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. Author manuscript; available in PMC: 2019 Jul 1.
Published in final edited form as: J Psychiatr Res. 2018 Apr 6;102:230–237. doi: 10.1016/j.jpsychires.2018.04.006

Individual Differences in Corticolimbic Structural Profiles Linked to Insecure Attachment and Coping Styles in Motor Functional Neurological Disorders

Benjamin Williams 1, Rozita Jalilianhasanpour 1, Nassim Matin 1, Gregory L Fricchione 2, Jorge Sepulcre 3, Matcheri S Keshavan 4, W Curt LaFrance Jr 5, Bradford C Dickerson 6,*, David L Perez 1,3,7,*
PMCID: PMC6005758  NIHMSID: NIHMS963517  PMID: 29702433

Abstract

Background

Insecure attachment and maladaptive coping are important predisposing vulnerabilities for Functional Neurological Disorders (FND)/Conversion Disorder, yet no prior structural neuroimaging studies have investigated biomarkers associated with these risk factors in FND populations. This magnetic resonance imaging study examined cortical thickness and subcortical volumes associated with self-reported attachment and coping styles in patients with FND. We hypothesized that insecure attachment and maladaptive coping would relate to limbic-paralimbic structural alterations.

Methods

FreeSurfer cortical thickness and subcortical volumetric analyses were performed in 26 patients with motor FND (21 women; 5 men) and 27 healthy controls (22 women; 5 men). For between-group comparisons, patients with FND were stratified by Relationship Scales Questionnaire, Ways of Coping Scale-Revised, and Connor-Davidson Resilience Scale scores. Within-group analyses were also performed in patients with FND. All analyses were performed in the complete cohort and separately in women only to evaluate for gender-specific effects. Cortical thickness analyses were whole-brain corrected at the cluster-wise level; subcortical analyses were Bonferroni corrected.

Results

In women with FND, dismissing attachment correlated with reduced left parahippocampal cortical thickness. Confrontive coping was associated with reduced right hippocampal volume, while accepting responsibility positively correlated with right precentral gyrus cortical thickness. These findings held adjusting for anti-depressant use. All FND-related findings were within the normal range when compared to healthy women.

Conclusion

These observations connect individual-differences in limbic-paralimbic and premotor structures to attachment and coping styles in FND. The relationship between parahippocampal thickness and dismissing attachment may indicate aberrant social-emotional and contextual appraisal in women with FND.

Keywords: conversion disorder, functional movement disorders, psychogenic non-epileptic seizures, parahippocampus, attachment

Introduction

Functional Neurological Disorder (FND)/ Conversion Disorder is a highly prevalent condition associated with significant morbidity and public health expense (Stone et al., 2009; Stone et al., 2010). Despite the frequency of FND in clinical settings, research in this population has lagged behind other neuropsychiatric disorders. The spectrum of motor functional neurologic symptoms includes functional movement disorders, psychogenic non-epileptic seizures (PNES; a.k.a. dissociative seizures), and functional limb weakness. The neurobio-psycho-social approach to FND emphasizes predisposing vulnerabilities, acute precipitants and perpetuating factors (Reuber, 2009). Predisposing factors for the development of functional (psychogenic) symptoms, the focus of this article, include not only adverse life events, but also insecure attachment, maladaptive coping, family dysfunction, bereavement and psychiatric co-morbidities (Perez and LaFrance, 2016; Reuber et al., 2007). To date, few studies have examined the neurobiology of insecure attachment or maladaptive coping in clinical populations (Vrtička and Vuilleumier, 2012), and no prior structural neuroimaging studies have investigated biomarkers of attachment and coping style in patients with FND.

According to attachment theory, innate drives for bonding and early child-caregiver relationships influence social-emotional development, which impacts the emergence of later-life psychopathology and internalized models of interpersonal relationships in adulthood (Bowlby, 1988; Fricchione, 2011). Insecure attachment is common in FND (Brown and Reuber, 2016; Holman et al., 2008; Reuber et al., 2004; Waller et al., 2004), potentially contributing to diminished quality of life and elevated depression and anxiety (Green et al., 2017). In a study of pediatric patients with FND using structured interviews, which are the gold standard for attachment assessment, distinct attachment styles were linked to specific functional neurologic symptom profiles (Kozlowska et al., 2011). Furthermore, high expressed emotion and other interpersonal difficulties, factors that may promote insecure attachment, are observed in relatives of some FND sub-populations (Stanhope et al., 2003).

