Handbook of Clinical Neurology, Vol.

139 (3rd series)

Functional Neurologic Disorders
M. Hallett, J. Stone, and A. Carson, Editors
http://dx.doi.org/10.1016/B978-0-12-801772-2.00014-X
© 2016 Elsevier B.V. All rights reserved

Chapter 14

Do (epi)genetics impact the brain in functional neurologic

disorders?

T. FRODL*
Department of Psychiatry and Psychotherapy, Otto von Guericke University of Magdeburg, Germany and Department
of Psychiatry, Trinity College, Dublin, Ireland

Abstract
Advances in neuropsychiatric research are supposed to lead to significant improvements in understanding
functional neurologic disorders and their diagnosis. However, epigenetic and genetic research on conver-
sion disorders and somatoform disorders is only at its start. This review demonstrates the current state
within this field and tries to bridge a gap from what is known on gene–stress interactions in other psychi-
atric disorders like depression. The etiology of conversion disorders is hypothesized to be multifactorial.
These considerations also suggest that potential etiologic factors lead to alterations in brain function, either
episodically or chronically, eventually leading to structural brain changes. In particular, the knowledge of
how the environment influences brain structure and function, e.g., via epigenetic regulation, may be inter-
esting for future research in functional neurologic disorders. Reviewing the literature results in evidence
that childhood adversities play a role in the development of functional neurologic disorders, whereby at
present no reports exist about the interactive effect between childhood adversity and genetic factors or
about the impact of epigenetics.

INTRODUCTION ENVIRONMENTAL EFFECTS

Conversion disorder is a functional neurologic symp-
tom disorder, as defined by the Diagnostic and
Statistical Manual of Mental Disorders, 5th edition
(DSM-5: American Psychiatric Assocation, 2013) –
or, as defined in the International Classification of
Diseases (ICD-10: World Health Organization, 2010),
is a dissociative disorder – marked by the presence of
pseudoneurologic symptoms. Criteria in DSM-5 now
emphasize the importance of the neurologic examina-
tion, and recognize that relevant psychologic factors
may not be demonstrable at the time of diagnosis.
Despite research in this area, the etiology is largely
unknown. It is hypothesized to be multifactorial, with
stress–environmental factors and potentially some
mediating genetic factors influencing the development
of psychopathology (Krem, 2004).
First, environmental factors are hypothesized to play a
major role in the development of psychiatric disorders.
This is true also for conversion disorders. A few studies
investigated the association between childhood trauma
or adversity and conversion disorders. Within a literature
review, nine out of nine studies showed that increased
physical and sexual abuse was found in patients with con-
version or somatization disorders compared to healthy,
organic, or psychiatric controls. Psychologic abuse also
was found to be more pronounced in conversion/somati-
zation disorders compared to controls. The review also
included other medically unexplained conditions.
The impact of childhood adversity is not unique to con-
version disorders, since it can also be seen in irritable-
bowel syndrome and chronic pelvic pain (Roelofs and
Spinhoven, 2007). In one more recent study, 56 female

*Correspondence to: Thomas Frodl, Department of Psychiatry and Psychotherapy, Otto von Guericke University of Magdeburg,
Germany. Tel: +49-391-67-15029, E-mail: Thomas.Frodl@med.ovgu.de
158 T. FRODL
patients with conversion disorder, who had psychogenic
nonepileptic seizures, were investigated using clinical
interviews about dissociation and childhood trauma. The
total score of the childhood trauma questionnaire as well
as its subscales – emotional abuse, emotional neglect,
physical abuse, and sexual abuse – was significantly
higher in the conversion group compared to control sub-
jects. Moreover, the amount of dissociation was statisti-
cally higher in the conversion group in line with a
traumatic background (Ozcetin et al., 2009).
