Functional neurological disorder is a feminist issue.

Functional neurological disorder (FND) is a common and disabling disorder, often misunderstood by clinicians. Although viewed sceptically by some, FND is a diagnosis that can be made accurately, based on positive clinical signs, with clinical features that have remained stable for over 100 years. Despite some progress in the last decade, people with FND continue to suffer subtle and overt forms of discrimination by clinicians, researchers and the public. There is abundant evidence that disorders perceived as primarily affecting women are neglected in healthcare and medical research, and the course of FND mirrors this neglect. We outline the reasons why FND is a feminist issue, incorporating historical and contemporary clinical, research and social perspectives. We call for parity for FND in medical education, research and clinical service development so that people affected by FND can receive the care they need.

Psychopathology in adults with copy number variants.

BACKGROUND: Copy number variants (CNVs) have been associated with the risk of schizophrenia, autism and intellectual disability. However, little is known about their spectrum of psychopathology in adulthood. METHODS: We investigated the psychiatric phenotypes of adult CNV carriers and compared probands, who were ascertained through clinical genetics services, with carriers who were not. One hundred twenty-four adult participants (age 18-76), each bearing one of 15 rare CNVs, were recruited through a variety of sources including clinical genetics services, charities for carriers of genetic variants, and online advertising. A battery of psychiatric assessments was used to determine psychopathology. RESULTS: The frequencies of psychopathology were consistently higher for the CNV group compared to general population rates. We found particularly high rates of neurodevelopmental disorders (NDDs) (48%), mood disorders (42%), anxiety disorders (47%) and personality disorders (73%) as well as high rates of psychiatric multimorbidity (median number of diagnoses: 2 in non-probands, 3 in probands). NDDs [odds ratio (OR) = 4.67, 95% confidence interval (CI) 1.32-16.51; p = 0.017) and psychotic disorders (OR = 6.8, 95% CI 1.3-36.3; p = 0.025) occurred significantly more frequently in probands (N = 45; NDD: 39[87%]; psychosis: 8[18%]) than non-probands (N = 79; NDD: 20 [25%]; psychosis: 3[4%]). Participants also had somatic diagnoses pertaining to all organ systems, particularly conotruncal cardiac malformations (in individuals with 22q11.2 deletion syndrome specifically), musculoskeletal, immunological, and endocrine diseases. CONCLUSIONS: Adult CNV carriers had a markedly increased rate of anxiety and personality disorders not previously reported and high rates of psychiatric multimorbidity. Our findings support in-depth psychiatric and medical assessments of carriers of CNVs and the establishment of multidisciplinary clinical services.

Using induced pluripotent stem cells to investigate human neuronal phenotypes in 1q21.1 deletion and duplication syndrome.

Copy Number Variation (CNV) at the 1q21.1 locus is associated with a range of neurodevelopmental and psychiatric disorders in humans, including abnormalities in head size and motor deficits. Yet, the functional consequences of these CNVs (both deletion and duplication) on neuronal development remain unknown. To determine the impact of CNV at the 1q21.1 locus on neuronal development, we generated induced pluripotent stem cells from individuals harbouring 1q21.1 deletion or duplication and differentiated them into functional cortical neurons. We show that neurons with 1q21.1 deletion or duplication display reciprocal phenotype with respect to proliferation, differentiation potential, neuronal maturation, synaptic density and functional activity. Deletion of the 1q21.1 locus was also associated with an increased expression of lower cortical layer markers. This difference was conserved in the mouse model of 1q21.1 deletion, which displayed altered corticogenesis. Importantly, we show that neurons with 1q21.1 deletion and duplication are associated with differential expression of calcium channels and demonstrate that physiological deficits in neurons with 1q21.1 deletion or duplication can be pharmacologically modulated by targeting Ca2+ channel activity. These findings provide biological insight into the neuropathological mechanism underlying 1q21.1 associated brain disorder and indicate a potential target for therapeutic interventions.

When war came home: air-raid shock in World War I.