The existing research on the neurobiology of human attachment implicates limbic/paralimbic neural circuits involved in social-affective and contextual appraisal, as well as fronto-temporal cognitive control/re-appraisal circuits, as core systems (Coria-Avila et al., 2014; Insel and Young, 2001; Lenzi et al., 2015; Vrtička and Vuilleumier, 2012). Functional alterations in premotor, lateral prefrontal, insular, and amygdalar regions were implicated in dismissing or insecure attachment in women responding to infant cues (Lenzi et al., 2013; Riem et al., 2012; Strathearn et al., 2009); in young adults, insecure attachment early in life predicted prefrontal activations during an emotion regulation task (Moutsiana et al., 2014). Attachment-derived negative self-representations in adolescents also correlated with altered amygdalar, parahippocampal, and temporal pole activity (Debbané et al., 2017). Though few structural neuroimaging studies have investigated brain-attachment relationships, increased amygdalar (Moutsiana et al., 2015) and decreased fronto-temporal volumes (Schneider-Hassloff et al., 2016) have been observed in healthy adults with insecure attachment. The only published study in clinical populations (borderline personality disorder) did not identify any structural brain relationships with insecure attachment, indicating the importance of further research in this field (Jin et al., 2016).

In addition to insecure attachment styles, patients with motor FND employ maladaptive stress coping strategies. For example, individuals with PNES commonly report using ineffective emotion-oriented coping approaches (i.e. escape-avoidance or solitary coping) in lieu of more action-oriented, problem-solving strategies (Frances et al., 1999; Goldstein et al., 2000; Myers et al., 2013; Plioplys et al., 2014; Testa et al., 2012). Maladaptive coping abilities have been linked to reduced health-related quality of life in patients with PNES (Cronje and Pretorius, 2013), and patients with functional movement disorders and functional paralysis have also reported using less adaptive coping strategies compared to healthy controls (van Beilen et al., 2009). In addition, individuals with FND exhibit emotion dysregulation, which overlaps with maladaptive coping (Brown et al., 2013; Uliaszek et al., 2012). Similarly, patients with other medically unexplained somatic symptoms also utilize solitary coping strategies, which are associated with increased psychiatric co-morbidities and illness duration (Elton et al., 1994).

While few studies have examined relationships between stress coping strategies and neural circuit profiles, insights into the neural mechanisms of coping can be gained from the literature on emotion regulation/reactivity, cognitive control and cognitive reappraisal in non-clinical and neuropsychiatric populations (Buhle et al., 2014; Etkin et al., 2015; Frank et al., 2014; Pico-Perez et al., 2017). The amygdala, dorsal anterior cingulate cortex, insula and periaqueductal grey are core limbic/paralimbic regions implicated in salience detection and emotion reactivity, while implicit (automatic) emotion regulation involves predominantly ventromedial prefrontal and subgenual cingulate cortices (Etkin et al., 2015). More effortful cognitive re-appraisal of negative emotion and behavioral control is facilitated by engagement of lateral prefrontal, dorsal anterior cingulate, insular, and premotor cortices (Buhle et al., 2014; Etkin et al., 2015). The hippocampus has also been implicated in contextual processing and regulation of amygdalar outflow (Bannerman et al., 2004). Notably, meta-analyses and systematic reviews show that many of these same regions are implicated in the structural and functional neurobiology of FND (Boeckle et al., 2016a; Voon et al., 2016) and other somatic symptom disorders (Boeckle et al., 2016b). Considering the emerging structural neurobiology of FND, in this present study we investigated brain-attachment and brain-coping relationships to further advance a neurobio-psycho-social perspective of FND.

This magnetic resonance imaging (MRI) study investigated cortical thickness and subcortical volumetric profiles associated with two predisposing vulnerabilities for the development of FND, insecure attachment and maladaptive stress coping, in 26 patients with motor FND and 27 healthy subjects. Patients with FND were stratified by attachment style and coping scores for between-group analyses with controls. Dimensional, within-group analyses were also performed in patients with FND. Given the importance of gender as a biological variable in the pathophysiology of FND (Asadi-Pooya, 2016), all analyses were performed in the complete cohort and in women separately. This study builds upon prior research in this cohort from our laboratory, where we have previously delineated structural profiles associated with adverse-life event burden (Perez et al., 2017a), health status and trait anxiety (Perez et al., 2017c), and dissociation severity (Perez et al., 2017b). Given that limbic/paralimbic regions have been implicated in the neurobiology of attachment, emotion processing and the pathophysiology of FND, we hypothesized that measures of insecure attachment and impaired stress coping would map onto limbic and paralimbic brain structures. We also hypothesized that FND patients with the most severe maladaptive coping and insecure attachment tendencies in stratified analyses would show group-level structural alterations in limbic/paralimbic regions compared to healthy controls.

Material and Methods

Adapted from Perez et al (2017) (Perez et al., 2017b).

