r Human Brain Mapping 00:00–00 (2017) r

Cortical Thickness Alterations Linked to

Somatoform and Psychological Dissociation
in Functional Neurological Disorders

David L. Perez ,1,2,3* Nassim Matin,1 Benjamin Williams,1 Kaloyan Tanev,2,3

Nikos Makris,4 W. Curt LaFrance Jr.,5 and Bradford C. Dickerson3,6
1
Department of Neurology, Functional Neurology Research Group, Cognitive Behavioral
Neurology Unit, Massachusetts General Hospital, Harvard Medical School,
Boston, Massachusetts
2
Department of Psychiatry, Neuropsychiatry Unit, Massachusetts General Hospital,
Harvard Medical School, Boston, Massachusetts
3
Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital,
Harvard Medical School, Charlestown, Massachusetts
4
Center for Morphometric Analysis, Departments of Neurology and Psychiatry, Massachusetts
General Hospital, Harvard Medical School, Charlestown, Massachusetts
5
Neuropsychiatry and Behavioral Neurology Division, Rhode Island Hospital,
Departments of Psychiatry and Neurology, Brown University, Alpert Medical School,
Providence, Rhode Island
6
Department of Neurology, Frontotemporal Disorders Unit, Massachusetts General Hospital,
Harvard Medical School, Boston, Massachusetts

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Abstract: Background: Links between dissociation and functional neurological disorder (FND)/conversion
disorder are well-established, yet the pathophysiology of dissociation remains poorly understood. This
MRI study investigated structural alterations associated with somatoform and psychological dissociation
in FND. We hypothesized that multimodal, paralimbic cingulo-insular regions would relate to the severity
of somatoform dissociation in patients with FND. Methods: FreeSurfer cortical thickness and subcortical
volumetric analyses were performed in 26 patients with motor FND and 27 matched healthy controls.
Patients with high dissociation as measured by the Somatoform Dissociation Questionnaire-20 (SDQ)
or Dissociative Experiences Scale (DES) were compared to controls in stratified analyses. Within-group
analyses were also performed with SDQ and DES scores in patients with FND. All cortical thickness
analyses were whole-brain corrected at the cluster-wise level. Results: Patients with FND and high

Contract grant sponsor: National Institute of Mental Health;
Contract grant number: 1K23MH111983-01A1; Contract grant
sponsor: Dupont Warren and Livingston Fellowships; Contract
grant sponsor: Massachusetts General Hospital Physician-Scientist
Development Award; Contract grant sponsor: Sidney R. Baer Jr.
Foundation; Contract grant sponsor: NIH Shared Instrument Grant;
Contract grant number: S10RR023043; Contract grant sponsor:
National Institutes of Aging; Contract grant number: R01AG04252.
*Correspondence to: David L. Perez, MD, MMSc, Massachusetts
General Hospital, Departments of Neurology and Psychiatry, 149 13th
Street, Charlestown, MA 02129, USA. E-mail: dlperez@partners.org
David L. Perez and Nassim Matin are co-first authors.
W. Curt LaFrance Jr. and Bradford C. Dickerson contributed
equally to this article.
Additional Supporting Information may be found in the online
version of this article.
All authors report no conflicts of interest.
Received for publication 14 June 2017; Revised 21 September
2017; Accepted 10 October 2017.
DOI: 10.1002/hbm.23853
Published online 00 Month 2017 in Wiley Online Library
(wileyonlinelibrary.com).

C 2017 Wiley Periodicals, Inc.

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 r Perez et al. r

somatoform dissociation (SDQ > 35) showed reduced left caudal anterior cingulate cortex (ACC) corti-
cal thickness compared to controls. In within-group analyses, SDQ scores inversely correlated with left
caudal ACC cortical thickness in patients with FND. Depersonalization/derealization scores positively
correlated with right lateral occipital cortical thickness. Both within-group findings remained statisti-
cally significant controlling for trait anxiety/depression, borderline personality disorder and post-
traumatic stress disorder, adverse life events, and motor FND subtypes in post-hoc analyses. Conclu-
sion: Using complementary between-group and within-group analyses, an inverse association between
somatoform dissociation and left caudal ACC cortical thickness was observed in patients with FND. A
positive relationship was also appreciated between depersonalization/derealization severity and corti-
cal thickness in visual association areas. These findings advance our neuropathobiological understand-
ing of dissociation in FND. Hum Brain Mapp 00:000–000, 2017. VC 2017 Wiley Periodicals, Inc.