Furthermore, in an earlier study, 54 patients with con-
version disorder reported a higher incidence of physical or
sexual abuse, a larger number of different types of physical
abuse, sexual abuse of longer duration, and incestuous
experiences more often than 50 comparison patients with
affective disorders (Roelofs et al., 2002). Moreover, a
series of patients with conversion disorder presenting as
epilepsy showed a significantly higher frequency of a his-
tory of sexual or physical abuse than 140 patients with
complex partial epilepsy. Also severity of sexual but not
physical abuse was significantly greater in the nonepilep-
tic seizure group relative to controls (Alper et al., 1993).
Furthermore, a diagnosis of psychogenic nonepileptic
seizures was associated with significantly higher rates
of childhood trauma in addition to female sex in a sample
of 82 subjects with epileptic seizures and 96 subjects
with psychogenic nonepileptic seizures (Kaplan et al.,
2013). There are many more studies in this area, already
summarized in a review and meta-analysis that comes to
the conclusion that there is growing evidence of an asso-
ciation between childhood sexual abuse and psychogenic
nonepileptic seizures (Sharpe and Faye, 2006).
To summarize, these studies all show significant higher
severity and rates of childhood adversity in functional neu-
rologic disorders compared to healthy controls or patients
with affective disorders. In particular, the comparison
between functional neurologic disorders and affective
disorders that already show higher rates of childhood
adversities compared to controls suggests that childhood
adversity might play a prominent role for later developing
a functional neurologic disorder. However, to date these
studies also have to be taken with caution because of meth-
odologic difficulties, e.g., that there is no common defini-
tion of childhood abuse, childhood abuse is usually
reported retrospectively, and case and comparison groups
were recruited, often not in a way that was representative
of the population.
LINK BETWEEN ENVIRONMENTAL
FACTORS LIKE STRESS AND THE BRAIN
SYSTEMS
Previous studies have suggested that a relationship exists
between childhood maltreatment and an increased risk of
developing a number of mental disorders in adulthood
(Heim and Nemeroff, 2001; Taylor et al., 2006), includ-
ing major depressive disorder (MDD) (Kessler, 1997),
posttraumatic stress disorder (Bonne et al., 2008), anxi-
ety disorders (Heim and Nemeroff, 2001), and substance
abuse (Dube et al., 2003).
The association between social early-life stressors and
development of psychiatric disorders has also been
explored experimentally and there is evidence suggesting
an impact of early-life adversity on brain function and
structure. Until only a few years ago, the adult brain
was considered to be an organ with a fixed structure,
unable to remodel or repair itself. However, recent
research shows that both structural and physiologic
changes occur in the adult nervous system, some arising
as a result of the individual’s interaction with the surround-
ing environment and some from internal adaptation, also
interacting with genetic factors.
Chronic social stress has been shown to induce
glucocorticoid-mediated pyramidal dendrite retraction
in the hippocampus and changes in dendrite arborization
in the prefrontal cortex (Woolley et al., 1990; Magarinos
et al., 1996; Wellman, 2001; Kole et al., 2004), which
might be associated with the behavioral manifestations
of stress-related disorders like MDD (Macqueen and
Frodl, 2011). There is mounting evidence that specific
neuronal circuits, particularly in the developing brain,
are damaged by environmental stress-inducing changes
in the hypothalamic–pituitary–adrenal (HPA) axis and
inflammatory pathways (Krishnan and Nestler, 2008).
Experimental studies have shown that stress or cortisol
administration may lead to depressive-like states and
atrophy of neurons in the hippocampus (Duman, 2002)
and that therapy with antidepressants reverses these
changes (Santarelli et al., 2003). Moreover, chronic
hypercortisolism has been shown to enhance tryptophan
breakdown in the brain and induce neurodegenerative
changes (Capuron and Miller, 2011). Other research
has shown that both physiologic and psychologic stress
can induce increased production of proinflammatory
mediators that can stimulate tryptophan catabolism in
the brain (Myint et al., 2012), with consequences on neu-
rotransmitter metabolism, neuroendocrine function, syn-
aptic transmission, and neurocircuits that regulate mood,
motor activity, motivation, anxiety, and alarm reactions
(Capuron and Miller, 2011).
