Effects of TPH2 gene variation and childhood trauma on the clinical and circuit-level phenotype of functional movement disorders.

BACKGROUND: Functional movement disorders (FMDs), part of the wide spectrum of functional neurological disorders (conversion disorders), are common and often associated with a poor prognosis. Nevertheless, little is known about their neurobiological underpinnings, particularly with regard to the contribution of genetic factors. Because FMD and stress-related disorders share a common core of biobehavioural manifestations, we investigated whether variants in stress-related genes also contributed, directly and interactively with childhood trauma, to the clinical and circuit-level phenotypes of FMD. METHODS: Sixty-nine patients with a 'clinically defined' diagnosis of FMD were genotyped for 18 single-nucleotide polymorphisms (SNPs) from 14 candidate genes. FMD clinical characteristics, psychiatric comorbidity and symptomatology, and childhood trauma exposure were assessed. Resting-state functional connectivity data were obtained in a subgroup of 38 patients with FMD and 38 age-matched and sex-matched healthy controls. Amygdala-frontal connectivity was analysed using a whole-brain seed-based approach. RESULTS: Among the SNPs analysed, a tryptophan hydroxylase 2 (TPH2) gene polymorphism-G703T-significantly predicted clinical and neurocircuitry manifestations of FMD. Relative to GG homozygotes, T carriers were characterised by earlier FMD age of onset and decreased connectivity between the right amygdala and the middle frontal gyrus. Furthermore, the TPH2 genotype showed a significant interaction with childhood trauma in predicting worse symptom severity. CONCLUSIONS: This is, to our knowledge, the first study showing that the TPH2 genotype may modulate FMD both directly and interactively with childhood trauma. Because both this polymorphism and early-life stress alter serotonin levels, our findings support a potential molecular mechanism modulating FMD phenotype.

Functional neurological symptom disorder (conversion disorder): A role for microglial-based plasticity mechanisms?

Functional Neurological Symptom Disorder (FND) is a relatively common neurological condition, accounting for approximately 3-6% of neurologist referrals. FND is considered a transient disorder of neuronal function, sometimes linked to physical trauma and psychological stress. Despite this, chronic disability is common, for example, around 40% of adults with motor FND have permanent disability. Building on current theoretical models, this paper proposes that microglial dysfunction could perpetuate functional changes within acute motor FND, thus providing a pathophysiological mechanism underlying the chronic stage of the motor FND phenotypes seen clinically. Core to our argument is microglia's dual role in modulating neuroimmunity and their control of synaptic plasticity, which places them at a pathophysiological nexus wherein coincident physical trauma and psychological stress could cause long-term change in neuronal networks without producing macroscopic structural abnormality. This model proposes a range of hypotheses that are testable with current technologies.

Serotonin Transporter Gene (SLC6A4) Polymorphism May Be Associated with Chinese Globus Pharyngeus and Its Antidepressant Effects.

BACKGROUND: Although globus pharyngeus is not rare in clinical practice, little is known about its associated gene polymorphism. We investigated the association between the SLC6A4 polymorphism and globus pharyngeus and its response to treatment with antidepressants. METHODS: A total of 84 patients were diagnosed with globus pharyngeus according to Rome III, and 160 healthy controls were genotyped for the SLC6A4 polymorphism using polymerase chain reaction amplification and agarose gel electrophoresis. All patients with globus were studied using high-resolution manometry pre-therapy. Globus patients were randomized into paroxetine or amitriptyline groups for a 6-week treatment and asked to complete the following pre- and post-therapy questionnaires: the Glasgow Edinburgh Throat Scale (GETS), the Pittsburgh Sleep Quality Index, and the Hamilton Rating Scale Anxiety/Depression. Treatment response was defined as a >50% reduction in the GETS scores. RESULTS: A significant difference was observed in the globus S/S genotype with anxiety compared to that without anxiety (χ2 = 14.579, p = 0.006). The L/S genotype showed a significant difference between high upper esophageal sphincter pressure (>104 mm Hg) and non-high upper esophageal sphincter pressure patients (χ2 = 14.433, p = 0.006). A significant association between the S/S genotype and the response to antidepressant treatment was also observed, while patients with sleep disorders or depression showed no association. CONCLUSION: A significant association was observed between the S/S genotype of the SLC6A4 polymorphism and globus pharyngeus, suggesting that SLC6A4 is a potential candidate gene involved in the pathogenesis of globus pharyngeus.