Participants

26 subjects with motor FND (21 women, 5 men; mean age: 40.3±11.5 years; average illness duration: 3.6±4.3 years) were recruited from the Massachusetts General Hospital FND Clinic (Matin et al., 2017). 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, respectively), and 12 showed signs on exam consistent with functional weakness. FND diagnoses were not mutually exclusive, as 9 individuals had mixed motor symptoms. Twenty-seven healthy controls (22 women, 5 men; mean age: 40.5±10.8) were recruited through advertisements. Informed consent was obtained for all participants, and this study was approved by the Institutional Review Board of Partners Healthcare.

Exclusion criteria for the FND cohort included any major neurological disorder with MRI abnormalities, epilepsy, poorly controlled medical illnesses with central nervous system consequences, ongoing substance dependence, a history of mania or psychosis, and/or active suicidality. Additional 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. 20 patients were on psychotropic medications, with 13 subjects taking selective serotonin reuptake inhibitors (SSRIs) and/or serotonin-norepinephrine reuptake inhibitors (SNRIs). All healthy controls were without any axis I psychiatric diagnosis or BPD, and were off psychotropic medications. Detailed clinical information including psychiatric comorbidities and psychotropic medication use is reported in Supplemental Table 1.

Psychometric measures

As part of a detailed psychometric battery, patients completed the Relationship Scales Questionnaire (RSQ) (Griffin and Bartholomew, 1994), Ways of Coping Scale-Revised (WoC) (Folkman and Lazarus, 1985), and the Connor-Davidson Resilience Scale (CD-RISC) (Connor and Davidson, 2003) as primary measures-of-interest. The RSQ is a 30-item, continuous measure of attachment where subjects rate on a 5-point Likert scale the extent to which certain statements characterize their close relationships. The questionnaire has four established dimensions: dismissing (5 items), preoccupied (4 items), secure (5 items), and fearful (4 items). A subsequent factor analysis study identified subscores related to anxious (5 items) and avoidant (8 items) attachment (Simpson et al., 1992). The WoC scale is a 66-item questionnaire assessing coping styles where subjects rate on a 4-point Likert scale how often they utilized specific coping strategies in the context of a stressful situation in the past week. There are eight subscales: confrontive coping (6 items), distancing (6 items), self-controlling (7 items), seeking social support (6 items), accepting responsibility (4 items), escape-avoidance (8 items), planful problem solving (6 items), and positive reappraisal (7 items). As recommended, relative scores for each subscale were generated (Vitaliano et al., 1987). Lastly, the 25-item CD-RISC is a measure of adaptive stress coping tendencies where subjects rate on a 5-point scale to what extent each identified strategy applied to themselves in the past month.

To control for potential confounding effects of anxiety, depression, and trauma burden, subjects completed the Spielberger Trait Anxiety Inventory (STAI-T) (Spielberger et al., 1970), the Beck Depression Inventory-II (BDI) (Beck et al., 1996), the Childhood Trauma Questionnaire (CTQ) (Bernstein et al., 1994), and the Life Events Checklist-5 (LEC-5) (Weathers, 2013).

MRI acquisition

Subjects were placed in a Siemens 3 Tesla Trio scanner to acquire a 3D T1-weighted magnetization prepared rapid acquisition gradient echo sequence with the following parameters: orientation=sagittal; matrix size=256×256; voxel size=1×1×1mm; slice thickness=1mm, slices=160; repetition time=2300ms; echo time=2.98ms; field of view=256mm. Bi-temporal foam pads were used to restrict head motion.

Cortical thickness and subcortical volumetric analyses

FreeSurfer 5.3.0 (https://surfer.nmr.mgh.harvard.edu/) was used to perform cortical reconstructions of the T1-weighted images. Cortical reconstructions were visually inspected to check for accuracy of the automatic 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 across all vertices in each hemisphere. Each subject’s reconstructed brain was then morphed and registered to an average spherical space that optimally aligned gyral and sulcal features. Individual thickness measures were mapped onto this new space. A Gaussian kernel of 10mm full-width at half-maximum was applied to the subjects’ cortical thickness maps. For subcortical data, volumes (bilateral putamen, caudate nucleus, globus pallidus, nucleus accumbens, thalamus, amygdala, and hippocampus) were calculated using the FreeSurfer segmentation pipeline, visually inspected for quality, and normalized for total intracranial volume at the subject-level.

