Epilepsy & Behavior 131 (2022) 108712

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Epilepsy & Behavior

journal homepage: www.elsevier.com/locate/yebeh

Diagnostic delay in functional seizures is associated with abnormal

processing of facial emotions
Jerzy P. Szaflarski a,⇑,1,2, Jane B. Allendorfer a,1, Adam M. Goodman a, Caroline G. Byington a, Noah S. Philip b,c,
Stephen Correia b, W. Curt LaFrance Jr. b,c
a
Department of Neurology, University of Alabama at Birmingham (UAB), UAB Epilepsy Center, Birmingham, AL, USA
b
VA RR&D Center for Neurorestoration & Neurotechnology, VA Providence Healthcare System, Providence, RI, USA
c
Dept of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Providence, RI, USA

a r t i c l e i n f o a b s t r a c t

Article history: Purpose: In patients with functional seizures (FS), delay in diagnosis (DD) may negatively affect out-
Received 8 February 2022 comes. Altered brain responses to emotional stimuli have been shown in adults with FS. We hypothesized
Revised 10 April 2022 that DD would be associated with differential fMRI activation in emotion processing circuits.
Accepted 16 April 2022
Methods: Fifty-two adults (38 females) with video-EEG confirmed FS prospectively completed assess-
ments related to symptoms of depression (BDI-II), anxiety (BAI), post-traumatic stress disorder (PCL-S),
a measure of how their symptoms affect day-to-day life (GAF), and fMRI at 3T with emotional faces task
Keywords:
(EFT). During fMRI, subjects indicated ‘‘male” or ‘‘female” via button press while implicitly processing
Functional seizures (FS)
Psychogenic nonepileptic seizures (PNES)
happy, sad, fearful, and neutral faces. Functional magnetic resonance imaging (FMRI) response to each
fMRI emotion was modeled and group analyses were performed in AFNI within pre-specified regions-of-
Emotion processing interest involved in emotion processing. A median split (507 days) defined short- (s-DD) and long-
Insula delay diagnosis (l-DD) groups. Voxelwise regression analyses were also performed to examine linear rela-
Posterior cingulate tionship between DD and emotion processing. FMRI signal was extracted from clusters showing group
Depression differences and Spearman’s correlations assessed relationships with symptom scores.
Results: Groups did not differ in FS age of onset, sex distribution, years of education, TBI characteristics,
EFT in-scanner or post-test performance, or scores on the GAF, BDI-II, BAI, and PCL-S measures. The s-DD
group was younger than l-DD (mean age 32.6 vs. 40.1; p = 0.022) at the time of study participation. After
correcting for age, compared to s-DD, the l-DD group showed greater fMRI activation to sad faces in the
bilateral posterior cingulate cortex (PCC) and to neutral faces in the right anterior insula. Within-group
linear regression revealed that with increasing DD, there was increased fMRI activation to sad faces in
the PCC and to happy faces in the right anterior insula/inferior frontal gyrus (AI/IFG). There were positive
correlations between PCC response to sad faces and BDI-II scores in the l-DD group (rho = 0.48, p = 0.012)
and the combined sample (rho = 0.30, p = 0.029). Increased PCC activation to sad faces in those in the l-DD
group was associated with worse symptoms of depression (i.e. higher BDI-II score).
Conclusions: Delay in FS diagnosis is associated with fMRI changes in PCC and AI/IFG. As part of the
default mode network, PCC is implicated in mood control, self-referencing, and other emotion-relevant
processes. In our study, PCC changes are linked to depression. Future studies should assess the effects
of interventions on these abnormalities.
Ó 2022 Elsevier Inc. All rights reserved.

1. Introduction

General neurologists and epilepsy specialists frequently

encounter patients with functional seizures (FS; also called psy-
⇑ Corresponding author at: Department of Neurology, University of Alabama at chogenic nonepileptic seizures (PNES)) in their out- and in-
Birmingham (UAB) Epilepsy Center, 312 Civitan International Research Center, patient practices. Despite the increasing awareness of FS and many
Birmingham, AL 35294, USA.
studies documenting their high incidence and prevalence, FS con-
E-mail address: jszaflarski@uabmc.edu (J.P. Szaflarski).
1 tinue to be under-recognized and under-treated. This results in fre-
Equal contributions.
2
ORCID: 0000-0002-5936-6627. quent delays between initial presentation and making the correct