During World War I, civilians became a target of the war machine. Air raids transformed the lives of those not involved in active combat and blurred the lines between the home front and the war front. This paper argues that the experience of air raids in World War I was comparable to the combat stress at the Western Front. The author bases her argument on contemporary publications in medical journals, measures taken by British authorities to prevent air-raid shock, and contemporary case records. The narratives of air-raid shock - similarly to those of shell-shocked soldiers - reflect the feelings of terror and loss of control, and demonstrate the profound effect these experiences could have on individuals' mental health.

Triggers and Clinical Presentations of Functional Neurological Disorders: Lessons from World War 1.

INTRODUCTION: The psychological contribution to functional neurological and somatic symptom disorders is a major topic in current medical debate. OBJECTIVE: For an understanding of the processes leading to functional somatic symptoms, it is paramount to explore their relationship with stress and life events and to elucidate the contribution of cultural factors. METHODS: A total of 937 case records of civilian and military patients with functional somatic disorders treated in London during World War 1 were analysed. Group differences in symptom profiles and contemporaneous diagnoses were tested with χ2 tests. RESULTS: Paralyses and speech disturbances were significantly more common in soldiers (43.3 and 17.2% of cases) than in civilian male (28.1 and 6.5%) and female patients (32.4 and 7.5%), whereas female patients had the highest rates of pain (48.6%) and somatic symptoms (67%). Triggers were identified in around two-thirds of cases and included accidents, physical illness, and work stress, in addition to the combat experience of the soldier patients. The nature of the trigger influenced symptom expression, with acute (combat and noncombat) events being particularly prone to trigger loss of motor function. Symptom profiles showed a great deal of multi-morbidity and overlap, although some symptom clusters were more (motor and speech disturbance) or less common (pain and loss of energy) in soldiers than civilians. Triggering life events in civilians were similar to those reported by patients with somatic symptom disorders today, with an important role of physical factors. Patterns of multi-morbidity and symptom clusters also resembled those of modern cohorts. CONCLUSIONS: Analysis of historical records, illness trajectories, and treatments can enhance the understanding of the presentation, mechanisms, and course of functional neurological and related disorders and their consistency over time.

Chromosome 17q12 duplications: Further delineation of the range of psychiatric and clinical phenotypes.

Copy number variants at chromosome 17q12 have been associated with a spectrum of phenotypes. Deletions of 17q12 are well described and associated with maturity onset diabetes of the young type 5 (MODY5) and cystic renal disease (HNF1ß) as well as cognitive impairment and seizures. Duplication of 17q12 is emerging as a new genetic syndrome, associated with learning disability, seizures, and behavioral problems. The duplication is often inherited from an apparently unaffected parent. Here, we describe a three-generation family with multiple individuals carrying a17q12 microduplication with varying clinical features, consistent with variable penetrance. The proband who inherited a 1.8 Mb interstitial 17q12 duplication from his mother presented with developmental delay, behavioral problems, and mild dysmorphism. One of his sisters, his maternal uncle, and his maternal grandmother also carry the 17q12 microduplication. Clinical features of the carriers include renal problems, diabetes mellitus, learning difficulties, epilepsy and mental illness. Cognitive abilities range from normal function to moderate impairment (full-scale IQ range: 52-99). In light of recent reports of association of this locus with schizophrenia, we performed a detailed psychiatric assessment and confirmed that one family member has symptoms consistent with a diagnosis of schizophrenia and another has a prodromal syndrome with attenuated positive symptoms of psychosis. This report extends the clinical phenotype associated with the 17q12 microduplication and highlights the phenotypic variability.

Shell shock at Queen Square: Lewis Yealland 100 years on.

This article reviews the treatment of functional neurological symptoms during World War I by Lewis Yealland at the National Hospital for the Paralysed and Epileptic in London. Yealland was among the first doctors in Britain to incorporate electricity in the systematic treatment of shell shock. Our analysis is based on the original case records of his treatment of 196 soldiers with functional motor and sensory symptoms, functional seizures and somatoform disorders. Yealland's treatment approach integrated peripheral and central electrical stimulation with a variety of other--psychological and physical--interventions. A combination of electrical stimulation of affected muscles with suggestion of imminent improvement was the hallmark of his approach. Although his reported success rates were high, Yealland conducted no formal follow-up. Many of the principles of his treatment, including the emphasis on suggestion, demonstration of preserved function and the communication of a physiological illness model, are encountered in current therapeutic approaches to functional motor and sensory symptoms. Yealland has been attacked for his use of electrical stimulation and harsh disciplinary procedures in popular and scientific literature during and after World War I. This criticism reflects changing views on patient autonomy and the social role of doctors and directly impacts on current debates on ethical justification of suggestive therapies. We argue that knowledge of the historical approaches to diagnosis and management of functional neurological syndromes can inform both aetiological models and treatment concepts for these challenging conditions.