Key words: conversion disorder; functional movement disorders; psychogenic nonepileptic seizures;
anterior cingulate cortex; occipital cortex

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2004; Reuber et al., 2003] and somatoform dissociation as eval-

INTRODUCTION
As originally conceptualized by the French psychologist
Pierre Janet (1859–1947), dissociation represents “a form of
mental depression characterized by retraction of the field of
personal consciousness and a tendency to the dissociation
and emancipation of the system of ideas and functions that
constitute personality” [Janet, 1907]. Dissociative symptoms
involve psychological and somatoform features, including
derealization, depersonalization, identity fragmentation,
amnesia, paralysis, seizures, analgesia, and loss of con-
sciousness [Nijenhuis et al., 1996]. Dissociation can also be
framed as occurring across four domains: behavior, affect,
sensation, and/or knowledge [Braun, 1988]. Although mod-
els of dissociation were first applied to conversion disorder,
now also termed functional neurological disorder (FND),
neurobiological investigations of FND have lagged behind
research in primary dissociative disorders, such as dissocia-
tive identify disorder (DID), and other psychiatric disorders
with prominent dissociative symptoms, including post-
traumatic stress disorder (PTSD) and borderline personality
disorder (BPD) [Bass et al., 2001]. The paucity of clinical
neuropathobiological studies in FND is striking given the
high disease prevalence and healthcare expenses incurred
by this population [Stone et al., 2009].
Although individual differences exist in the magnitude
of endorsed dissociative symptoms [Kranick et al., 2011],
links between FND and dissociation are well-established
[Sar et al., 2004]. Many patients with FND also meet
diagnostic criteria for other psychiatric conditions with
prominent dissociation including PTSD [Myers et al., 2013]
and/or BPD [Stone et al., 2004]. Conversely, medically
unexplained somatic symptoms are also common in
dissociative disorders and PTSD [Saxe et al., 1994; van der
Kolk et al., 1996]. Dissociation in FND is linked to poor
prognosis [Schrag et al., 2004] and suicidality [Sar et al.,
2004]. Dimensionally, patients with FND report elevated
rates of trait psychological dissociation as measured by the
Dissociative Experiences Scale (DES) [Bernstein and
Putnam, 1986; Goldstein and Mellers, 2006; Guz et al.,
uated by the Somatoform Dissociation Questionnaire-20 (SDQ)
[Brown et al., 2013; Nijenhuis et al., 1996, 1999; Pick et al., 2017;
Roelofs et al., 2002b; Sar et al., 2009]. These observations sup-
port investigating neural mechanisms of dissociation in FND
to advance our knowledge of the neuropathobiology of FND
and further elucidate mechanisms linked to dissociative stress
responses across psychopathologies.
Despite the connection between FND and dissociation, few
neuroimaging studies have investigated brain–dissociation
relationships in FND. A structural magnetic resonance imag-
ing (MRI) study in patients with psychogenic nonepileptic
seizures (PNES) (a.k.a. conversion disorder, with seizures
subtype/dissociative seizures) showed inverse associations
between left inferior frontal gyrus cortical thickness and SDQ
scores [Labate et al., 2012]. Dissociative symptoms have also
positively correlated with increased resting-state functional
connectivity across cognitive/executive control regions (ante-
rior cingulate cortex (ACC), inferior frontal gyrus, anterior
insula) and premotor areas in patients with PNES [van der
Kruijs et al., 2012, 2014]. To date, there are no other neuroim-
aging studies that have investigated neural circuit alterations
linked to dissociation severity across the spectrum of motor
FND, which includes not only PNES, but also functional
movement disorders and functional limb weakness [Perez
et al., 2015].
Insights into the neurobiology of dissociation in FND may
also be gained through advances made in primary dissocia-
tive disorders, such as DID, and other conditions with disso-
ciative symptoms, for example, PTSD, and BPD. Across
psychopathologies, dissociation has been linked to increased
prefrontal engagement, diminished amygdalar activity, and
altered somatosensory and visual processing [Krause-Utz
et al., 2017]. For example, structural MRI studies in patients
with DID showed reduced amygdalar, hippocampal, and
parahippocampal volumes compared to controls [Chalavi
et al., 2015a, 2015b; Ehling et al., 2008; Vermetten et al., 2006].
Individuals with DID and co-morbid PTSD have also
displayed decreased insular volumes compared to controls
[Chalavi et al., 2015a]. Functional neuroimaging studies in