Neuroimaging studies provide growing evidence that
childhood maltreatment, defined as maltreatment or
trauma in the form of emotional, physical, or sexual
abuse, or emotional or physical neglect, could have det-
rimental effects on brain structure. Vythilingam et al.
(2002) compared 32 women with recurrent unipolar
depression and prepubertal physical or sexual abuse to
11 women with depression without prepubertal abuse
 DO (EPI)GENETICS IMPACT THE BRAIN IN FUNCTIONAL NEUROLOGIC DISORDERS?
and to 14 healthy controls. They found that the left hip-
pocampus was 18% smaller in women with depression
and prepubertal abuse than those without abuse and
15% smaller than healthy controls.
Emotional neglect has also been found to be associ-
ated with smaller hippocampal volumes. Smaller left
hippocampal white-matter volumes were reported in
MDD patients who had experienced emotional child-
hood neglect compared to those without neglect. Both
emotional neglect and brain structural abnormalities pre-
dicted cumulative illness duration (Frodl et al., 2010b).
Eighty-four healthy controls and patients with MDD
who reported a history of emotional maltreatment during
childhood had smaller left dorsomedial prefrontal cortex
volumes compared to 96 comparison subjects without
maltreatment (van Harmelen et al., 2010).
Recent studies in healthy participants and community
samples have added to the evidence indicating that child-
hood maltreatment is associated with morphologic brain
changes. In a large study (n ¼ 193) of young adults with
and without childhood maltreatment, a reduction in left
hippocampal subfields CA2–CA3 and CA4–DG, CA1
and subiculum was revealed. This population was not
characterized by histories of MDD or posttraumatic stress
disorder (Teicher et al., 2012). In 148 healthy participants,
reduced gray-matter volumes in the hippocampus, insula,
orbitofrontal cortex, anterior cingulate gyrus, and caudate
were found to be associated with high scores of childhood
maltreatment. This association was not influenced by trait
anxiety, depression level, age, intelligence, education, or
more recent stressful life events (Dannlowski et al., 2012).
In a single-voxel magnetic resonance spectroscopy
study, the ratio of n-acetylaspartate to creatine was signif-
icantly lower in the anterior cingulate cortex in 11 mal-
treated subjects with posttraumatic stress disorder than
in the comparison 11 subjects without maltreatment
(De Bellis et al., 2000).
A study of 18 maltreated children, compared to
20 children who were not maltreated, showed reduced
gray matter in the medial orbitofrontal cortex and the left
middle temporal gyrus in those with maltreatment
(De Brito et al., 2013).
To date, most studies have been conducted cross-
sectionally in adults. A longitudinal magnetic resonance
imaging study involving 15 children aged 7–13 years
with childhood adversity and posttraumatic stress disor-
der symptoms reported that the presence of childhood
maltreatment was related to a decrease in hippocampal
volumes over a 12- and 18-month interval. However, this
study did not have a comparison group of individuals
who were not maltreated, hence no definite conclusion
can be drawn about whether children with childhood
maltreatment are more vulnerable for hippocampal
changes over time (Carrion et al., 2007).
159
In contrast, maltreatment leading to childhood post-
traumatic stress disorder has been reported to result in
larger hippocampal volumes in comparison to matched
healthy children who were not maltreated (Tupler and
De Bellis, 2006). Recently, we demonstrated that
gray-matter volume was significantly decreased in the
hippocampus and significantly increased in the dor-
somedial prefrontal cortex and the orbitofrontal cortex
in subjects who had experienced childhood maltreat-
ment in comparison to those who had not (Chaney
et al., 2014).