Biological underpinnings of psychogenic nonepileptic seizures: directions for future research.

Psychogenic nonepileptic seizures (PNES) are relatively common occurrences in epilepsy centers, but their pathophysiology is still poorly understood. Research that elucidates the pathophysiology of PNES, including their neurobiological basis and biomarkers, may have important clinical implications. The literature provides some evidence that genetic factors, intrinsic factors, and environmental factors probably play a significant role as the biological underpinnings of PNES. Researchers may be able to learn more about the pathophysiology of PNES by investigating the effects of each of these factors on functional and structural brain connectivity.

Cathecol-O-methyl transferase Val158Met genotype is not a risk factor for conversion disorder.

Alterations in catechol-O-methyltransferase (COMT) activity are involved in various types of neurological disorders. We examined a possible association between the COMT Val158Met polymorphism and conversion disorder in a study of 48 patients with conversion disorder and 48 control patients. In the conversion disorder group, 31 patients were Val/Met heterozygotes, 15 patients were Val/Val homozygotes and 2 patients were Met/Met homozygotes. In the control group, 32 patients were Val/Met heterozygotes and 16 patients were Val/Val homozygotes. There was no significant difference between the groups. We conclude that the COMT Val158Met genotype is quite common in Turkey and that it is not a risk factor for conversion disorder in the Turkish population.

Conversion disorder in women with the FMR1 premutation.

Women with fragile X mental retardation (FMR1) gene premutations (55-200 CGG repeats) were until recently believed to be unaffected. It is now known that up to 8% of older female FMR1 premutation carriers develop fragile X-associated tremor/ataxia syndrome (FXTAS). Female carriers may also develop primary ovarian insufficiency, thyroid disease, hypertension, seizures, peripheral neuropathy, and fibromyalgia. We present a 60-year-old woman with FMR1 premutation who had depression, anxiety, and conversion disorder with seizures. The FMR1 premutation with its associated mRNA toxicity is postulated as an underlying neurobiological mechanism of conversion symptoms, through functional and structural neural dysconnectivity.

Childhood trauma and dissociation in women with pseudoseizure-type conversion disorder.

BACKGROUND: Conversion disorder is thought to be associated with psychological factors because of the presence of conflict and other stressors prior to the condition. AIM: The aim of this study is to compare adult patients with pseudoseizure-type conversion disorder with healthy control group in terms of childhood trauma, dissociative disorder and family history of psychiatric disorders. METHOD: 56 female patients were admitted to the general psychiatry hospital outpatient clinic between January and July 2005. All patients had a negative experience about their families just before having the conversion. Diagnosis was made according to the DSM-IV criteria. A control group consisting of similar patient demographics of the disease group has been selected. Socio-demographic information forms, the Childhood Trauma Questionnaire (CTQ) and Dissociation Questionnaire (DIS-Q), were completed on the patients. RESULTS: CTQ total (t=12.12, P<0.001) and subscales, emotional abuse and emotional neglect (EA-EN) (t=12.74, P<0.001), physical abuse (PA) (t=10.05, P<0.001), and sexual abuse (SA) (t=7.69, P<0.001) were significantly high in the conversion group. DIS-Q mean points were statistically higher in the conversion group (t=11.05, P<0.001). CONCLUSIONS: The findings suggest that pseudoseizures (conversion disorder) should be included within dissociative disorders in DSM system as in ICD. It is usually uncommon for the patient to tell about childhood trauma without being specially questioned about this issue. Thus, it would be helpful to uncover these experiences by using related scales in conversion disorder patients.

Evolution of the human fear-circuitry and acute sociogenic pseudoneurological symptoms: the Neolithic balanced-polymorphism hypothesis.