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 r Cortical Thickness Alterations
DID also report amygdalar-hippocampal [Mathew et al.,
1985; Reinders et al., 2003] and frontoparietal [Reinders et al.,
2003; Sar et al., 2001, 2007] abnormalities. In depersonaliza-
tion disorder, increased medial prefrontal and reduced
striato-thalamic volumes have been observed [Daniels et al.,
2015]. Hyperactivation of “top–down” regulatory prefrontal
(ACC, dorsolateral prefrontal cortex) and parieto-occipital
regions, along with reduced limbic activity, are well-
described in depersonalization disorder [Lemche et al., 2007,
2008; Medford et al., 2016; Phillips et al., 2001; Simeon et al.,
2000].
Studies in the dissociative subtype of PTSD and BPD fur-
ther support a model of prefrontal over-modulation of
emotion processing areas [Lanius et al., 2010] and altered
activity in visual processing areas [Daniels et al., 2012]. Stud-
ies demonstrate increased task-based prefrontal/ACC activ-
ity [Lanius et al., 2002] and heightened fronto-amygdalar
resting-state connectivity [Nicholson et al., 2015] in patients
with dissociative PTSD compared to controls. Dissociative
symptoms in PTSD also positively correlated with medial
prefrontal hyperactivity and volumetric profiles [Daniels
et al., 2016; Hopper et al., 2007; Nardo et al., 2013]. Peritrau-
matic dissociation has been linked to occipital hyperactiva-
tions [Daniels et al., 2012]. In BPD, high dissociation is linked
to increased prefrontal activity [Ludascher et al., 2010; Winter
et al., 2015] and heightened dorsal ACC-amygdalar connec-
tivity [Krause-Utz et al., 2014]. Notably, most neurobiological
studies across psychopathologies have focused on trait
psychological dissociation, with somatoform dissociation
receiving considerably less research attention to date.
In this FreeSurfer-based MRI study, we compared cortical
thickness and subcortical volumes in 26 FND patients and 27
age- and gender-matched healthy controls. We used stratified
comparative analyses to specifically compare FND patients
with high somatoform or psychological dissociation to
controls. Within-group dimensional approaches were also
utilized to investigate structural brain profiles associated with
somatoform and/or psychological trait dissociation in
patients with FND. Based on the existing literature in dissoci-
ation and our published models of the neurobiology of FND
[Lanius et al., 2010; Perez et al., 2012, 2015], we hypothesized
that FND patients with elevated psychological dissociation
would exhibit cortical thickness alterations in regulatory pre-
frontal regions. We also hypothesized that somatoform disso-
ciation, in comparison to trait psychological dissociation,
would map onto cingulo-insular (salience network) brain
areas given that these regions mediate the multimodal inte-
gration of sensory-motor, affective, and cognitive processes
[Sepulcre et al., 2012; Shackman et al., 2011].
MATERIALS AND METHODS
Participants
Twenty-six subjects with FND (21 women, 5 men; mean
age: 40.3 6 11.5 years; average illness duration: 3.6 6 4.3
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years) were recruited from the Functional Neurological
Disorders Clinic at the Massachusetts General Hospital
(MGH) [Matin et al., 2017; Perez et al., 2017b]. FND diag-
noses were based on the clinical evaluation by a dual-
trained board certified neurologist and psychiatrist
(D.L.P.). For subjects with FND, 13 met diagnostic criteria
for clinically established functional movement disorders
[Williams et al., 1995], 10 had documented or clinically
established PNES [LaFrance et al., 2013] (9 and 1, respec-
tively), and 12 showed signs on exam consistent with
functional weakness [American Psychiatric Association,
2013]. Nine individuals had mixed motor FND, and a
distinct 9 subjects exhibited nondermatomal sensory
deficits. Twenty-seven matched healthy controls (22
women, 5 men; mean age: 40.5 6 10.8) without psychiatric,
neurologic or poorly controlled medical conditions were
recruited through local advertisements.
Exclusion criteria for the FND cohort included any major
neurological disorder with MRI abnormalities, epilepsy,
poorly controlled medical illnesses with known central ner-
vous system consequences, ongoing substance dependence,
a history of mania or psychosis, and/or active suicidality.
Additional current psychiatric diagnoses were assessed
through the Structured Clinical Interview (SCID) for DSM-
IV-TR Axis I Disorders; a limited SCID for axis II personality
disorders (SCID-II) was also performed to assess for BPD.
All participants provided signed informed consent, and
the study was approved by the Partners Human Research
Committee.
Current comorbid psychiatric diagnoses in the FND
cohort included major depressive disorder (N 5 8), dysthy-
mia (N 5 3), generalized anxiety disorder (N 5 10), obsessive
compulsive disorder (N 5 1), panic disorder (N 5 12), agora-
phobia without panic disorder (N 5 2), social phobia (N 5 1),
specific phobia (N 5 1), other somatoform disorders
(N 5 12), eating disorder not otherwise specified (N 5 1),
and alcohol abuse (N 5 1). Eight had lifetime PTSD (5 with
current PTSD, 3 with a past diagnosis). Four individuals had
BPD. 20 patients were on psychotropic medications, with 13
subjects taking selective serotonin reuptake inhibitors
(SSRIs) and/or serotonin–norepinephrine reuptake
inhibitors (SNRIs). All patients were free of drug abuse/
dependence for at least 6 months prior to study participa-
tion. All healthy controls were without any axis I psychiatric
diagnosis or BPD, and were off psychotropic medications.
Detailed clinical information including psychotropic medi-
cation use is found in Supporting Information, Table 1.
Psychometric Measures
Study participants completed the SDQ [Nijenhuis et al.,
1996] and DES [Bernstein and Putnam, 1986] as primary mea-
sures of interest. The SDQ is a 20-item self-report question-
naire where individuals report the frequency of somatoform
(bodily) dissociative symptoms (e.g., analgesia, anesthesia,
altered sensory preferences, loss of consciousness, and motor