Research in functional neurologic disorders is rare
and no significant effects of childhood adversity on brain
structure have been investigated in these disorders. Inter-
estingly, significantly smaller left thalamic volumes were
found in 14 patients with conversion disorder compared
with 31 controls when corrected for intracranial volume
(Nicholson et al., 2014). Another voxel-based morphom-
etry and cortical thickness study in patients with psycho-
genic nonepileptic seizures revealed abnormal cortical
atrophy of the motor and premotor regions in the right
hemisphere and the cerebellum bilaterally (Labate
et al., 2012). These differences may reflect a disease pro-
cess, or could be a secondary consequence of having a
symptom for a while, or even a consequence of comor-
bidities such as depression. Therefore, larger and longi-
tudinal studies are required in the future to explore these
effects in more detail.
Childhood adversity, inflammation, brain structure, and
neurotrophic factors are not standalone measurements.
They seem to be related to each other. A history of child-
hood trauma and high levels of recent stressors predicted
lower brain-derived neurotrophic factor (BDNF) expres-
sion through an inflammation-mediated pathway and, in
turn, lower BDNF expression, increased interleukin-6
expression, and increased cortisol levels significantly
and independently predicted a smaller left hippocampal
volume (Mondelli et al., 2011).
There is one study investigating BDNF blood levels
in patients with conversion disorders. Interestingly, serum
BDNF levels were found to be significantly smaller in
15 patients with conversion disorders compared to
26 healthy controls. Moreover, there was no difference
between BDNF levels between patients with conversion
disorders and patients with MDD. This suggests that
BDNF level may be altered in a similar way in MDD
and conversion disorders (Deveci et al., 2007). However,
the impact of childhood adversity, other environmental
stressors and genetics on inflammation, neurotrophic fac-
tors, and brain structure and function has not yet been
explored in conversion disorders. There may be some sys-
tems like the stress hormone, neurotrophic and inflamma-
tion system that may be most interesting to look at with
regard to genetic and epigenetic research.
160 T. FRODL
GENETICS
The role of heritability in conversion and somatization
disorders is far from being clear, and twin studies were
not conclusive (Torgersen, 1986; Guze, 1993).
Studies in conversion disorders
A PubMed search with the words “conversion disorder”
in the title/abstract and “genetics” only results in six lit-
erature hits. For a search on “conversion disorder” in
title/abstracts and “epigenetics,” there were no hits.
There is only one study that investigated the effect
of a single-nucleotide polymorphism (SNP) (catechol-
O-methyltransferase (COMT) polymorphism) on the
occurrence of conversion disorders in 48 patients with
conversion disorder and 48 control patients. Alterations
in COMT activity are involved in various types of neu-
rologic disorders. There was no significant difference
between the groups (Armagan et al., 2013). Based on
the sample size, it has to be argued that this study was
underpowered to detect any significant effects.
Studies in somatoform disorders
Another study investigated whether there is an associa-
tion between somatoform disorder symptoms with
genetic variants that were found in previous studies to
be associated with pain. Pain is a major symptom of
somatoform disorders, including functional neurologic
symptom disorders. A total of 148 somatoform patients
with pain as the leading clinical symptom and 149 age-
and gender-matched healthy controls participated in this
study. Interestingly, the common G-allele of rs1800629
(tumor necrosis factor-a) occurred significantly more
often in the control group than in the group of patients
with somatoform disorder and thus seems to have protec-
tive effects. Being carrier of the A-allele on the other
hand might be a risk factor for somatoform disorder
(Gil et al., 2011).
Polymorphisms in the COMT gene are associated
with COMT enzymatic activity and pain sensitivity;
the effect of COMT polymorphisms was investigated
in the same sample. None of the six SNPs investigated,
including the functionally relevant common SNP in
codon 158 (Val158Met), showed a statistically signifi-
cant allelic, genotypic, or haplotypic association with
multisomatoform disorder (Jakobi et al., 2010).