https://doi.org/10.1016/j.yebeh.2022.108712
1525-5050/Ó 2022 Elsevier Inc. All rights reserved.
J.P. Szaflarski, J.B. Allendorfer, A.M. Goodman et al.
diagnosis [1–3]. This delay is frequently related to low suspicion
for, low awareness of, and substantial overlap in the clinical pre-
sentation between FS and epilepsy. However, epilepsy specialists
in contrast to other neurologists have a specific tool – video/EEG
monitoring – that can provide an accurate diagnosis when habitual
spells are captured during the evaluation [4]. The availability of
video/EEG monitoring is a major advantage in the clinical approach
to patients with seizures/spells compared to patients with other
functional neurological disorders (FNDs; e.g., functional movement
disorders (FMDs)). There is growing evidence of a significant over-
lap between all FNDs including FS in their epidemiology, demo-
graphics, aspects of clinical presentation, social and educational
status, risk factors, psychiatric comorbidities and co-occurrence
of somatoform disorders [5,6]. This evidence supports common
and unifying pathophysiology of all FNDs with clinical manifesta-
tions depending on which brain structures or network connections
are affected by the disorder [5,7]. Thus, studying FS can provide
specific insights into not only the pathophysiology of this entity
but also into other FNDs.
The delay in diagnosis (DD) of FS may be substantial and reach
years or, in some patients, even decades [1,2]. These delays may
have specific long-term consequences including effects on FS con-
trol and may have detrimental effects on many specific patient-
and society-dependent factors [1,8]. In turn, the persistence and
possible worsening of psychiatric comorbidities associated with
the delays in establishing the correct diagnosis may have negative
effects on psychosocial, physical, and emotional well-being of
patients and their caregivers [8,9]. Family involvement and educa-
tional status are also important predictors of seizure-free outcome
after diagnosis of FS [8]. Further, age at onset, disease duration, and
FS frequency may predict long-term functional outcomes [10].
Despite that, we were only able to identify few works specifically
focusing on the issue of DD in patients with FS. In one of the earlier
studies, longer duration of the disease and the presence of psychi-
atric comorbidities were associated with poor long-term outcomes
(i.e., not seizure-free status) [11]. In another study, younger age at
diagnosis was an important factor in achieving good outcome
while the diagnostic latency trended in the correct direction, but
was not significant [12]. In an fMRI study, we have recently shown
that in patients with FS processing of stressful experiences exam-
ined with an acute psychosocial stress task is modulated by DD
and that it is not specifically related to psychopathology assessed
with several standardized measures of psychiatric comorbidities,
severity of disease, or cognitive functioning [13]. In pediatric FS,
similar to adults, better outcomes are also associated with lower
disease chronicity [14] and treatments focusing on targets other
than psychopathology may be more effective in controlling sei-
zures [15,16]. Additionally, in at least one study, earlier diagnosis
was associated with improved cognitive outcomes at one year
[17]. Despite the clearly articulated relationships between DD, psy-
chological and psychiatric comorbidities, and seizure freedom we
were able to identify only the previously mentioned neuroimaging
study that specifically investigated DD as a contributor to FS patho-
physiology [13]. After taking this and other evidence into account,
a recent ‘‘call to action” specifically singled out DD as one of the
important factors that needed in-depth investigation [18]. This is
because the chronicity may likely have different neuroimaging cor-
relates including possibly compensatory neuroplasticity related to
specific function use or disuse and changes in brain connectivity
that may be reversible with function improvement or normaliza-
tion [18,19] – however, to date only the above introduced neu-
roimaging study has investigated this issue in FS or FNDs [13].
Recent neuroimaging studies have contributed to our under-
standing of the neurobiology of FS [7,18]. Some authors suggested
that abnormalities in emotion processing, including emotional
dysregulation reported frequently by patients, may be one of the
2
Epilepsy & Behavior 131 (2022) 108712
pathophysiologic mechanisms that underlie initiation and mainte-
nance of FS [20–22] and that such alterations may be the key link
between psychological risk factors and core features of FS and
other FNDs [23]. Attention to and concurrent processing of facial
expressions has been reported to disrupt cognitive processing in
FS [24]. A recent review of FNDs proposed a specific role for emo-
tion processing in generation and maintenance of various presen-
tations of FNDs including FS [23]. It also identified a range of
vulnerabilities that might predispose toward abnormal emotion
processing in FS – abnormal amygdala responses and limbic sys-
tem hyperactivation, impaired interoception, suboptimal emotion
regulation, and problems with interpretation of affective stimuli
(e.g., facial expressions) [23]. Thus, better grasp of the abnormali-
ties in the neural networks and signals involved in emotion pro-
cessing in FS may be an essential step toward improved
understanding of the neuropathophysiology of the disorder, for
developing other methods for differential diagnosis beyond the
gold standard of video/EEG monitoring, and for developing more
efficacious interventions [21,25–27].
The neuroimaging literature that investigates emotion process-
ing in FS and FNDs is relatively limited [18]. Of the existing studies,
some have utilized a variation of fMRI emotion recognition task
(EFT) that investigates emotion recognition [28,29]. The purpose
of this fMRI task is to evaluate the emotion processing circuits in
various populations. Typical areas visualized with this task are
regions involved in emotion control including medial temporal
and medial orbitofrontal regions, and areas involved in conscious
representation of emotional facial expressions such as anterior cin-
gulate, prefrontal, and somatosensory cortices; stimuli presented
with this task may also activate other nodes in the emotion pro-
cessing circuits such as medial and lateral frontal lobes [30–33].
Thus, in the present study, we sought to identify differences in
neuropathophysiology of facial emotion processing between
patients with short- (s-DD) and long-DD (l-DD). We also wanted
to determine whether the observed group differences in response
to fMRI EFT are associated with altered mood and disease severity
measure. Our hypothesis was that DD would be associated with
differential fMRI activation in emotion processing circuits
(e.g., insula or cingulate cortex) in response to emotional stimuli
and that these differences would be associated with mood
measures.
2. Methods
2.1. Participants
We prospectively recruited 52 adults  18 years of age from
the University of Alabama at Birmingham (UAB), Rhode Island
Hospital (RIH) and Providence Veterans Affairs Medical Center
(PVAMC). History of traumatic brain injury (TBI) prior to FS
diagnosis was necessary for study inclusion and was established
by extensive history, review of medical records including source
documents, and a TBI screening questionnaire. Limiting enroll-
ment to participants with preexisting TBI was motivated by
the fact that 50% and, in some studies, up to 83% of patients
with FS report TBI preceding the onset of their seizures [34]
and for uniformity of the studied cohort. A diagnosis of sole FS
was established via video-EEG monitoring using criteria recom-
mended by the International League Against Epilepsy including
capturing all types of events the patient was reporting and con-
firming all were FS [4]. In order to be admitted to the study, par-
ticipants had to be able and willing to undergo MRI at 3T. All
participants provided written informed consent prior to study