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disturbances) in the past year. Items are scored on a 5-point
Likert scale ranging from “this applies to me not at all” to
“this applies to me extremely.” Scores range from 20 to 100
with higher scores indicating greater somatoform dissocia-
tion; consistent with prior reports a score of 35 was consid-
ered pathologic [Farina et al., 2011; Sar et al., 2004, 2009; Tsar
et al., 2001]. The DES is a 28-item self-report questionnaire of
psychological dissociation where individuals specify the fre-
quency of a variety of dissociative experiences (e.g., derealiza-
tion) in daily life with scores ranging from 0% to 100% per
item. Average DES scores above 30% are considered patho-
logic [Putnam et al., 1996; Sar et al., 2009]. Based on factor
analyses [Ross et al., 1991], there are 3 DES subscales: deper-
sonalization/derealization (6 items), amnestic dissociation
(8 items), and absorption/imaginative involvement (9 items).
To control for potential confounding effects of anxiety
and mood symptoms, subjects completed the Spielberger
Trait Anxiety Inventory (STAI-T) [Spielberger et al., 1970]
and the Beck Depression Inventory-II (BDI) [Beck et al.,
1996]. The STAI-T is a 20-item self-report measure of trait
anxiety, and the BDI is a 21-item self-report measure of
depression. Given potential links between adverse life
events and dissociation [van der Kolk et al., 1996], subjects
also completed the Childhood Trauma Questionnaire (CTQ)
[Bernstein et al., 1994] and the Life Events Checklist-5
(Weathers et al., 2013) (LEC-5). The CTQ is a 25-item mea-
sure of childhood/adolescent abuse and neglect, and the
LEC-5 is a 17-category measure of lifetime adverse events.
MRI Acquisition
Subjects were placed in a Siemens 3 T Trio scanner to
acquire a 3D T1-weighted magnetization prepared rapid
acquisition gradient echo sequence with the following
parameters: orientation 5 sagittal; matrix size 5 256 3 256;
voxel size 5 1 3 1 3 1 mm; slice thickness 5 1 mm, slices 5
160; repetition time 5 2300 ms; echo time 5 2.98 ms; field of
view 5 256 mm. Bitemporal foam pads were used to restrict
head motion.
Cortical Thickness and Subcortical
Volumetric Analyses
T1-weighted structural scans were inspected to ensure
good acquisition quality. FreeSurfer 5.3.0 (https://surfer.
nmr.mgh.harvard.edu/) was used to perform cortical
reconstructions of the T-weighted images as previously
described [Collins et al., 2017]. Cortical reconstructions
were visually inspected to check for accuracy of the auto-
matic segmentation of the grey/white matter boundary,
and no scans required manual editing. This boundary was
then used by the deformable surface algorithm to identify
the pial surface for each subject. Cortical thickness was
measured by calculating the distance between the white
matter and pial surfaces at 160,000 vertices in each
hemisphere. Each subject’s reconstructed brain was then
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morphed and registered to an average spherical space that
optimally aligned gyral and sulcal features, thus enabling
the matching of cortical locations among individuals across
the entire cortical surface. Individual thickness measures
were mapped onto this new space. A Gaussian kernel of
10 mm full-width at half-maximum was applied to the sub-
jects’ cortical thickness maps. For subcortical data, volumes
(bilateral putamen, caudate nucleus, globus pallidus,
nucleus accumbens, thalamus, amygdala, and hippocam-
pus) were calculated using the automatic segmentation
pipeline in FreeSurfer, visually inspected for quality, and
normalized for total intracranial volume at the individual
subject level.
To compare subjects with FND to controls, cortical thick-
ness analyses were performed using a 2-class general lin-
ear model (GLM) for the effect of clinical status (e.g., FND
vs controls). Given that there were no age 3 group effects
as tested using the QDEC tool in FreeSurfer, we used the
different onset, same slope (DOSS) settings for between-
group analyses. FND patients were stratified dichoto-
mously based on dissociation severity to compare FND
subjects with the highest dissociation severity to controls.
A SDQ cutoff of 35 delineated the “high somatoform dis-
sociation FND subgroup” (N 5 10), and the 16 FND
patients with SDQ scores <35 were placed into the “low
somatoform dissociation FND subgroup.” For DES scores,
most of our FND cohort endorsed only subthreshold psy-
chological dissociation, and thus we were unable to use an
established cutoff of 30 (only 7 patients with FND had
DES scores 30). A “high psychological dissociation FND
subgroup” was alternatively defined as those in the upper
50th percentile of the cohort, and a “low psychological
dissociation FND subgroup” was defined as those in the
lower 50th percentile.
For within-group analyses, a 1-class GLM was per-
formed to evaluate for the effect of the covariate of interest
(i.e., SDQ, DES). All between-group and within-group
analyses included age and gender as covariates-of-non-
interest. For cortical thickness analyses, statistical signifi-
cance of P < 0.05 was corrected for multiple comparisons
at the cluster-wise level using the mri_glmfit-sim com-
mand. The Desikan–Killiany automated labeling system
was used for cortical structures [Desikan et al., 2006]. For
between-group subcortical analyses, separate logistic
regression analyses were performed in IBM SPSS v23 to
examine group-level differences in normalized subcortical
volumes. For within-group subcortical analyses in the
FND cohort, separate linear regression analyses were per-
formed to investigate associations between dissociation
severity and normalized subcortical volumes. A Bonferroni
correction was applied to all subcortical analyses to reduce
type-I errors.
Following identification of statistically significant
within-group analyses, separate post-hoc analyses were
performed to determine if significant findings held when
controlling for (1) lifetime PTSD and BPD; (2) STAI-T and
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TABLE I. Statistically significant between-group and within-group cortical thickness findings in patients with func-
tional neurological disorders