For all between-group analyses, FND patients were stratified into sub-groups based on the median split of RSQ, WoC and CD-RISC scores to specifically enable comparisons between FND subgroups scoring in the upper range of insecure attachment styles (i.e. dismissive attachment) or maladaptive coping strategies compared to controls. We have previously demonstrated the utility of this group-level approach in patients with FND (Perez et al., 2017b). These between-group cortical thickness analyses were performed using a 2-class general linear model (GLM) for the effect of clinical status. Given that there were no age x group effects, as tested using the QDEC tool in FreeSurfer, we used the different onset, same slope (DOSS) settings for between-group analyses.

For within-group analyses, a 1-class GLM was performed to evaluate for the effect of the covariate of interest (i.e. WoC-confrontive subscore). All between-group and within-group analyses included age and gender as covariates-of-non-interest; secondary between-group and within-group analyses performed in women only adjusted for age effects. For cortical thickness analyses, statistical significance of p<0.05 was corrected for multiple comparisons at the cluster-wise level using the mri_glmfit-sim command. 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 performed to investigate associations between covariates of interest and normalized subcortical volumes. A Bonferroni correction of p<0.05 was applied to all subcortical analyses to reduce type-I errors.

Following identification of statistically significant within-group findings, separate post-hoc analyses were performed to determine if significant findings held controlling for: 1) STAI-T, 2) BDI, 3) CTQ-total, 4) LEC-5 “happened to me” scores, 5) SSRI and/or SNRI medication use, and 6) motor FND subtypes. Given sample size limitations, SSRI/SNRI use was controlled for as a dichotomous (yes/no) covariate.

Results

Demographic information and psychometric scores for patients and controls are summarized in Supplemental Tables 1–2.

Between-group MRI differences

In stratified analyses for RSQ, WoC, and CD-RISC, there were no whole-brain corrected cortical thickness or subcortical volumetric differences between FND subgroups and controls, including analyses examining women only cohorts.

Within-group MRI associations

In women with FND only, a dismissing attachment style was associated with reduced left parahippocampal cortical thickness (pwhole-brain-corrected=0.0002) (See Table 1, Figure 1). In separate post-hoc analyses, this finding remained significant adjusting for CTQ-total, LEC “happened to me,” SSRI/SNRI use, and PNES and FMD subtypes; the finding did not remain significant controlling for STAI-T, BDI, and functional weakness subtype (See Supplemental Table 3).

Table 1.

Statistically significant within-group structural findings in women with functional neurological disorders (n=21).

Contrast of Interest Cerebral
Regions		 Peak
Coordinates in
MNI Space
(mm)
 T-value
Max		 P Value N. Vtx Cluster Size
(mm2)
x y z
RSQ Dismissing Attachment Left Parahippocampal Gyrus −32.3 −40.5 −9.9 −3.95 0.0002 1701 944.03
WoC Confrontive Right Hippocampus - - - −3.66 0.03 - -
WoC Accepting Responsibility Right Precentral Gyrus 49.9 3.9 23.8 4.15 0.03 867 424.9
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P-values represent whole-brain corrected values. N. Vtx, number of vertices; MNI, Montreal Neurological Institute; FND, Functional Neurological Disorder; RSQ, Relationship Scales Questionnaire; WoC, Ways of Coping Scale-Revised.

Figure 1. Individual-differences in left parahippocampal cortical thickness inversely correlated with dismissing attachment style in women with motor functional neurological disorders (FND).

Figure 1

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A) Dismissing attachment, as measured by the Relationship Scales Questionnaire (RSQ), negatively correlated with left parahippocampal cortical thickness (pwhole-brain-corrected=0.0002). B) For visual display purposes only, a scatter plot of cortical thickness values for the statistically significant parahippocampal region is plotted against individual RSQ-Dismissing scores. C) Box and whisker plots show the circumscribed parahippocampal cortical thickness values shown in panel A for the 10 women with FND reporting the highest levels of dismissing attachment, the other 11 women with FND, and 22 healthy women. Note, images are thresholded at an uncorrected p-value of 0.01.

For women with FND only, a confrontive coping style was associated with reduced right hippocampal volume (pwhole-brain-corrected=0.03) (See Figure 2). In post-hoc analyses, this finding remained significant when separately controlling for STAI-T, BDI, SSRI/SNRI use, and PNES and FMD subtypes; the finding did not hold adjusting for functional weakness or trauma burden.

Figure 2. Individual-differences in right hippocampal volume inversely correlated with confrontive coping in women with motor functional neurological disorders (FND).

Figure 2

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A) Confrontive coping, as measured by the Ways of Coping-Revised (WoC), negatively correlated with right hippocampal volume (pwhole-brain-corrected=0.03). B) For visual display purposes only, a scatter plot of normalized hippocampal values is plotted against individual WoC-Confrontive scores. C) Box and whisker plots show the normalized hippocampal volumes shown in panel A for the 10 women with FND reporting the highest confrontive coping, the other 11 women with FND, and 22 healthy women. Note, images are thresholded at an uncorrected p-value of 0.01.