German battle casualties: the treatment of functional somatic disorders during World War I.

World War I witnessed the admission of large numbers of German soldiers with neurological symptoms for which there was no obvious organic cause. This posed a considerable challenge for the military and medical authorities and resulted in an active discussion on the etiology and treatment of these disorders. Current historiography is reliant on published physician accounts, and this represents the first study of treatment approaches based on original case notes. We analyzed patient records from two leading departments of academic psychiatry in Germany, those at Berlin and Jena, in conjunction with the contemporaneous medical literature. Treatment, which can be broadly classified into reward and punishment, suggestion, affective shock, cognitive learning, and physiological methods, was developed in the context of the emerging fields of animal learning and neurophysiology. A further innovative feature was the use of quantitative methods to assess outcomes. These measures showed good response rates, though most cured patients were not sent back to battle because of their presumed psychopathic constitution. While some treatments appear unnecessarily harsh from today's perspective and were also criticized by leading psychiatrists of the time, the concentration of effort and involvement of so many senior doctors led to the development of psychotherapeutic methods that were to influence the field of psychiatric therapy for decades to come.

The morbidity and mortality linked to melancholia: two cohorts compared, 1875-1924 and 1995-2005.

For over a century, melancholia has been linked to increased rates of morbidity and mortality. Data from two epidemiologically complete cohorts of patients presenting to mental health services in North Wales (1874-1924 and 1995-2005) have been used to look at links between diagnoses of melancholia in the first period and severe hospitalized depressive disorders today and other illnesses, and to calculate mortality rates. This is a study of the hospitalized illness rather than the natural illness, and the relationship between illness and hospitalization remains poorly understood. These data confirm that melancholia is associated with a substantial increase in the standardized mortality rate both formerly and today, stemming from a higher rate of deaths from tuberculosis in the historical sample and from suicide in the contemporary sample. The data do not link melancholia to cancer or cardiac disease. The comparison between outcomes for melancholia historically and severe mood disorder today argue favourably for the effectiveness of asylum care.

The neurological manifestations of trauma: lessons from World War I.

Changes in the clinical presentation of functional disorders and the influence of social and cultural factors can be investigated through the historical case notes from mental hospitals. World War I (WWI) was a potent trigger of functional disorders with neurological or psychiatric symptoms. We analysed 100 randomly selected case files of German servicemen admitted to the Department of Psychiatry of the Charité Medical School of Berlin University during WWI and classified them according to contemporaneous and retrospective modern diagnoses. We compared the clinical presentations with accounts in the German and British medical literature of the time. Most patients obtained the contemporaneous diagnosis of 'psychopathic constitution' or hysteria reflecting the general view of German psychiatrists that not the war but an individual predisposition was the basis for the development of symptoms. The clinical picture was dominated by pseudoneurological motor or sensory symptoms as well as pseudoseizures. Some soldiers relived combat experiences in dream-like dissociative states that partly resemble modern-day post-traumatic stress disorder. Most servicemen were classified as unfit for military service but very few of them were granted compensation. Severe functional disorders of a neurological character could develop even without traumatic exposure in combat, which is of interest for the current debate on triggers of stress disorders. The high incidence of pseudoseizures accords with the psychiatric literature of the time and contrasts with accounts of war-related disorders in Britain. The tendency of German psychiatrists not to send traumatised servicemen back to active duty also distinguished between German and British practice. Our data contribute to the debate on the changing patterns of human responses to traumatic experience and their historical and social context.

Brain activity supporting working memory accuracy in patients with paranoid schizophrenia: a functional magnetic resonance imaging study.