Peak coordinates in
MNI space (mm)
Cluster
Analysis Contrast of interest Cerebral regions x y z T value max P value N. Vtx size (mm2)

Between FND-high SDQ (n 5 10) vs Caudal ACC 22.1 19.8 19.1 22.94 0.035 870 413.2
group healthy controls (n 5 27)
Within SDQ (n 5 26) Caudal ACC 21.6 13.9 22.9 25.04 0.008 1268 569.0
group DES-depersonalization/ Lateral 30.1 289.1 20.2 4.00 0.007 757 590.7
derealization (n 5 26) occipital cortex

P values represent whole-brain corrected values based on cluster-wise correction. N. Vtx, number of vertices; MNI, Montreal Neurological
Institute; FND, functional neurological disorder; ACC, anterior cingulate cortex, SDQ, Somatoform Dissociation Questionnaire-20; DES,
Dissociative Experiences Scale.

BDI scores; (3) adverse-life event burden as measured by a
cumulative index of childhood abuse (sexual, physical,
and emotional (CTQ-Abuse)) and LEC-5-“happened to
me” scores; (4) motor FND subtypes; (5) SSRI and/or
SNRI use. Given sample size limitations and heteroge-
neous medications, SSRIs/SNRIs were controlled for as a
dichotomous (yes/no) covariate of noninterest.
RESULTS
Demographic information and psychometric scores for
the 26 patients with FND and 27 matched healthy controls
are summarized in Supporting Information, Tables 1 and 2.
Associations Between Dissociation and
Adverse Life Events in FND
In patients with FND, a significant statistical correlation
was observed between SDQ scores and DES scores (spearman
correlation coefficient 5 0.51, P value 5 0.008). However, the
association between SDQ and CTQ-abuse scores was not
significant (spearman correlation coefficient 5 0.31, P val-
ue 5 0.12), and DES and CTQ-abuse scores showed only
trend-level positive associations (spearman correlation coef-
ficient 5 0.38, P value 5 0.059). There was also no significant
relationship between SDQ and LEC “happened to me” scores
(spearman correlation coefficient5-0.07, P value 5 0.73), nor
between DES and LEC “happened to me” scores (spearman
correlation coefficient 5 0.04, P value 5 0.87). Scatter plots are
displayed in Supporting Information, Figure 1.
Between-Group Structural MRI Differences
There were no whole-brain corrected cortical thickness
or subcortical volumetric differences between the complete
FND cohort and controls. In stratified between-group anal-
yses, FND patients with high somatoform dissociation
showed reduced cortical thickness in the left caudal
(dorsal) ACC (Pwhole-brain-corrected 5 0.035) compared to
controls (Table I and Fig. 1). There were no other group-
level cortical thicknesses or subcortical volumetric differ-
ences in stratified analyses by SDQ, DES, or the 3 DES
subscores.
Within-Group MRI Associations With
Somatoform and Psychological Dissociation
In patients with FND, left caudal ACC cortical thickness
inversely correlated with SDQ scores controlling for age and
gender (Pwhole-brain-corrected 5 0.008) (Fig. 2). This relationship
remained significant when adjusting for (1) lifetime PTSD
and BPD; (2) BDI and STAI-T scores; (3) CTQ-Abuse and
LEC “happened to me” scores; (4) motor FND subtypes;
and (5) SSRI/SNRI use in separate post-hoc analyses
(Supporting Information, Table 3).
A significant positive association was also observed
between right lateral occipital cortical thickness and DES-
depersonalization/derealization sub-scores in FND patients
(Pwhole-brain-corrected 5 0.007) (Fig. 3). This relationship held
when adjusting for (1) lifetime PTSD and BPD; (2) BDI and
STAI-T scores; (3) CTQ-Abuse and LEC “happened to me”
scores; (4) motor FND subtypes; and (5) SSRI/SNRI use in
separate post-hoc analyses. There were no other significant
associations between structural MRI profiles and dissocia-
tion scores.
DISCUSSION
This structural MRI study investigated the neural under-
pinnings of the pathologic fragmentation of bodily experi-
ences, termed somatoform dissociation [Nijenhuis et al.,
1996], along with psychological dissociative experiences
(e.g., derealization/depersonalization) in a cohort of
patients with FND. Our findings suggest that individuals
with FND endorsing the most severe rates of somatoform
dissociation exhibited reduced left caudal ACC cortical
thickness compared to healthy controls. In within-group
analyses, somatoform dissociation severity inversely