In light of the increasing threat of large-scale massacres such as terrorism against non-combatants (civilians), more attention is warranted not only to posttraumatic stress disorder (PTSD) but also to acute sociogenic pseudoneurological ("conversion") symptoms, especially epidemic sociogenic symptoms. We posit that conversion disorders are etiologically related to specific evolutionary pressures (inescapable threats to life) in the late stage of the human environment of evolutionary adaptedness (EEA). Bracha et al. have recently argued that from the neuroevolutionary perspective, medically unexplained efferent vasovagal syncope and medically unexplained craniofacial musculoskeletal pain in young otherwise healthy individuals, may be taxonomized as stress and fear-circuitry disorders. In the present article, we extend neuroevolutionary perspectives to acute pseudoneurological sociogenic ("conversive") symptoms: psychogenic non-epileptic attacks ("pseudoseizures"), epidemic sociogenic disorders (DSM-IV-TR Epidemic "Hysteria"), conversive motor deficits (pseudo-paralysis and pseudo-cerebellar symptoms), and psychogenic blindness. We hypothesize that these perplexing pseudoneurological stress-triggered symptoms, which constitute psychopathology in extant humans, are traceable to allele-variant polymorphisms which spread during the Neolithic EEA. During Neolithic warfare, conversive symptoms may have increased the survival odds for some non-combatants by visually (i.e., "non-verbally") signaling to predatory conspecifics that one does not present a danger. This is consistent with the age and sex pattern of conversive disorders. Testable and falsifiable predictions are presented; e.g., at the genome-transcriptome interface, one of the major oligogenic loci involved in conversive spectrum disorders may carry a developmentally sensitive allele in a stable polymorphism (balanced polymorphism) in which the gene expression mechanism is gradually suppressed by pleiotropic androgens especially dehydroxyepiandrosterone sulfate (DHEA-S). Taxonomic implications for the much-needed rapprochement between the forthcoming Diagnostic and Statistical Manual for Mental Disorders, Fifth Edition (DSM-V) and the International Classification of Diseases (ICD) are discussed.

Mass family hysteria: a report from India.

The case of a 31-member family displaying mass hysteria in up to 10 members at one time is reported. The mass hysteria emerged in the context of the strong religious and cultural beliefs held by this closely knit family. The varied presentations included somatoform disorder, recurrent vomiting, conversion, dissociative and possession attacks. Two members had bipolar affective disorder that was recognized by the family as a 'medical' illness in contrast to other problems attributed to religiosity. The rarity of mass hysteria in a family and issues related to its medical and social management are highlighted.

[Familial clustering of conversion disorder]. / Familiär gehäuftes Auftreten einer Konversionsstörung.

This paper reports the result of a study conducted in a single family, in which members of three generations were affected by a conversion disorder. The phenotype and the age of onset were very similar in all the family members affected. The etiology is best understood in terms of a genetic condition and as the result of imitation and identification with an affected family member.

[Clinical genealogical research on hysterical psychopathy]. / Kliniko-genealogicheskoe issledovanie istericheskoi psikhopatii.

Thirty probands with the diagnosis of hysterical psychopathy were studied using clinical and genealogic techniques. An analysis of the obtained data made with the help of modern geneticomathematical methods identified a significant correlation between the type of psychopathy in probands and the corresponding type of personality disorders in the first-kin relatives of the probands. The calculated rate of heredity in relation to the risk of hysterical pathology manifestation (in the framework of quasi-permanent multifactor model) (79.9%) suggests that the formation of hysterical psychopathy is to a considerable degree determined by genetic mechanisms.

The validity of broadly defined hysteria and DSM-III conversion disorder: outcome, family history, and mortality.

Patients who fail to meet criteria for Briquet's syndrome (or somatization disorder) despite a chart diagnosis of hysteria have been shown previously to resemble patients with primary depression in terms of familial psychopathology. The same patients are shown here to have excess mortality which also resembles that seen in patients with primary depression. The isolation of patients meeting DSM-III criteria for conversion disorder yielded very similar results. Outcome and mortality data clearly separated conversion disorder from Briquet's syndrome patients; family history data suggested substantial diagnostic heterogeneity. Until the validity of this diagnosis is established, the label "conversion disorder" is recommended as a descriptive alternative to the label "undiagnosed."

The validity and significance of the clinical diagnosis of hysteria (Briquet's syndrome).

The author states that a valid diagnostic classification based on the medical model is a sine qua non for progress in psychiatric research and treatment and that such classification requires follow-up and family studies. To illustrate this point he reports on studies showing that hysteria, or Briquet's syndrome, is a valid clinical entity that follows a predictable course and clusters in certain families. He also reports that an association between hysteria and sociopathy has been demonstrated, suggesting that the two conditions may arise from sililar etiologic and pathogenetic factors.