participation, and all study procedures were approved by the
Institutional Review Boards of RIH, PVAMC, and UAB.
J.P. Szaflarski, J.B. Allendorfer, A.M. Goodman et al.
2.2. Demographic and clinical variables and assessments
Demographic (sex, age, years of education) and clinical (age of FS
onset, number of seizures in the past month, time lag to FS diagno-
sis, age at first TBI, years since first TBI, number of TBIs, TBI severity,
known abnormal anatomical MRIs, number of anti-seizure medica-
tions and the overall number of medications) variables were col-
lected for each participant. The date of reported onset for FS
symptoms was subtracted from the date of reported FS diagnosis
(in days) to assess individual variation in the factor of time lag to
diagnosis (i.e., DD). A median split to time lag to FS diagnosis was
determined to be 507 days (approximately 17 months) and it was
used to define s-DD and l-DD groups. Given a positive skew in the
distribution of time lag to FS diagnosis, we used a square root trans-
form to normalize this variable for subsequent group level analyses
that assumed a normal distribution. Participants completed the
Structured Clinical Interview for Diagnostic and Statistical Manual
of Mental disorders, 5th edition (SCID) and assessments relating to
global functioning, psychiatric comorbidities of depression and anx-
iety, post-traumatic stress disorder (PTSD), and duration between
onset of symptoms and FS diagnosis. Global Assessment of Function-
ing (GAF) was used to index individual differences in disease sever-
ity. The Beck Depression Inventory (BDI-II) assessed symptoms of
depression [35], the Beck Anxiety Inventory (BAI) assessed symp-
toms of anxiety [36], the PTSD checklist – stressor specific version
(PCL-S) assessed PTSD symptoms [37]. Independent-samples
t-tests or chi-squared tests, when appropriate, were used to exam-
ine differences between s-DD and l-DD groups.
2.3. Magnetic resonance imaging (MRI) scan procedures
Participants underwent MRI scan on a 3T Siemens Prisma scan-
ner (Siemens Healthcare, Erlangen, Germany) using a 64-channel
head coil at either UAB or RIH using identical scanning protocols,
with all scanner firmware and software synchronized across sites
prior to start of data collection for the study [38]. Quality assurance
(QA) tests were also performed weekly at each site throughout the
study using the FIRST-BIRN QA protocol to confirm that stability
of signal-to-fluctuation-noise ratio, signal fluctuations, signal-to-
noise ratio, and signal drift were not significantly different between
sites [38]. Participants were placed head-first in the supine position
on the scanner table, fitted with an MR compatible headset for audi-
tory presentations, and given a button box placed in the right hand
for task responses, as well as an emergency bulb in the other hand in
case of distress or emergency during the task. A mirror affixed to the
head coil allowed the participant to visualize the task stimuli on a
video monitor placed behind the scanner bore (BOLDscreen, Cam-
bridge Research Systems). A high-resolution 3-dimensional T1-
weighted anatomical scan using a magnetization prepared rapid
acquisition with gradient echo (MPRAGE) sequence was acquired
in the sagittal plane with the following parameters: repetition
time/echo time (TR/TE) = 2400/2.22 ms, inversion time = 1000 ms,
flip angle = 8°, field of view [39] = 24.0  25.6  16.7 cm,
matrix = 256  256, 0.8 mm isotropic slices). A T2*-weighted
gradient-echo echoplanar imaging (EPI) sequence was used to
acquire blood oxygenation-level dependent (BOLD) fMRI responses
to the experimental task with the following parameters: TR/
TE = 1000/35.8 ms, flip angle = 60°, FOV = 26.0  26.0  15.0 cm,
matrix = 260  260, 2.5 mm isotropic voxels, multiband accelera-
tion factor = 6). The MRI scan lasted approximately 1 h with partic-
ipants visually monitored throughout the scan by study personnel.
2.4. Emotional faces task (EFT)
The event-related EFT was designed to assess response to basic
emotional stimuli, programmed using E-Prime (V.2.0, Psychology
3
Epilepsy & Behavior 131 (2022) 108712
Software Tools, Inc.), and presented during fMRI. The participants
were presented with a series of faces with happy, fearful, sad, or
neutral expressions in a pseudo-randomized order [32,40] and
asked to identify the face as male or female by pressing the left
or right button with their pointer finger or middle finger, respec-
tively, using the button box held in their right hand. The processing
of emotional expressions is subliminal and automatic however, it
requires attention to the task [41]. One hundred and twenty
unique images consisting of 60 female faces and 60 male faces
were presented with 30 images per expression equally divided
between male and female faces. Each face was presented for 2 s,
followed by a screen with a fixation ‘‘+” in the center during a vari-
able inter-stimulus interval of 1–6 s to allow for event-related
modeling of each event type (happy, fearful, sad, neutral)
[28,32,42,43]. After completing the MRI scan, participants identi-
fied the emotional expression on each of the previously presented
faces as happy, fearful, sad, neutral, or unknown. Intra- and extra-
scanner performanceswere recorded. Independent-samples t-tests
were used to examine differences between s-DD and l-DD groups
for EFT in-scanner and post-scan performance.
2.5. Magnetic resonance imaging data preprocessing and analysis
FMRI data for the EFT were analyzed and visualized using Anal-
ysis of Functional NeuroImages (AFNI) software [44]. Standard pre-
processing algorithms were performed for each participant data-
set. Briefly, this included slice-timing correction, correction for
head motion (including exclusion of TRs with simultaneous head
movement that surpassed 3% of the total number of voxels), struc-
tural and fMRI scan co-registration, spatial smoothing using a 4-
mm full-width at half-maximum (FWHM) Gaussian filter, normal-
ization of anatomical scan into Montreal Neurologic Institute
(MNI) coordinate space and applying the same transformation
matrix to normalize the fMRI scans into MNI space, resampling
of functional images to a 1  1  1 mm3 voxel resolution, and cal-
culation of percent signal change.
Single-participant statistical modeling of the BOLD response to
each event type of happy, fearful, sad, and neutral was performed
using the 3ddeconvolve program in AFNI. For each participant, the
event times were extracted from the behavioral data files recorded
in E-prime, and each event type was convolved with a gamma vari-
ate hemodynamic response function in AFNI while also accounting
for low frequency signal drift using the EPI signal mean and linear,
quadratic and cubic polynomial functions as covariates, as well as
accounting for head motion using motion-correction parameters as
covariates. The 3dttest++ program in AFNI was used to perform
regression analyses to determine the differences between s-DD
and l-DD groups in processing each type of facial emotion while
covarying for scanner location. Due to group differences in age,
we also included age as a covariate in the regression model. To
reduce the likelihood of false positives, group analysis was
restricted to a gray matter mask consisting of regions involved in
emotion processing including the bilateral prefrontal cortex, cingu-
late gyrus, insula, amygdala, hippocampus and parahippocampal
gyrus which were defined using the Harvard-Oxford Montreal
Neurological Institute atlas. These regions of interest are based
on prior fMRI literature showing differences in stress and emotion
processing between patients with FS compared to controls [28,45].
Finally, we performed voxelwise regression analyses within the
same gray matter mask of the emotion network brain regions using
the square root transform as a regressor of interest to examine lin-
ear relationship between DD and processing each type of facial
emotion.
The spatial autocorrelation function (ACF) in the 3dFWHx pro-
gram was used to estimate values for the smoothness of noise,