Another study investigated 102 patients with undiffer-
entiated somatoform disorder, 106 patients with MDD,
and 133 healthy subjects for differences in the genotype
frequency of tryptophan hydroxylase gene polymor-
phism and associations between this polymorphism
and aggression. No significant differences were found
in TPH1 C-allele and CC homozygote frequencies
between the undifferentiated somatoform disorder
patients and the healthy subjects. The group of patients
with MDD, however, had significantly higher frequen-
cies of TPH1 C-allele (p ¼ 0.0002) and CC homozygos-
ity ( p ¼ 0.0003) than healthy subjects, with the same
genotypes, regardless of sex and age. Moreover, TPH1
CC homozygotes in the MDD group scored significantly
higher in terms of verbal aggression and total aggression
questionnaire score than A-carrier genotypes, regardless
of sex and age. While there was an association between
frequency of this polymorphism and MDD and the poly-
morphism was associated with aggression within the
group of patients with MDD, this was not found for
somatoform disorder (Koh et al., 2012).
It has been suggested that serotonergic hypofunction
and serotonergic pathway genes underlie the somatic
symptoms of somatoform disorders. This hypothesis
was investigated using a variety of serotonin-related gene
polymorphisms to determine whether undifferentiated
somatoform disorder is associated with specific serotonin-
related gene pathways. A total of 102 patients with undif-
ferentiated somatoform disorder and 133 healthy subjects
were enrolled. Patients with undifferentiated somatoform
disorder had higher frequencies of the TPH1 (A218C)
C-allele than healthy controls, but the difference was
not significant after Bonferroni correction. The frequency
of TPH1 genotype in addition to TPH2 rs1386494, 5-HTR
2A-T102C, 5-HTR 2A-G1438A, and 5HTTLPR allele
and genotype frequencies did not differ significantly
between the two groups. These findings suggest that a
variety of serotonin-related gene pathways are unlikely
to be genetic risk factors for undifferentiated somatoform
disorder. The authors thus concluded that the pathogenesis
of the disorder may be related to epigenetic factors, includ-
ing psychosocial and cultural factors (Koh et al., 2011).
In conclusion, so far there is only one study that
reports an association between the SNP rs1800629 of
the tumor necrosis factor-a gene in a rather moderate
sample size. Thus, larger samples are needed to investi-
gate the effects of rare copy number variants or for
looking with a genomewide approach. Thus, no major
significant effect of genetic polymorphisms has to date
been observed for functional neurologic disorders.
ENVIRONMENT–GENE INTERACTIONS
AND EPIGENETICS
A number of research groups have suggested that gene–
environmental interactions may be important to consider.
To date there are no studies available on the effects of
epigenetics on conversion disorders, so we need to
discuss this aspect more theoretically.
Studies show that patients with conversion disorders
show an excess number of childhood adversity events
 DO (EPI)GENETICS IMPACT THE BRAIN IN FUNCTIONAL NEUROLOGIC DISORDERS?
compared to comparison subjects, so childhood adver-
sity is one factor that should be taken into account. It
is known that childhood adversity interacts with genetic
predisposition to even influence brain development and
brain structure. For example, previously, we found that
childhood maltreatment interacts with the s allele of
the 5-HTTLPR and is associated with smaller hippocam-
pal volumes in patients with MDD (Frodl et al., 2010a).
Since there are no studies in conversion disorders, it is
relevant to look at other studies that examined the asso-
ciation of other disorders, such as dissociation, with
early-life adversity and genetics.
Dissociation is a failure of perceptual, memory, and
emotional integration that is associated with a variety
of psychiatric disorders and usually dissociative pro-
cesses are related to childhood trauma. One study inves-
tigated whether there was a potential gene–childhood
abuse interaction for dissociation in bipolar disorder
subjects and their affected and unaffected relatives.
A sample of 178 affected and unaffected family members
from patients with bipolar disorder was investigated for
this purpose. Interestingly, the low-activity Met allele of
the Val66Met polymorphism of the BDNF gene was
associated with lower levels of self-reported dissocia-
tion. The COMT Val158Met polymorphism interacted
significantly with total abuse scores obtained from the
childhood trauma questionnaire to impact on dissocia-
tion. Here the Val/Val genotype was associated with
increasing levels of dissociation in participants exposed
to higher levels of childhood trauma, whereby those with
the Met/Met genotypes seemed to display decreased dis-
sociation with increasing self-reported childhood trauma
(Savitz et al., 2008). These findings increase the likeli-
hood that conversion disorders may also be related to
childhood adversity by gene–environment interactions.