BACKGROUND: Dysfunctional working memory (WM) has been recognized as one of the most consistent deficits in schizophrenia. Studies that investigated the neural correlates of WM-related pathology by comparing patients with schizophrenia and control participants have produced controversial results, reporting task-related hyper- or hypoactivity in frontoparietal networks. METHOD: We addressed this question by comparing BOLD signals for accurate responses during a WM task for emotional faces between a homogeneous group of high-performing patients and a control group. RESULTS: Our results confirm previous findings of left prefrontal hyperactivity contrasted with hypoactivity in right prefrontal cortex to support WM performance. We also extend previous work by reporting enhanced activity in higher visual areas of patients during encoding and maintenance. CONCLUSION: Our findings and those of the literature can be integrated into a model, where preserved visual cognition in high-functioning patients with hypofrontality is explained by activation of contralateral homologue areas combined with enhanced recruitment of sensory areas.

The psychiatric phenotypes of 1q21 distal deletion and duplication.

Copy number variants are amongst the most highly penetrant risk factors for psychopathology and neurodevelopmental deficits, but little information about the detailed clinical phenotype associated with particular variants is available. We present the largest study of the microdeletion and -duplication at the distal 1q21 locus, which has been associated with schizophrenia and intellectual disability, in order to investigate the range of psychiatric phenotypes. Clinical and cognitive data from 68 deletion and 55 duplication carriers were analysed with logistic regression analysis to compare frequencies of mental disorders between carrier groups and controls, and linear mixed models to compare quantitative phenotypes. Both children and adults with copy number variants at 1q21 had high frequencies of psychopathology. In the children, neurodevelopmental disorders were most prominent (56% for deletion, 68% for duplication carriers). Adults had increased prevalence of mood (35% for deletion [OR = 6.6 (95% CI: 1.4-40.1)], 55% for duplication carriers [8.3 (1.4-55.5)]) and anxiety disorders (24% [1.8 (0.4-8.4)] and 55% [10.0 (1.9-71.2)]). The adult group, which included mainly genetically affected parents of probands, had an IQ in the normal range. These results confirm high prevalence of neurodevelopmental disorders associated with CNVs at 1q21 but also reveal high prevalence of mood and anxiety disorders in a high-functioning adult group with these CNVs. Because carriers of neurodevelopmental CNVs who show relevant psychopathology but no major cognitive impairment are not currently routinely receiving clinical genetic services widening of genetic testing in psychiatry may be considered.

Cognitive deficits in childhood, adolescence and adulthood in 22q11.2 deletion syndrome and association with psychopathology.

22q11.2 Deletion Syndrome (22q11.2DS) is associated with high risk of psychiatric disorders and cognitive impairment. It remains unclear to what extent key cognitive skills are associated with psychopathology, and whether cognition is stable over time in 22q11.2DS. 236 children, adolescents and adults with 22q11.2DS and 106 typically developing controls were recruited from three sites across Europe. Measures of IQ, processing speed, sustained attention, spatial working memory and psychiatric assessments were completed. Cognitive performance in individuals was calculated relative to controls in different age groups (children (6-9 years), adolescents (10-17 years), adults (18+ years)). Individuals with 22q11.2DS exhibited cognitive impairment and higher rates of psychiatric disorders compared to typically developing controls. Presence of Autism Spectrum Disorder symptoms was associated with greater deficits in processing speed, sustained attention and working memory in adolescents but not children. Attention deficit hyperactivity disorder in children and adolescents and psychotic disorder in adulthood was associated with sustained attention impairment. Processing speed and working memory were more impaired in children and adults with 22q11.2DS respectively, whereas the deficit in sustained attention was present from childhood and remained static over developmental stages. Psychopathology was associated with cognitive profile of individuals with 22q11.2DS in an age-specific and domain-specific manner. Furthermore, magnitude of cognitive impairment differed by developmental stage in 22q11.2DS and the pattern differed by domain.

Electrophysiological network alterations in adults with copy number variants associated with high neurodevelopmental risk.