which were then fit to a mixed model that combines the
J.P. Szaflarski, J.B. Allendorfer, A.M. Goodman et al.
Gaussian-shaped ACF with a mono-exponential function. The
mixed model was used in the 3dClustSim program to generate
noise random fields, estimate the probability of false-positive clus-
ters and determine the threshold for the number of voxels in a
cluster using Monte Carlo simulations (n = 10,000) to achieve a cor-
rected p-value < 0.05 using a voxelwise threshold of p = 0.005 [46].
FMRI signal was extracted from clusters in brain regions showing
significant group differences. For all clusters showing significant
between-group differences, within-group posthoc Spearman’s cor-
relations were performed to assess the relationships between the
magnitude of the fMRI response in each cluster and the scores on
the BDI-II, BAI and PCL-S. We report correlations greater than |
0.30| of at least medium effect sizes. Results of correlations were
considered significant at p < 0.05, and at p < 0.0167 after Bonfer-
roni correction for multiple comparisons.
3. Results
Table 1 summarizes the results of statistical comparisons
between s-DD and l-DD groups. Groups did not differ in onset
age of PNES, number of seizures in the past month, age at first
TBI, number of TBIs, distribution of TBI severity, sex distribution,
or years of education. The s-DD group was younger than l-DD
(mean age 32.6 vs. 40.1; p = 0.022). Groups did not differ on scores
on the GAF, BDI-II, BAI and PCL-S, or for EFT in-scanner and post-
scan performance.
The l-DD group showed significantly greater fMRI activation
than s-DD to sad faces in the bilateral posterior cingulate cortex
(PCC; 403 mm3; t = 4.66; peak MNI coordinates at x = 2,
y = 43, z = 18; Fig. 1A) and to neutral faces in the right anterior
insula (AI; 384 mm3; t = 5.04; peak MNI coordinates at x = 32,
y = 20, z = 12; Fig. 1B). By extracting the average signal from these
regions showing significant group differences it becomes apparent
that the increased activation in l-DD relative to s-DD is not only
due to greater fMRI reactivity of l-DD to the sad and neutral faces
compared to baseline, but also because s-DD exhibit an opposite
response of decreased activation to these faces compared to base-
line. Voxelwise regression analyses within the emotion network
brain regions revealed significant linear relationship between DD
and facial emotion processing. With increasing DD, there was
increased fMRI activation to sad faces in the bilateral posterior cin-
gulate cortex (PCC; 520 mm3; t = 4.97; peak MNI coordinates at
x = 4, y = 43, z = 18; Fig. 2A) and to happy faces in the right ante-
rior insula/inferior frontal gyrus (AI/IFG; 361 mm3; t = 4.89; peak
MNI coordinates at x = 44, y = 27, z = 2; Fig. 2B). Between-group
activation differences and within-group linear regressions with
DD were corrected at p < 0.05 (voxelwise p = 0.005, clus-
ter > 306 mm3 for neutral faces, cluster > 292 mm3 for sad faces,
cluster > 301 mm3 for happy faces) as determined by Monte Carlo
simulations.
As hypothesized, there were positive correlations between PCC
response to sad faces and BDI-II scores in the l-DD group
(rho = 0.48, p = 0.012; Fig. 3A) and the combined sample
(rho = 0.30, p = 0.029; Fig. 3B). The s-DD group showed a non-
significant trend for a negative correlation between PCC response
to sad faces and PCL-S scores (rho = 0.29, p = 0.15; Fig. 3C). Corre-
lation in the l-DD group between PCC fMRI response to sad faces
and BDI-II scores remained significant at p < 0.0167 after Bonfer-
roni correction for multiple comparisons. There were no significant
correlations between PCC response to sad faces and BAI or PCL-S
scores in the combined sample, or the s-DD or l-DD groups. There
were also no significant correlations between right AI response to
neutral faces and BDI-II, BAI or PCL-S scores in any of the groups.
4
Epilepsy & Behavior 131 (2022) 108712
4. Discussion
The focus of this neuroimaging study is on investigating the
effect of time lag to diagnosis (i.e., DD) on processing of facial emo-
tions and on the relationship between these findings and the mea-
sures of mood states – anxiety, depression, and PTSD
symptomatology. Our findings are that compared to s-DD, the
delayed diagnostic group (l-DD) showed greater fMRI activation
to sad faces in the bilateral PCC and to neutral faces in the right
AI. PCC findings from the between-group analysis positively corre-
lated with BDI-II scores (PCC response to sad faces) and increased
PCC activation to sad faces in those in the l-DD group was associ-
ated with worse symptoms of depression (i.e. higher BDI-II score).
Finally, voxelwise regression analyses identified significant rela-
tionships between DD and facial emotion processing in the bilat-
eral posterior cingulate (sad faces) and right AI/IFG (happy faces).
We discuss these findings and their implications below.
In general, emotion processing in FNDs has been studied with
two types of neuroimaging tasks – facial emotion (valence) recog-
nition and response to aversive/unpleasant stimuli. Investigations
with diverse versions of the EFT fMRI task have demonstrated dif-
ferences in activation and/or connectivity patterns between
patients with functional movement disorders (FMDs) and HCs
[29,47] or between patients with FNDs and a corresponding neuro-
logical condition e.g., essential tremor or epilepsy [28,43]. Several
emotion processing studies utilizing aversive stimuli previously
implicated PCC as a node important for this process in FNDs
[42,48,49]. The PCC connects structurally and functionally to other
brain regions [50] including the generators of EEG alpha rhythm
(hence contribution to alertness/wakefulness) and networks
responsible for the internal adaptive processes of retrieval, repre-
sentation, and manipulation of working memory [51,52]. PCC is
also responsible for ‘‘mind-wandering” with activity in this net-
work correlating well with this ability [53]. All these processes
tend to be negatively affected by the presence of FS (or other FNDs)
and, as shown here, their duration. This has clear implications for
the management as earlier interventions may help to alleviate
the progression of these symptoms and their negative effects on
psychosocial outcomes e.g., mood or quality of life [3,54,55]. How-
ever, the directionality of the changes has not been fully deter-
mined to date and it remains to be ascertained whether they
precede the onset of FS or are their result [6]. Failure of PCC deac-
tivation has been linked to poor cognitive functioning indicating
that PCC also takes part in processes of attention and general cog-
nitive processes [51,56]. This is of importance as patients with FS
frequently report cognitive difficulties/deficits that are comparable
to those present in patients with epilepsy [57–59]. More recently,
PCC has been implicated in depression; baseline activation within
PCC has been shown to positively correlate with dynamic changes
in depressive symptoms over time indicating that the midline acti-
vations may be a predictor of long-term depressive symptomatol-
ogy [60]. In another study, increase in PCC connectivity was
associated with increasing symptoms of depression while treat-
ment with antidepressant medications tended to normalize this
connectivity [61]. The results of our study speak directly to the
results of previous research – baseline PCC activation in response
to sad faces was associated with worse depressive symptoms as
measured by BDI-II. Our findings are also in direct agreement with
the concept of impaired emotion regulation, cognitive control, and
interoception being part of the circuit responsible for overall
abnormal emotion processing that is present in FNDs including
FS [7,23]. Thus, our findings speak to the involvement of PCC in
the neuropsychopathology of FS and indicate that the duration of
illness is associated with PCC dysfunction that drives or is associ-
ated with the presence of these symptoms. Based on the results
J.P. Szaflarski, J.B. Allendorfer, A.M. Goodman et al. Epilepsy & Behavior 131 (2022) 108712