The physiologic mechanisms accounting for such
gene–environment interactions are not known. One of
the potential mechanisms by which gene–environment
interacts and affects brain development is via environ-
mentally induced stable changes in genetic expression
(Szyf, 2009; Booij et al., 2013; Nestler, 2014). These
changes in stable expression are most probably caused
by epigenetic mechanisms (Szyf, 2009; Booij et al.,
2013; Nestler, 2014). Following the observation of
tissue-specific DNA methylation changes in the hippo-
campal glucocorticoid receptor (GR) gene in postmor-
tem brains of victims of childhood abuse (McGowan
et al., 2009), a number of studies have analyzed DNA
methylation processes in peripheral tissues. With regard
to the 5-hydroxytryptamine (5-HT) system, an increasing
number of studies have found associations between
peripheral methylation in the SLC6A4 gene and
early-life adversity (Booij et al., 2013), or depression
(Nestler, 2014). Specifically, studies demonstrated that
161
early stress, including a history of childhood abuse,
was associated with altered levels of peripheral methyl-
ation in SLC6A4 promoter regions later in life (Beach
et al., 2010, 2011; Devlin et al., 2010; van Ijzendoorn
et al., 2010; Kang et al., 2013).
In addition, it was recently found in a healthy sample
that DNA methylation at the SLC6A4 promoter in white
blood cells of adults was associated with lower in vivo
measures of brain 5-HT synthesis in the orbitofrontal cor-
tex, irrespective of 5-HTTLPR genotype.
The functional relevance of DNA methylation in
SLC6A4 promotor regulation was further demonstrated
by an in vitro experiment, showing that DNA methylation
of the SLC6A4 promoter in a luciferase reporter construct
suppressed its transcriptional activity (Wang et al., 2012).
These findings, taken together, suggest that DNA methyl-
ation in the SLC6A4 promoter may be one of the physio-
logic mechanisms of how early stress could translate
into altered brain development. Hippocampal changes
might be particularly relevant here, since this brain region
is densely innervated with 5-HT, and highly involved
in stress regulation (Lupien et al., 2009; Frodl and
O’Keane, 2013). However, other candidate genes and
the whole epigenome need to be investigated first to
understand how specific these associations might be
and also how many other methylation regions might
be affected.
Recently we found that methylation of 5-HT trans-
porter polymorphism was significantly associated with
higher amount of childhood adversity and smaller hippo-
campal volumes (Booij et al., 2015). Moreover, methyla-
tion of 5-HT transporter polymorphism also was
functionally relevant for brain activation during emotional
attention-processing tasks, as measured using functional
magnetic resonance imaging (Frodl et al., 2015).
We need to consider that multiple factors are interact-
ing over time to explain the associations between early-
childhood maltreatment, hippocampus, and HPA axis
functioning. Other influences, like genetic and tempera-
mental factors, probably also play a significant role. Key
personality traits that have been demonstrated to predict
HPA axis stress responses are self-esteem and an internal
locus of control. In healthy subjects of all ages these traits
are significantly correlated with hippocampal volume
(Pruessner et al., 2005). Environmental factors like stress
and genetic variation are linked together via epigenetic
processes. Animal models tracking the trajectory from
early-life stress to adult depression indicate that sus-
tained stress during development leads to hypermethyla-
tion of the GR promoter gene, leading to reduced
function of the GR and inability to shut down stress
responses (McGowan et al., 2011). An impact of parental
care on epigenetic regulation of hippocampal GR was
demonstrated in a study observing that suicide victims
162 T. FRODL
with a history of early-life adversity display decreased
GR mRNA expression and increased cytosine methyla-
tion of a neuron-specific GR (NR3C1) promoter in post-
mortem hippocampus compared to either suicide victims
with no early-life adversity or controls (McGowan
et al., 2009).