The tendency to engage in adaptive coping by accepting responsibility was positively associated with right precentral gyrus cortical thickness in women with FND (pwhole-brain-corrected=0.03) (See Figure 3). This finding held adjusting for STAI-T, CTQ-total, LEC “happened to me,” SSRI/SNRI use, and PNES and FMD subtypes in separate post-hoc analyses; the finding did not remain significant controlling for BDI or functional weakness. There were no other statistically significant within-group findings for the RSQ, WoC, or CD-RISC subscores.

Figure 3. Individual-differences in right precentral gyrus cortical thickness positively correlated with accepting responsibility in women with motor functional neurological disorders (FND).

Figure 3

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A) Coping through accepting responsibility, as measured by the Ways of Coping-Revised (WoC), positively correlated with right precentral cortical thickness (pwhole-brain-corrected=0.03). B) For visual display purposes only, a scatter plot of cortical thickness values for the statistically significant precentral gyrus region is plotted against individual WoC-Accepting Responsibility scores. C) Box and whisker plots show the circumscribed precentral cortical thickness values shown in panel A for the 11 women with FND reporting the greatest tendency to cope through accepting responsibility, the other 10 women with FND, and 22 healthy women. Note, images are thresholded at an uncorrected p-value of 0.01.

Discussion

This MRI study examined the neurobiology of attachment and stress coping styles in patients with FND. Within-group analyses in women with FND identified an inverse relationship between dismissing attachment and left parahippocampal cortical thickness. In the same group, increased reliance on a confrontive coping style was associated with reduced right hippocampal volume, while a tendency to cope adaptively by accepting responsibility was positively associated with right precentral gyrus cortical thickness. Each of these findings held for SSRI/SNRI medication use. There were no statistically significant associations between coping abilities or attachment style in the mixed-gender FND cohort or in stratified between-group analyses. Thus, all significant structural within-group findings were within the lower or upper limits of the normal range when compared to healthy women. This study re-affirms that gender is an important biological variable in the study of FND (Asadi-Pooya, 2016; Perez et al., 2017a). Overall, these findings implicate individual differences in limbic/paralimbic and motor cortices in the pathophysiology of insecure attachment and coping behaviors in women with FND.

The novel finding of a relationship between dismissing attachment style and left parahippocampal cortical thinning in women with FND suggests a potential neural mechanism for the tendency to reject social encounters. Dismissive attachment reflects a pervasive difficulty trusting others and reaching out for support. The parahippocampal gyrus, strategically placed in an important part of the connectome, links the medial temporal lobe memory system and cortical nodes of the default mode network (Ward et al., 2014). Thus, the processing of past experiences can mix with self-awareness, and if self-awareness is fraught with insecure attachment, social-behavioral consequences may ensue (Chase et al., 2014). Patients with motor FND have exhibited increased ACC - parahippocampal resting-state connectivity (Arthuis et al., 2015) and decreased parahippocampal/hippocampal activity when recalling specific adverse events compared to controls (Aybek et al., 2014b). Furthermore, a facial emotion processing study demonstrated increased left parahippocampal-right temporal functional connectivity in patients with PNES compared to healthy controls and epilepsy patients (Szaflarski et al., 2018). In patients with somatic symptom disorders, dismissing attachment is a common insecure attachment style (Waller et al., 2004). Compared to controls, patients with somatic symptom disorders have also exhibited parahippocampal hypoperfusion (Koh et al., 2010), reduced parahippocampal activity during performance of an empathy-based facial viewing task (de Greck et al., 2012), and heightened parahippocampus - anterior insular connectivity during the intersection of sad-emotion processing and mild nociceptive experience (Yoshino et al., 2013). A systematic review of facial emotion processing identified parahippocampal hypoactivation as a reliable characteristic of social anxiety disorder (Binelli et al., 2014), and a neuroimaging study probing attachment experiences showed that illicit substance-using mothers demonstrated reduced parahippocampal and amygdalar responses during exposure to infant cries or faces (Landi et al., 2011). Additionally, the literature supports a role for the parahippocampus in automatic negative thoughts, negative interpersonal evaluations, anti-social behavior, and fear of negative evaluations (Busso et al., 2017; Debbané et al., 2017; Du et al., 2015; Kajimura et al., 2015).