Table 1
Demographic and clinical variables and assessment scores for patients with functional seizures (FS).

Overall N=52 Short delay N=26 Long delay N=26 Test statistic p-value
Age, years 36.3 (11.9) 32.6 (10.8) 40.1 (12.0) t = 2.36 0.022*
Sex, female 38 (73.1) 18 (69.2) 20 (76.9) X2 = 0.39 0.53
Education, years 13.1 (4.3) 13.5 (4.8) 12.7 (3.8) t = 0.60 0.55
Age of FS onset 31.2 (12.6) 30.6 (11.3) 31.8 (14.1) t = 0.33 0.75
#
# of seizures in past month 30.1 (58.7) 29.4 (64.0) 30.8 (54.2) # t = 0.08 0.94
Time lag to FS diagnosis, days 1539 (2805) 215 (166) 2863 (3519) t = 3.83 0.000**
Square root of Time lag to FS diagnosis 30.2 (25.3) 13.1 (6.6) 47.3 (25.6) t = 6.59 0.000**
Age at first TBI, years 14.9 (12.1) 15.5 (11.5) 14.4 (12.9) t = 0.32 0.74
Years since first TBI 21.4 (13.3) 17.2 (12.6) 25.7 (12.7) t = 2.43 0.019*
Number of TBIs 4.3 (6.9) 4.2 (4.7) 4.5 (8.6) t = 0.18 0.86
TBI severity, n (%) X2 = 4.97 0.17
mild 39 (84.62) 22 (84.62) 17 (65.38)
moderate 8 (7.69) 2 (7.69) 6 (23.08)
severe 2 (3.85) 0 (0) 2 (7.69)
unknown 3 (5.77) 2 (7.69) 1 (3.85)
Abnormal MRI, n (%) 8 (15.38) 5 (19.23)$ 3 (11.54)& X2 = 0.60 0.74
SCID
2
ADHD 10 (19.2) 4 (15.4) 6 (23.1) X = 0.50 0.48
Alcohol abuse 14 (26.9) 6 (23.1) 8 (30.8) X2 = 0.39 0.53
Dysthymia 8 (15.4) 3 (11.5) 5 (19.2) X2 = 0.59 0.44
GAD 24 (46.2) 10 (38.5) 14 (53.9) X2 = 1.24 0.27
MDD 34 (65.4) 18 (69.2) 16 (61.5) X2 = 0.34 0.56
Panic disorder 10 (19.2) 5 (19.2) 5 (19.2) X2 = 0.0 1
PTSD 16 (30.8) 9 (34.6) 7 (26.9) X2 = 0.36 0.55
Other somatoform 1 (2.0) 0 (0) 1 (3.9) X2 = 1.02 0.31
Number of current ASDs 0.7 (1.1) 0.5 (0.5) 0.6 (0.5) t = 0.55 0.58
Number of current medications 6.2 (6.7) 5.7 (6.0) 6.7 (7.4) t = 0.56 0.58
GAF 55.5 (7.4) 55.1 (7.7) 56.0 (7.2) t = 0.41 0.68
BDI-II score 22.9 (12.9) 21.7 (13.2) 24.1 (12.7) t = 0.66 0.51
BAI score 24.8 (11.7) 23.9 (10.9) 25.8 (12.6) t = 0.58 0.57
PCL-S score 44.1 (17.2) 43.4 (14.3) 44.8 (19.9) t = 0.30 0.77
EFT accuracy, %/response time, ms 88.5 (24.0)/762 (195) 87.0 (26.1)/752 (210) 90.1 (22.2)/773 (182) t = 0.46/t = 0.39 0.65/0.70
Post-scan faces rating accuracy, %/response time, ms
Fearful 83.1 (16.6)/2392 (752) 86.8 (7.1)/2301 (671) ^ 80.0 (21.8)/2480 (827) # t = 1.58/t = 0.83 0.12/0.41
Happy 97.2 (4.8)/1708 (755) 97.5 (4.7)/1767 (969) ^ 97.0 (5.0)/1651 (485) # t = 0.30/t = 0.53 0.76/0.60
Neutral 85.7 (15.4)/2384 (624) 87.5 (15.9)/2319 (713) ^ 83.9 (15.0)/2445 (532) # t = 0.82/t = 0.70 0.42/0.49
Sad 83.8 (7.9)/2119 (660) 83.3 (8.3)/2177 (804) ^ 84.5 (7.8)/2063 (494) # t = 0.54/t = 0.59 0.59/0.56