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Figure 1.
Functional neurological disorder (FND) patients with high soma-
toform dissociation showed reduced left caudal anterior cingu-
late cortex (ACC) cortical thickness compared to healthy
controls. (A) In stratified analyses using the general linear model,
FND patients with high somatoform dissociation (somatoform
dissociation questionnaire-20 (SDQ) scores  35) displayed
reduced cortical thickness in the left caudal ACC (Pwhole-brain-
correlated with left caudal ACC cortical thickness in
patients with FND. The within-group relationship between
ACC cortical thickness and somatoform dissociation
remained significant when controlling for lifetime PTSD
and BPD diagnoses, trait anxiety and depression, adverse-
life event burden, motor FND subtypes, and SSRI/SNRI
medication use in separate post-hoc analyses. In addition,
depersonalization–derealization correlated with increased
right lateral occipital cortical thickness in patients with
FND. These findings support a potential role for the cau-
dal ACC in the neuropathobiology of somatoform dissoci-
ation and reinforce the existing psychiatric literature
linking fragmented perception of the self and/or the envi-
ronment to disturbances in visual association cortices.
Figure 2.
Somatoform dissociation severity inversely correlated with cau-
dal anterior cingulate cortex (ACC) cortical thickness in patients
with functional neurological disorders (FND). (A) Somatoform
dissociation, as measured by the Somatoform Dissociation
Questionnaire-20 (SDQ), negatively correlated with left caudal
ACC cortical thickness (Pwhole-brain-corrected 5 0.008) in patients
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corrected 5 0.035) compared to controls. (B) Box and whisker
plots show the median, quartiles, and range of the circumscribed
ACC cortical thickness values shown in panel A for healthy con-
trols, 10 FND patients with high somatoform dissociation, and
16 FND patients with low somatoform dissociation (SDQ < 35).
Note: images are thresholded at an uncorrected P value of 0.01.
[Color figure can be viewed at wileyonlinelibrary.com]
Our observation of reduced caudal ACC cortical thick-
ness in patients with FND reporting high somatoform
dissociation compared to controls is consistent with
ACC volumetric reductions previously observed in PNES
[Labate et al., 2012] and other somatic symptom disorders
[Valet et al., 2009]. Here, we specifically extend these find-
ings by linking ACC cortical thickness to the magnitude of
endorsed somatoform dissociation experienced by patients
with motor FND. An extensive literature connects the
ACC to the neuropathobiology of FND [Aybek et al., 2015;
Burke et al., 2014; Mailis-Gagnon et al., 2003; Marshall
et al., 1997; Perez et al., 2012, 2015; Saj et al., 2009; Voon
et al., 2016], including resting-state studies characterizing
abnormal ACC connectivity profiles linked to dissociation
with FND using a one-group general linear model. (B) For visual
display purposes only, a scatter plot of cortical thickness values
for the statistically significant ACC region is plotted against indi-
vidual SDQ scores. Note: images are thresholded at an uncor-
rected P value of 0.01. [Color figure can be viewed at
wileyonlinelibrary.com]
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 r Cortical Thickness Alterations
Figure 3.
Depersonalization/derealization scores positively correlated with
right lateral occipital cortical thickness in patients with functional
neurological disorders (FND). (A,B) In within-group analyses
using the general linear model, a significant positive correlation
was observed between depersonalization/derealization subscale
scores of the Dissociative Experiences Scale (DES) and right lat-
eral occipital cortical thickness (Pwhole-brain-corrected 5 0.007) in
patients with FND. (C) Box and whisker plots show the median,
[van der Kruijs et al., 2012] and PNES frequency [Li et al.,
2015]. The caudal ACC, implicated in appraisal and the
behavioral expression of affective states, is structurally
connected to lateral prefrontal and premotor regions [Etkin
et al., 2011]. Posterior aspects of the ACC and adjacent
anterior middle cingulate cortex constitute a cortical hub
for the multimodal integration of negative affective proc-
essing, nociception and cognitive control [Sepulcre et al.,
2012; Shackman et al., 2011]. Conceptual models dating
back to Janet have theorized that dissociation represents a
failure to integrate cognitive, affective, and sensory-motor
functions, which overlaps with a framing of dissociative
symptoms as related to altered states of consciousness.
Our study provides a neuropathobiological substrate for
this concept by implicating the caudal ACC as an impor-
tant node in the neural circuitry of somatoform dissocia-
tion. The connection between the caudal ACC and
somatoform dissociation can be further contextualized
through the construct of “neural functional unawareness,”
a framework that we proposed for the neurobiology of
functional (psychogenic) neurological symptoms that
emphasizes disturbances in emotional and bodily aware-
ness as important in the neurobiology of FND [Perez
et al., 2012, 2015]. Distributed across cingulo-insular, lim-
bic and subcortical brain areas, the salience network is a
core network implicated in the neurobiology of FND, with
potentially distinct nodes of this circuit mediating specific
disturbances in emotional and self-awareness, dissociation,
selective attention, interoception, arousal, and fear
responses [Perez et al., 2012, 2015, 2017a, 2017b]. Addi-
tional research is needed to determine if somatoform