In the cognitive-affective neuroscience literature, the parahippocampus is implicated in a complex array of cognitive, social-emotional and contextual-sensory processing functions (Aminoff et al., 2013; Catani et al., 2013). Given the role of oxytocin in the neurobiology of attachment (Insel and Young, 2001), it is notable that a meta-analysis of oxytocin administration during functional MRI demonstrated consistent modulation of parahippocampal reactivity to negative socio-affective stimuli (Wang et al., 2017). A recent preliminary study revealed increased methylation of the oxytocin receptor gene in patients with motor FND (Apazoglou et al., 2017a). Thus, while additional research is needed to investigate brain-attachment relationships in patients with FND, our findings suggest that individual-differences in parahippocampal structural profiles may play a role in negatively biasing the appraisal of socially relevant interpersonal experiences. In addition, the association between dismissing attachment and parahippocampal cortical thickness held adjusting for adverse life event burden, implying that connections between trauma-related aberrant neuroplasticity and attachment styles, if present, do not reflect simple linear relationships. Additional factors such as developmental trajectories and critical periods, as well as the onset, frequency and intensity of adverse life events, warrant consideration in future neuroimaging studies of attachment styles and traumatic experiences in patients with FND.

In this study, hippocampal volumetric reductions in women with FND were associated with increased reliance on a confrontive coping style, which did not remain significant adjusting for trauma burden. We have previously characterized an inverse relationship between the magnitude of adverse life events and hippocampal volume in patients with FND (Perez et al., 2017a). Similar inverse associations between sexual abuse and reduced hippocampal volume have been identified in patients with PNES (Johnstone et al., 2016). Associations between trauma-related disorders and decreased hippocampal volume are also well-documented (Hull, 2002). As such, we speculate that the relationship between reduced hippocampal volume and confrontive coping styles may relate either to decreased hippocampal-mediated amygdalar inhibition and/or represent a marker of aberrant neuroplasticity in the context of hypothalamic-pituitary-axis dysfunction (Apazoglou et al., 2017b; Bakvis et al., 2009; Bakvis et al., 2010; Bannerman et al., 2004). For example, individuals with motor FND exhibited elevated basal cortisol levels that positively correlated with both the burden and perceived impact of adverse life events (Apazoglou et al., 2017b). Future studies should investigate relationships between neuroendocrine profiles, neuroimaging biomarkers, and coping styles in patients with FND (Strathearn, L. et al., 2009).

We also observed an association between right precentral gyrus cortical thickness and adaptive coping by accepting responsibility in women with FND. Structural neuroimaging studies in FND have been inconsistent regarding the identification of group-level differences in motor cortices compared to controls, with some reporting increased (Aybek et al., 2014a) and others decreased structural profiles (Labate et al., 2011; Ristic et al., 2015). Decreased precentral gyrus activations have been described in functional neuroimaging studies of FND using several motor paradigms (de Lange et al., 2010; Marshall et al., 1997; Schrag et al., 2013; Stone et al., 2007). While differences in clinical characteristics such as illness duration and motor symptomatology may help contextualize structural MRI findings across studies, our results suggest a role for the right precentral gyrus in adaptive stress coping. The ventral premotor cortex has been implicated in social cognition (Fujii et al., 2008) and the mirror neuron system (Vogeley, 2017). Fronto-parietal regions of the mirror neuron system may be engaged in early-stage processing of bodily and spatial cues subserving social evaluative functions (Vogeley, 2017). Similar mechanisms may link individual-differences in precentral gyrus cortical thickness to a greater tendency to accept responsibility during conflict-laden situations.

Limitations of this study include a modest sample size, reliance on self-report measures, low number of male patients, psychiatric co-morbidities and psychotropic medication use. In studies of attachment, the Adult Attachment Interview is the gold standard, and additional research investigating neural mechanisms of attachment in FND populations should be conducted using this and other scales (de Haas et al., 1994). Related but distinct concepts such as unresolved trauma or loss also warrant future study in FND (Kim et al., 2014). In addition, we did not obtain attachment or coping style data in healthy subjects, preventing specific comparisons to a control group with known secure attachment or adaptive stress coping tendencies. Future follow-up studies should compare FND patients with insecure attachment styles against healthy control and psychiatric populations with attachment data to determine if the parahippocampal gyrus – dismissing attachment relationship described here is FND-specific or common across other populations. We also did not identify structural associations with the CD-RISC, emphasizing that more research is needed at the intersection of resilience and trauma in FND. In post-hoc analyses, all within-group findings held adjusting for PNES and functional movement disorder FND subtypes, but did not remain statistically significant controlling for a diagnosis of functional weakness. While our sample was under-powered to robustly adjust for motor subtypes in our cohort of 21 women with FND (9 with functional weakness), these initial observations suggest that more research is needed to investigate structural biomarkers of attachment and coping across motor FNDs. By design, our cohort is a trans-diagnostic mixed group spanning the motor spectrum of FND, which incorporates the known overlap across FND subtypes (Matin et al., 2017; Perez et al., 2015) and the propensity for patients to develop multiple symptoms over the course of their illness (McKenzie et al., 2011). This study was also limited by a relatively low number of male subjects, though our predominantly female cohort is representative of the gender imbalance in FND (Asadi-Pooya, 2016). Given the documented role of gender in the development of psychopathology (MacMillan et al., 2001), further neurobiological investigations of attachment in FND should determine whether gender differences are related to environmental factors or represent in part the interplay of gene-environment interactions. More research is also required to investigate the neurobiology of attachment and coping in children/adolescents with FND, as important differences may exist across the lifespan (Kozlowska et al., 2017); in addition, longitudinal serial MRI studies in FND populations may help clarify the extent to which the brain-attachment and brain-coping relationships delineated here represent acquired structural alterations or predisposing vulnerabilities for the development of particular attachment or coping tendencies.