Note: Data are presented as mean (SD), except for sex and presentation of SCID diagnoses, which are presented as frequency (percentage). Results of test statistic for
comparing short- and long-delay in diagnosis and p-value are in adjacent columns to the right. *p < 0.05; **p < 0.001. #There was missing data for 1 participant. ^There was
missing data for 2 participants. $Missing 7 pre-enrollment MRI. &Missing 8 pre-enrollment MRI. FS = functional seizures; TBI = traumatic brain injury; SCID = Structured
Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders; ADHD = attention deficit hyperactivity disorder; GAD = generalized anxiety disorder;
MDD = major depressive disorder; PTSD = posttraumatic stress disorder; GAF = global assessment of functioning; BDI-II = Beck Depression Inventory; BAI = Beck Anxiety
Inventory; PCL-S = PTSD checklist – stressor specific version; EFT = emotional faces task; ASDs = antiseizure drugs.

of this and the other available studies we postulate that manipula-
tion of this brain region with interventions (e.g., cognitive behav-
ioral therapy [62], pharmacological agents [63], or
neurostimulation [64]) may affect the course of the disease or, at
least, the psychosocial symptoms associated with FS. However,
more important to our hypothesis for this study is that making
the diagnosis earlier in the course of FS will directly affect patients’
mood states and the brain networks supporting mood and emotion
processing and will provide an earlier window for interventions.
Insula, as part of the limbic system, has been implicated in emo-
tion processing [13,45,65]. Similar to our study, insular abnormal-
ities have been identified in other functional and structural studies
of FS [18,27,66–69]. Interestingly, the increased right AI activation
in l-DD is consistent with findings of limbic system hyperactiva-
tion in emotion processing in FNDs [23], in contrast to the
decreased activation in s-DD, suggesting that insula hyperactiva-
tion may be modulated by the duration of the disorder. Further,
in one FND study, structural insular findings (increased insular cor-
tex thickness) were associated with severe health impairments
[70]. In a structural MRI study, changes to the insular sulcal depth
were associated with GAF, BAI, and Symptom Checklist 90 Revised
(SCL-90-R) Somatization subscale scores [68]. Directly to these
points, recent meta-analysis of neuroimaging studies in FS specif-
ically implicated insula as the only brain region consistently
observed in neuroimaging studies as directly or indirectly impli-
5
cated in FNDs [66]. These findings were interpreted as evidence
for the presence of structural/functional abnormalities in func-
tional neurological processes that are typically interpreted as
purely psychological or psychogenic. Later studies not included
in the meta-analysis also showed differences in insular involve-
ment in response to aversive stimuli (CPT-END task) [42]. In a dif-
ferent participant population, we described altered involvement of
insula in implicit facial emotion processing in FS compared to
healthy controls for neutral faces [28]. Thus, the findings of the
present study are in line with other studies where insula took a
center stage in explaining the findings associated with FS/FNDs.
Our findings add to a substantial body of literature in support of
the involvement of insula in the generation and maintenance of
FNDs in populations with or without psychopathology and further
support the organic nature of the process (i.e., our findings further
challenge the mind–body dualism) [71,72]. An additional finding
from FND neuroimaging studies is that the abnormalities, whether
structural or functional, are observed in the left or right insula
[13,72]. Further, different parts of insula may be differently associ-
ated with FS [72]. One study specifically investigated the resting-
state connectivity of the left and right insulae in patients with FS
to find differential connectivity patterns [72] of insular subregions
and left/right insular subfields to the sensorimotor cortices, pari-
etal cortex, and putamen, which they felt were explained by differ-
ent and complex mechanisms that precipitate FS. Finally, resting-
J.P. Szaflarski, J.B. Allendorfer, A.M. Goodman et al. Epilepsy & Behavior 131 (2022) 108712