dissociation correlates specifically with the caudal ACC or
r 7
r
quartiles, and range of the circumscribed lateral occipital cortical
thickness values shown in panel A for healthy controls, the 13
FND patients with highest depersonalization/derealization
scores, and the 13 FND patients with the lowest depersonaliza-
tion/derealization scores. Note: images are thresholded at an
uncorrected P value of 0.01. [Color figure can be viewed at
wileyonlinelibrary.com]
if distributed salience network structural profiles more
broadly (including the insula) relate to the neurobiology of
somatoform dissociation.
Our findings connecting somatoform dissociation to the
caudal ACC suggest that psychological and somatoform
dissociation may localize to distinct cingulate gyrus subre-
gions. In women with FND, we have previously identified
left anterior insular volumetric reductions linked to both
self-reported sensory-motor functional neurological symp-
tom severity and childhood abuse burden [Perez et al.,
2017a]. In this prior study, we also observed that PTSD-
related hyperarousal and avoidance were linked to perige-
nual ACC volumetric reductions in FND; lifetime adverse
event burden was associated with hippocampal reductions.
Notably, structural MRI meta-analyses in PTSD report peri-
genual ACC, ventromedial prefrontal, and hippocampal
volumetric reductions compared to controls [Kuhn and Gal-
linat, 2013]; fMRI meta-analyses also show hypoactivations
in the dorsal/perigenual ACC and ventromedial prefrontal
cortices in PTSD [Etkin and Wager, 2007]. Models of disso-
ciation in PTSD, as proposed by Lanius et al. [2010], suggest
that hyperarousal, avoidance, and re-experiencing phenom-
ena relate to reduced engagement of perigenual ACC and
ventromedial prefrontal regions facilitating impaired emo-
tion regulation. Conversely, dissociative symptoms, particu-
larly depersonalization and derealization, have been linked
to pathological overengagement of regulatory prefrontal
regions. This model connecting psychological dissociation to
increased perigenual ACC and ventromedial prefrontal acti-
vations has been supported not only by the dissociative
PTSD literature [Felmingham et al., 2008; Lanius et al.,
2002], but also by studies in primary dissociative disorders
r
 r Perez et al.
[Medford et al., 2016; Phillips et al., 2001] and BPD
[Ludascher et al., 2010]. The fragmentation of bodily experi-
ences in somatoform dissociation may be less closely linked
to rostral cingulate regions implicated in emotion regulation
and more closely connected to caudal ACC areas mediating
the failed integration of cognitive, affective, viscerosomatic,
and sensory-motor functions. In support of this interpreta-
tion, graph-theory methods and large-scale meta-analyses
have identified the caudal ACC and adjacent middle cingu-
late cortex as a critical component of the multimodal inte-
gration network [Paus, 2001; Sepulcre et al., 2012; Shackman
et al., 2011].
The observation that our within-group inverse relation-
ship between caudal ACC cortical thickness and somato-
form dissociation was independent of adverse-life event
burden is somewhat unexpected and requires further
inquiry. Notably, while many studies have linked dissocia-
tion severity to trauma burden, associations between dis-
sociation and psychological trauma may not reflect simple
linear relationships [Merckelbach and Muris, 2001]; other
environmental factors such as pathologic family structures
may be important [Nash et al., 1993]. Large-scale structural
neuroimaging studies in healthy subjects have connected
cumulative adverse life-event burden to reduced cingulo-
insular, ventromedial prefrontal, striatal, and hippocampal
volumes [Ansell et al., 2012; Dannlowski et al., 2012]. It
remains unclear, however, if traumatic experiences medi-
ate aberrant neuroplastic changes to facilitate a general
predilection for the development of psychopathology, or if
a combination of genetic and environmental factors inter-
acts to promote distinct neural and phenotypic profiles
across clinical populations. Brain-adverse life event rela-
tionships, when studied across trauma-related disorders
including PTSD, dissociative disorders, BPD and FND,
may identify some convergent biological features as well
as some disorder-specific components. Future studies in
FND with larger sample sizes should clarify brain-
dissociation and brain-past trauma/abuse burden relation-
ships by considering the effects of trauma type, age of
onset, frequency of experienced adversity, gender differ-
ences, and genetic/epigenetic influences.
The positive relationship between the magnitude of
endorsed depersonalization/derealization experiences and
right lateral occipital cortical thickness in patients with FND
reinforces prior reports of altered metabolism and connectiv-
ity in this region. In comparison to controls, patients with
depersonalization disorder exhibited higher metabolic activity
in parieto-occipital areas [Simeon et al., 2000], and patients
with DID showed increased bilateral cerebral blood flow in
occipital regions [Sar et al., 2007]. A study in acutely trauma-
tized patients also detected positive correlations between
occipital hyperactivity and peritraumatic dissociation [Daniels
et al., 2012]. The lateral occipital cortex is implicated in higher-
order visual processing, visuospatial imagery [Horikawa
et al., 2013] and visual (autobiographical) working memory
[Harrison and Tong, 2009; Tong, 2013]. It has been
r 8
r
hypothesized that “bottom–up” amygdala engagement may
be responsible for enhanced visual processing of emotionally
valenced events [Vuilleumier and Pourtois, 2007]. There may