In conclusion, we identified individual differences in corticolimbic structures related to dismissing attachment style and adaptive and maladaptive stress coping in women with FND. This study also highlights the importance of studying gender-specific effects in the pathophysiology of FND. Future studies should investigate if associations between insecure attachment and the parahippocampal gyrus reflect disruptions in the connections between the default mode “self-concerned” network and the medial temporal lobe memory system.

Supplementary Material

supplement

Supplemental Table 1. Demographic characteristics of patients with functional neurological disorders (FND). †Indicates that these patients had splitting of the midline functional numbness. *Indicates that these patients also had functional voice symptoms. Abbreviations: M, male; F, female; PNES, Psychogenic Nonepileptic Seizures; FW, Functional Weakness; FMD, Functional Movement Disorders; NOS, not otherwise specified; MDD, Major Depressive Disorder; PDwAg, Panic Disorder with Agoraphobia; PDwoAg, Panic Disorder without Agoraphobia; GAD, Generalized Anxiety Disorder; Undiff Somatoform, Undifferentiated Somatoform Disorder; PTSD, Post-Traumatic Stress Disorder; OCD, BPD, Borderline Personality Disorder; Obsessive Compulsive Disorder; Ag, Agoraphobia without Panic Disorder; APM, Amphetamine; APZ, Aripiprazole; BUP, Bupropion; CLN, Clonidine; CLP, Clonazepam; CTP, Citalopram; DLX, Duloxetine; DOX, Doxepin; DVX, Desvenlafaxine; DXAM, Dextroamphetamine; DZP, Diazepam; ECP, Escitalopram; FLX, Fluoxetine; GBP, Gabapentin; LTG, Lamotrigine; LRZ, Lorazepam; LSD, Lysergic Acid Diethylamide; MIR, Mirtazapine; NRT, Nortriptyline; PGN, Pregabalin; PZN, Prazosin; QTP, Quetiapine; ROP, Ropinirole; SERT, Sertraline; THP, Trihexyphenidyl; TPM, Topiramate; TZD, Trazodone; VPA, Valproic Acid; VEN, Venlafaxine; ZLP, Zolpidem.

Supplemental Table 2. Psychometric scores for 26 patients with functional neurological disorders and 27 matched healthy controls. FND, Functional Neurological Disorder; SD, standard deviation; F, Female; M, Male; STAI-Trait Anxiety, Spielberger Trait Anxiety Inventory; BDI, Beck Depression Inventory-II; CTQ, Childhood Trauma Questionnaire; LEC, Life Event Checklist; RSQ, Relationship Scales Questionnaire; WoC, Ways of Coping Scale- Revised; CD-RISC, Connor-Davidson Resilience Scale. WoC relative scores were calculated by dividing the average score of each sub-scale by the sum of the averages of all the sub-scales and multiplying by 100.

Supplemental Table 3. Statistically significant within-group structural associations in patients with functional neurological disorders (FND) adjusting for trait anxiety, depression, adverse life event burden, SSRI/SNRI medication use, and FND subtype. All pvalues are whole-brain corrected. MNI, Montreal Neurological Institute; N. Vtx, number of vertices; RSQ, Relationship Scales Questionnaire; WoC, Ways of Coping Scale- Revised; BDI, Beck Depression Inventory-II; STAI-T, Spielberger Trait Anxiety Inventory; CTQ, Childhood Trauma Questionnaire total abuse score; LEC, Life Events Checklist; PNES, Psychogenic Non-Epileptic Seizures; FMD, Functional Movement Disorders; FW, Functional Weakness; SSRI, selective serotonin reuptake inhibitor; SNRI, serotonin-norepinephrine reuptake inhibitor.