Fig. 1. Statistical maps illustrating group differences in fMRI activation during the emotion faces task between those with a long (l-DD) vs. short (s-DD) delay in diagnosis of
functional seizures. The l-DD group exhibited greater activation than the s-DD group in processing (A) sad faces in the posterior cingulate cortex (PCC; Mean ± SEM for s-
DD = 0.32 ± 0.066 and for l-DD = 0.20 ± 0.073) and (B) neutral faces in the right anterior insula (AI; Mean ± SEM for s-DD = 0.030 ± 0.030 and for l-DD = 0.19 ± 0.030).
Activation clusters are significant at corrected p < 0.05, and peak MNI coordinates (x, y, z) are indicated. Mean ± SEM are indicated on the graphs to the right.

Fig. 2. Statistical maps illustrating results of voxelwise linear regression analyses examining associations between delay in diagnosis (DD) of functional seizures and fMRI
activation during the emotion faces task. With increasing DD, there is increasing activation in processing (A) sad faces in the posterior cingulate cortex (PCC) and (B) happy
faces in the right anterior insula/inferior frontal gyrus (AI/IFG). Activation clusters are significant at corrected p < 0.05, and peak MNI coordinates (x, y, z) are indicated.

state functional connectivity studies have documented increases in regions in the inferior frontal and parietal cortices [73]. This speaks
connectivity between emotion processing region in insula, primary directly to the observation in one study of early treatment being
motor control cortex in precentral gyrus, and executive control associated with better cognitive outcomes [17]. Thus again, our