also be a convergence between the pathophysiology of deper-
sonalization/derealization in idiopathic dissociative disorders
and the neurobiology of secondary dissociation in neuropsy-
chiatric populations. Reports have linked temporo-parietal-
occipital lesions to a vision-specific form of derealization
termed visual hypoemotionality, which may occur following
right inferior longitudinal fasciculus disruptions leading to a
visual-limbic disconnection syndrome [Fischer et al., 2016].
Our findings may also be contextualized through neurobio-
logical links between hypnosis, dissociation, and FND [Deeley,
2017]. Studies of dissociation and FND have generated
renewed interest in hypnosis as a potential model of study for
these disorders. Indeed, studies have demonstrated that highly
hypnotizable patients more commonly report functional neu-
rological symptoms and/or dissociation [Bliss, 1984; Roelofs
et al., 2002a]. Furthermore, neurophysiological studies impli-
cate some overlapping brain processes between hypnosis and
FND, highlighting the ACC as one potential point of intersec-
tion [Cojan et al., 2015; Halligan et al., 2000; Jiang et al., 2017].
However, findings have been inconsistent as to whether the
hypnotized state is associated with increased [Halligan et al.,
2000] or decreased ACC [Jiang et al., 2017] activation. Future
research should continue to investigate potential overlaps
between dissociation and hypnosis, and any therapeutic
implications.
This study has several limitations including a modest
sample size and the use of psychotropic medications in most
patients with FND. While we controlled our within-group
findings for SSRI/SNRI medication use, we were unable to
explore dose-dependent medication effects. Psychotropic
medications, however, have mainly been shown to increase
prefrontal and subcortical volumes which relate less directly
to the findings of our study [Dusi et al., 2015]. Additionally,
our cohort had significant comorbid psychiatric conditions,
which is common in FND and adds to the external validity
of our patient sample. Considering the comorbidities pre-
sent, a strength of this study is the ability to control for
mood/anxiety and comorbid psychiatric conditions with
prominent dissociative symptoms in post-hoc analyses.
Given the cross-sectional design of our study, we are unable
to draw conclusions about the causal relationships between
the neuropsychiatric phenomena and associated brain
regions. In addition, the FND cohort included patients
across the spectrum of motor functional neurological symp-
toms. While the clinical and neurobiological overlap
between motor FND subtypes remains debated [Kanaan
et al., 2017], it is increasingly recognized that FND subpopu-
lations share many commonalities and well as some more
potentially subtle distinctions [Driver-Dunckley et al., 2011;
Ekanayake et al., 2017; Hopp et al., 2012; Stone et al., 2004].
We have previously demonstrated the utility and feasibility
of using a trans-diagnostic approach to investigate the full
spectrum of motor functional neurological symptoms
r
 r Cortical Thickness Alterations
[Matin et al., 2017; Perez et al., 2015, 2016, 2017a]. In 100 con-
secutive patients with FND evaluated in our clinic, 1 in 4
demonstrated mixed functional motor symptoms, sugges-
ting an inherent clinical phenotypic overlap [Matin et al.,
2017]. Future studies should compare FND to trauma con-
trols and other psychiatric populations with prominent dis-
sociative symptoms to investigate the specificity of our
reported brain-dissociation relationships. While this study
primarily aimed to investigate FND patients with high rates
of dissociative symptoms in comparison to healthy subjects,
additional research with increased sample size is needed to
contextualize and clarify cortical and subcortical structural
profiles across FND populations [Aybek et al., 2014; Labate
et al., 2012; Nicholson et al., 2014].
In conclusion, this is the first MRI study to our knowl-
edge investigating the structural correlates of somatoform
and psychological dissociation across the spectrum of
motor FND. Using complementary between-group and
within-group analyses, we observed an inverse association
between somatoform dissociation severity and left caudal
ACC cortical thickness in patients with FND. We also
identified a positive relationship between depersonaliza-
tion/derealization severity and right lateral occipital
cortical thickness. These findings advance our neuropatho-
biological understanding of dissociation in FND.
DECLARATION OF INTERESTS
BCD, consultant at Merck, Med Learning Group and
Haymarket; royalties from Oxford University Press and
Cambridge University Press; on the editorial board of Neu-
roimage: Clinical, Cortex, Hippocampus, Neurodegenerative
Disease Management. WCL has served on the editorial
boards of Epilepsia, Epilepsy & Behavior and Journal of Neu-
ropsychiatry and Clinical Neurosciences; receives editor’s roy-
alties from the publication of Gates and Rowan’s
Nonepileptic Seizures, 3rd ed. (Cambridge University
Press, 2010) and 4th ed. (2017); author’s royalties for Tak-
ing 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 Soci-
ety (AES), the Epilepsy Foundation (EF), Brown University
and the Siravo Foundation; serves on the Epilepsy Foun-
dation Professional Advisory Board; has received hono-
raria for the American Academy of Neurology Annual
Meeting Annual Course; has served as a clinic develop-
ment consultant at University of Colorado Denver, Cleve-
land Clinic, Spectrum Health and Emory University; and
has provided medico legal expert testimony.
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