, Childhood Trauma Questionnaire and the Life Events Checklist-5 (LEC) ‘happened to me’ scores were also available (see the online supplementary tables 2 and 3).

MRI acquisition

MRI acquisition and statistical parametric mapping preprocessing using VBM8 were performed as previously described.4

VBM analyses

Within-group regression analyses adjusting for age and gender were performed in subjects with FND to examine relationships between mental or physical health outcome and baseline volumes. For small volume corrections (SVC), bilateral regions-of-interest included the insula, anterior cingulate cortex (ACC), amygdala and hippocampus based on the WFU Pickatlas. A family-wise-error rate of P<0.05 was used for SVCs at the peak–voxel level.

To contextualise statistically significant within-group findings, age and gender-adjusted secondary analyses using the general linear model compared patients with FND in the top (or bottom) 50 percentile of those who improved in their mental health (n=11) to 27 controls.



Significant associations were observed between mental health outcomes and baseline trait anxiety (P=0.046, Spearman coefficient=0.43) and lifetime adverse event burden (P=0.024, Spearman coefficient=−0.48). There were no other significant associations across psychometrics (online supplementary figure 1).

Supplementary file 2

Voxel-based morphometry

Across patients, mental health improvement positively correlated with baseline left anterior hippocampal grey matter volumes (Psvc=0.027) (figure 1, online supplementary table 4). The anterior hippocampus label is based on a y-axis between −10 and −21.7 In separate post-hoc analyses, associations between mental health and hippocampal volume did not remain significant controlling for baseline STAI-T or LEC ‘happened to me’ scores.

Figure 1

(A) In within-group voxel-based morphometry analyses, improvements in mental health outcome positively correlated with individual differences in left anterior hippocampal grey matter volumes (z-score=3.76; Psvc=0.027). (B) In secondary between-group analyses, patients with FND reporting the least improvement in their mental health at a 6-month follow-up (N=11) exhibited decreased baseline right anterior hippocampal grey matter volume compared with 27 healthy controls (z-score=−3.97; Psvc=0.011). As also displayed, subthreshold group effects were appreciated in the left anterior hippocampus (Puncorrected<0.001). Images are thresholded at an uncorrected P value of 0.005. To display in the scatter plots a measure of grey matter volumes for visualisation purposes only, the MarsBar toolbox ( was used to extract mean grey matter volumes for each subject at a 5 mm sphere centred at the peak–voxel of statistically significant findings. FND, functional neurological disorder; L, left; R, right; SF-36, Short Form Health Survey-36; SVC, small volume corrections.

Compared with controls, patients with FND with the least mental health improvement showed decreased baseline right anterior hippocampal grey matter volume (Psvc=0.011) and a trend towards reduced left anterior hippocampal grey matter volume (Puncorrected <0.001) (online supplementary table 5).


In this pilot study, a relationship was observed between relative increases in baseline anterior hippocampal grey matter and 6-month mental health outcome in FND. In secondary between-group analyses, patients with FND with the least mental health improvement showed reduced anterior hippocampal volume compared with controls. These findings suggest that hippocampal volume, predictive of outcome in mood disorders,6 may represent a biomarker of prognosis across several psychopathologies. While the hippocampus has been linked to learning and memory, the anterior hippocampus also plays important roles in anxiety-related processes.7 The anterior hippocampus is structurally connected to limbic and subcortical structures mediating hypothalamic–pituitary–adrenal axis function; resting-state connectivity profiles in healthy subjects also show that the anterior hippocampus is functionally coupled to the amygdala, ACC and premotor areas.7 We speculate that modulation of amygdalar function is a mechanism through which hippocampal volume predicts mental health outcomes.3

Adjusting for baseline trait anxiety or lifetime adverse event burden, the relationship between hippocampal volume and outcome did not remain significant. This suggests that more research with larger sample sizes is needed to investigate interactions between baseline neuropsychiatric factors, regional brain volumes and outcome. Limitations include a modest sample size, patient heterogeneity, medication use, reliance on self-report measures and that management was not restricted to one institution. A possible type I error cannot be excluded in this pilot study. While more research is needed, we provide preliminary evidence that anterior hippocampal volume may predict mental health outcomes in FND.



  • WCLFJ and MSK contributed equally.

  • Contributors DLP, MSK, WCL and BCD: designed the study. DLP, BW and NM: collected and analysed the data. DLP: drafted the manuscript. All authors: critically interpreted the data and critically reviewed and edited the manuscript.

  • Funding DLP was funded by the National Institute of Mental Health Grant 1K23MH111983-01A1, Sidney R Baer Jr. Foundation and the Massachusetts General Hospital Physician-Scientist Development Award.

  • Disclaimer BCD is a consultant at Merck, Med Learning Group and Haymarket; received royalties from Oxford University Press and Cambridge University Press; on the editorial board of NeuroImage: Clinical, Cortex, Hippocampus, Neurodegenerative Disease Management. MSK is a consultant at Forum Pharmaceuticals; editor for Schizophrenia Research. WCL has served on the editorial boards of Epilepsia, Epilepsy & Behavior and Journal of Neuropsychiatry & Clinical Neurosciences; receives editor’s royalties from the publication of Gates and Rowan’s Nonepileptic Seizures, 3rd edition (Cambridge University Press, 2010) and 4th edition (2017); receives 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 (principal investigator)), Department of Defense, Rhode Island Hospital, the American Epilepsy Society (AES), the Epilepsy Foundation (EF), Brown University and the Siravo Foundation; serves on the Epilepsy Foundation 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.

  • Competing interests None declared.

  • Ethics approval Partners Human Research Committee.

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

  • Correction notice Since this letter was first published online the author surname LaFrance has been updated to include the suffix Jr.