Acknowledgments

Acknowledgements/Funding

D.L.P. was funded by the National Institute of Mental Health Grant 1K23MH111983-01A1, Massachusetts General Hospital Physician-Scientist Development Award, and the Sidney R. Baer Jr. Foundation. This study was also supported by the NIH shared instrument grant S10RR023043.

Declaration of Interests

B.C.D., consultant at Merck, Med Learning Group and Haymarket; royalties from Oxford University Press and Cambridge University Press; on the editorial board of Neuroimage: Clinical, Cortex, Hippocampus, Neurodegenerative Disease Management. W.C.L., has served on the editorial boards of Epilepsia, Epilepsy & Behavior and Journal of Neuropsychiatry and Clinical Neurosciences; receives editor's royalties from the publication of Gates and Rowan's Nonepileptic Seizures, 3rd ed. (Cambridge University Press, 2010) and 4th ed. (2017); author’s royalties for Taking Control of Your Seizures: Workbook and Therapist Guide (Oxford University Press, 2015); has received research support from the NIH (NINDS 5K23NS45902 [PI]), Rhode Island Hospital, the American Epilepsy Society (AES), the Epilepsy Foundation (EF), Brown University 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 medico legal expert testimony. MSK: consultant at Forum Pharmaceuticals; editor for Schizophrenia Research.

Footnotes

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All authors report no conflicts of interest.

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Supplementary Materials

supplement

Supplemental Table 1. Demographic characteristics of patients with functional neurological disorders (FND). †Indicates that these patients had splitting of the midline functional numbness. *Indicates that these patients also had functional voice symptoms. Abbreviations: M, male; F, female; PNES, Psychogenic Nonepileptic Seizures; FW, Functional Weakness; FMD, Functional Movement Disorders; NOS, not otherwise specified; MDD, Major Depressive Disorder; PDwAg, Panic Disorder with Agoraphobia; PDwoAg, Panic Disorder without Agoraphobia; GAD, Generalized Anxiety Disorder; Undiff Somatoform, Undifferentiated Somatoform Disorder; PTSD, Post-Traumatic Stress Disorder; OCD, BPD, Borderline Personality Disorder; Obsessive Compulsive Disorder; Ag, Agoraphobia without Panic Disorder; APM, Amphetamine; APZ, Aripiprazole; BUP, Bupropion; CLN, Clonidine; CLP, Clonazepam; CTP, Citalopram; DLX, Duloxetine; DOX, Doxepin; DVX, Desvenlafaxine; DXAM, Dextroamphetamine; DZP, Diazepam; ECP, Escitalopram; FLX, Fluoxetine; GBP, Gabapentin; LTG, Lamotrigine; LRZ, Lorazepam; LSD, Lysergic Acid Diethylamide; MIR, Mirtazapine; NRT, Nortriptyline; PGN, Pregabalin; PZN, Prazosin; QTP, Quetiapine; ROP, Ropinirole; SERT, Sertraline; THP, Trihexyphenidyl; TPM, Topiramate; TZD, Trazodone; VPA, Valproic Acid; VEN, Venlafaxine; ZLP, Zolpidem.

Supplemental Table 2. Psychometric scores for 26 patients with functional neurological disorders and 27 matched healthy controls. FND, Functional Neurological Disorder; SD, standard deviation; F, Female; M, Male; STAI-Trait Anxiety, Spielberger Trait Anxiety Inventory; BDI, Beck Depression Inventory-II; CTQ, Childhood Trauma Questionnaire; LEC, Life Event Checklist; RSQ, Relationship Scales Questionnaire; WoC, Ways of Coping Scale- Revised; CD-RISC, Connor-Davidson Resilience Scale. WoC relative scores were calculated by dividing the average score of each sub-scale by the sum of the averages of all the sub-scales and multiplying by 100.

Supplemental Table 3. Statistically significant within-group structural associations in patients with functional neurological disorders (FND) adjusting for trait anxiety, depression, adverse life event burden, SSRI/SNRI medication use, and FND subtype. All pvalues are whole-brain corrected. MNI, Montreal Neurological Institute; N. Vtx, number of vertices; RSQ, Relationship Scales Questionnaire; WoC, Ways of Coping Scale- Revised; BDI, Beck Depression Inventory-II; STAI-T, Spielberger Trait Anxiety Inventory; CTQ, Childhood Trauma Questionnaire total abuse score; LEC, Life Events Checklist; PNES, Psychogenic Non-Epileptic Seizures; FMD, Functional Movement Disorders; FW, Functional Weakness; SSRI, selective serotonin reuptake inhibitor; SNRI, serotonin-norepinephrine reuptake inhibitor.

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