6
J.P. Szaflarski, J.B. Allendorfer, A.M. Goodman et al.
Fig. 3. Scatterplots showing associations between activation during the emotion faces task and symptom scores in patients with functional seizures (FS). There was a positive
correlation between posterior cingulate cortex (PCC) activation to sad faces and score on the Beck Depression Inventory-II (BDI-II) in (A) the combined sample and (B) those
with long-delay in diagnosis (l-DD) of FS. (C) There was a negative association between PCC activation to sad faces and score on the PTSD checklist – stressor specific version
(PCL-S).
findings not only support the insular involvement in the genera-
tion and maintenance of FS but also indicate that the insular
response to emotional stimuli may be different depending on the
duration of the illness.
The main limitation of our study is limiting study participation
to patients with history of TBI. While this provides for better uni-
formity of the studied population, the results may not apply to
patients with FS/FNDs who never had TBI. However, since TBI
may be an important factor preceding the development of FS in
50% and, in some studies, up to 83% of patients [34] we feel the
restriction of including only participants with history of TBI pre-
ceding the development of FS was well justified. However, future
studies should include an additional comparison group of FS with-
out history of TBI in assessing the specific impacts of diagnostic
delays in FS on emotion processing. Another potential limitation
of this study is our approach that focuses on specific and pre-
specified regions-of-interest involved in emotion processing rather
than whole-brain analyses. However, we believe this approach is
justified as it was driven by pre-specified hypotheses that are well
grounded in FND and mental health literature. Additionally, our
study specifically focused on DD. While we have controlled our
analyses for the age at diagnosis while the ages of onset were sim-
ilar between the groups (Table 1), this approach may not address
the issue of illness duration and this aspect of FS/FND care will
need to be examined in future studies. Finally, in this study, we
did not collect information on the use of psychoactive medications
(e.g., SSRIs) but rather on specific psychiatric diagnoses (SCID;
Table 1) and the use of antiseizure medications and the overall
number of medications. While none of these variables were differ-
ent between groups (Table 1), the use of psychoactive medications
should be included as a variable in future studies/analyses because
of the known effects of these medications on brain activity [74,75].
5. Conclusion
Outcomes in patients with FS are affected by many factors
including a delay in diagnosis. Neuroimaging of patients with FS
indicates alterations in various networks including networks
involved in emotion processing. Further, altered brain responses
to emotional stimuli have been shown in adults with FS. This study
investigated a hypothesis that delay to diagnosis is associated with
differential fMRI activation in emotion processing circuits. Our
results confirm that the delay is associated with fMRI changes in
insula and PCC. Both are implicated in mood control, self-
referencing, and other emotion-relevant processes. Future studies
should assess the effects of interventions on these abnormalities.
7
Epilepsy & Behavior 131 (2022) 108712
Acknowledgements
The U.S. Army Medical Research Acquisition Activity, 820 Chandler
Street, Fort Detrick MD 21702-5014 is the awarding and adminis-
tering acquisition office. This work was supported by the Office of
the Assistant Secretary of Defense for Health Affairs, through the
Epilepsy Research Program under Award No. W81XWH-17-1-
0619 to WCL and JPS. Opinions, interpretations, conclusions, and
recommendations are those of the author and are not necessarily
endorsed by the Department of Defense. This material is the result
of work supported with resources and the use of facilities at the
Providence VA Medical Center, Providence RI. The contents do
not represent the views of the U.S. Department of Veterans Affairs,
Department of Defense, or the United States Government.
Data availability
All data included in this article will be made available in FITBIR
upon completion of the project.
Disclosures
J.P. Szaflarski is funded by NIH, NSF, DoD (DoD W81XWH-17-
0169), State of Alabama, Shor Foundation for Epilepsy Research,
UCB Pharma Inc., NeuroPace Inc., Greenwich Biosciences Inc., Bio-
gen Inc., Xenon Pharmaceuticals, Serina Therapeutics Inc., and
Eisai, Inc. He serves or has served on consulting/advisory boards
for Greenwich Biosciences Inc., NeuroPace, Inc., Serina Therapeu-
tics Inc., AdCel Biopharma Inc, iFovea Inc, LivaNova Inc., UCB
Pharma Inc., SK Lifesciences Inc., and provided medico-legal ser-
vices. He serves as an editorial board member for Epilepsy &
Behavior, Journal of Epileptology (associate editor), Epilepsy &
Behavior Reports (associate editor), Journal of Medical Science, Epi-
lepsy Currents (contributing editor), and Folia Medica Copernicana.
J.B. Allendorfer receives salary support from the U.S. Depart-
ment of Defense (W81XWH-17-1-0619), as well as salary support
from state of Alabama ‘‘Carly’s Law”, research support from the
Evelyn F. McKnight Brain Institute, funding from NIH
(R01HD102723 (PI)), and consultantship for LivaNova Inc, all unre-
lated to the current study.
A.M. Goodman is funded by US Department of Defense grant
W81XWH-17-1-0619.
C. Byington reports no conflicts of interest.
N.S. Philip reports no conflicts of interest.
S. Correia reports no conflicts of interest.
J.P. Szaflarski, J.B. Allendorfer, A.M. Goodman et al.
W.C. Lafrance Jr. Dr. LaFrance has served on the editorial boards
of Epilepsia, Epilepsy & Behavior; Journal of Neurology, Neuro-
surgery and Psychiatry, and Journal of Neuropsychiatry and Clini-
cal Neurosciences; 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 Department of Defense (DoD W81XWH-17-0169), NIH
(NINDS 5K23NS45902 (PI)), Providence VAMC, Center for Neu-
rorestoration and Neurorehabilitation, Rhode Island Hospital, the
American Epilepsy Society (AES), the Epilepsy Foundation (EF),
Brown University and the Siravo Foundation; serves on the Epi-
lepsy Foundation New England Professional Advisory Board, the
Functional Neurological Disorder Society Board of Directors, the
American Neuropsychiatric Association Advisory Council; has
received honoraria for the AES Annual Meeting; has served as a
clinic development consultant at University of Colorado Denver,
Cleveland Clinic, Spectrum Health, Emory University, and Oregon
Health Sciences University; and has provided medico legal expert
testimony.
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