Epigenetic influences on the HPA system may also
be transgenerational. One study has shown that mater-
nal childhood abuse is associated with lower cortisol
responses in their infants (Brand et al., 2010). Interest-
ingly, HPA axis development commences in utero.
For most of the duration of pregnancy, the baby and
mother share a common corticotropin-releasing hor- Fig. 14.1. There is some evidence that early-life adversity is
mone (CRH)–adrenocorticotropic hormone (ACTH)– associated with the development of functional neurologic
disorders. While there is the assumption that stress–gene inter-
cortisol axis, because the placenta produces CRH
action plays a significant role, to date there is no study avail-
(McLean et al., 1995). CRH production by the placenta
able showing that a genetic variation or single-nucleotide
is positively controlled by maternal and fetal cortisol, polymorphism (SNP) is clearly associated with functional neu-
so that if mother or baby is stressed, CRH production rologic disorders. However, samples investigated to date are
will increase (Smith and Nicholson, 2007). Increased clearly too small. Experimental data and observations about
production of placental CRH will result in increased the stress–gene interactions suggest that epigenetic modula-
cortisol levels in baby and mother and, because of a tion of gene expression might play a central role. This idea
positive feedforward loop between cortisol and placen- needs further investigation.
tal CRH, there will be increased CRH production
(McLean et al., 1995). Babies born to women who
were psychologically stressed during pregnancy tend
showed larger gray-matter volumes in the superior and
to have disorganized sleep, to be less responsive emo-
middle frontal gyri, orbital gyrus, superior temporal gyrus,
tionally (Field, 2011), and to have higher cortisol
and fusiform gyrus (Kim et al., 2010). Birth weight
responses to stressors (Davis et al., 2011). The HPA
significantly positively predicted hippocampal volume
axis seems to be “programmed” in utero, via GR mech-
in adulthood in female subjects reporting low maternal
anisms, so that the developing brain is primed to
care, suggesting a complex picture with some protective
respond to a fixed “set point” in postuterine life
factors (Buss et al., 2007). Thus, events postbirth may
(Glover et al., 2010).
also reverse the damaging effects of a harsh intrauterine
Thus, developmental factors may play a role in some
environment, and the greater plasticity within the HPA
cases of medically unexplained (or “functional”) symp-
system during childhood can provide greater resilience
toms like conversion disorder (Buffington, 2009).
for the developing adult (Fisher et al., 2006).
Experimental data suggest that, when a pregnant mother
perceives a threatening environment, this situation may
be transmitted to the fetus when hormones cross the
CONCLUSIONS
placenta and affect the course of fetal development
(Meaney et al., 2007). These changes also appear to To date there is a significant lack of data about gene–
increase vulnerability to life stressors, putting these environment interactions in functional neurologic disor-
individuals at greater risk of developing disorders char- ders. Also to date there is no major evidence that genetics
acterized by pain and discomfort (Bateson et al., 2004). alone play a crucial role, although this research is limited
Medically unexplained symptoms need to be consid- by relatively small samples under investigation. Another
ered from the perspective of underlying developmental limitation is that comorbidity with other psychiatric
influences involving epigenetic modulation of gene disorders is high in functional neurologic disorders
expression that affect function of a variety of organs and somatoform disorders, e.g., with affective disorders,
based on familial (genetic and environmental) predispo- substance use disorders, and personality disorders. Evi-
sitions (Fig. 14.1). dence already exists that childhood adversity is a factor
These observations may also indicate that good mater- influencing the vulnerability for functional neurologic
nal care could protect against excessive stress responses disorders; however, again, the mechanism for how this
and result in larger brain structural volumes. Indeed, is provided is unknown, in part because research on epi-
mothers who reported higher maternal care in childhood genetics in this area is just at its start.
 DO (EPI)GENETICS IMPACT THE BRAIN IN FUNCTIONAL NEUROLOGIC DISORDERS?
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