Rare copy number variants associated with increased risk for neurodevelopmental and psychiatric disorders (referred to as ND-CNVs) are characterized by heterogeneous phenotypes thought to share a considerable degree of overlap. Altered neural integration has often been linked to psychopathology and is a candidate marker for potential convergent mechanisms through which ND-CNVs modify risk; however, the rarity of ND-CNVs means that few studies have assessed their neural correlates. Here, we used magnetoencephalography (MEG) to investigate resting-state oscillatory connectivity in a cohort of 42 adults with ND-CNVs, including deletions or duplications at 22q11.2, 15q11.2, 15q13.3, 16p11.2, 17q12, 1q21.1, 3q29, and 2p16.3, and 42 controls. We observed decreased connectivity between occipital, temporal, and parietal areas in participants with ND-CNVs. This pattern was common across genotypes and not exclusively characteristic of 22q11.2 deletions, which were present in a third of our cohort. Furthermore, a data-driven graph theory framework enabled us to successfully distinguish participants with ND-CNVs from unaffected controls using differences in node centrality and network segregation. Together, our results point to alterations in electrophysiological connectivity as a putative common mechanism through which genetic factors confer increased risk for neurodevelopmental and psychiatric disorders.

Genetic risk for schizophrenia and developmental delay is associated with shape and microstructure of midline white-matter structures.

Genomic copy number variants (CNVs) are amongst the most highly penetrant genetic risk factors for neuropsychiatric disorders. The scarcity of carriers of individual CNVs and their phenotypical heterogeneity limits investigations of the associated neural mechanisms and endophenotypes. We applied a novel design based on CNV penetrance for schizophrenia (Sz) and developmental delay (DD) that allows us to identify structural sequelae that are most relevant to neuropsychiatric disorders. Our focus on brain structural abnormalities was based on the hypothesis that convergent mechanisms contributing to neurodevelopmental disorders would likely manifest in the macro- and microstructure of white matter and cortical and subcortical grey matter. Twenty one adult participants carrying neuropsychiatric risk CNVs (including those located at 22q11.2, 15q11.2, 1q21.1, 16p11.2 and 17q12) and 15 age- and gender-matched controls underwent T1-weighted structural, diffusion and relaxometry MRI. The macro- and microstructural properties of the cingulum bundles were associated with penetrance for both developmental delay and schizophrenia, in particular curvature along the anterior-posterior axis (Sz: pcorr = 0.026; DD: pcorr = 0.035) and intracellular volume fraction (Sz: pcorr = 0.019; DD: pcorr = 0.064). Further principal component analysis showed alterations in the interrelationships between the volumes of several midline white-matter structures (Sz: pcorr = 0.055; DD: pcorr = 0.027). In particular, the ratio of volumes in the splenium and body of the corpus callosum was significantly associated with both penetrance scores (Sz: p = 0.037; DD; p = 0.006). Our results are consistent with the notion that a significant alteration in developmental trajectories of midline white-matter structures constitutes a common neurodevelopmental aberration contributing to risk for schizophrenia and intellectual disability.

Correction: Psychiatric disorders in children with 16p11.2 deletion and duplication.

One of the co-authors, Marianne B.M. van den Bree has had her name incorrectly abbreviated by citation manager. It was stated as "Bree MBMVD14", but has been updated to "van den Bree, M.B.M." in the HTML, PDF, and XML versions of this article.

Psychiatric disorders in children with 16p11.2 deletion and duplication.

Deletion and duplication of 16p11.2 (BP4-BP5) have been associated with an increased risk of intellectual disability and psychiatric disorder. This is the first study to compare the frequency of a broad spectrum of psychiatric disorders in children with 16p11.2 deletion and duplication. We aimed to evaluate (1) the nature and prevalence of psychopathology associated with copy number variation (CNV) in children with 16p11.2 by comparing deletion and duplication carriers with family controls; (2) whether deletion and duplication carriers differ in frequency of psychopathology. 217 deletion carriers, 77 deletion family controls, 114 duplication carriers, and 32 duplication family controls participated in the study. Measures included standardized research diagnostic instruments. Deletion carriers had a higher frequency of any psychiatric disorder (OR = 8.9, p < 0.001), attention deficit hyperactivity disorder (ADHD) (OR = 4.0, p = 0.01), and autism spectrum disorder (ASD) (OR = 39.9, p = 0.01) than controls. Duplication carriers had a higher frequency of any psychiatric diagnosis (OR = 5.3, p = 0.01) and ADHD (OR = 7.0, p = 0.02) than controls. The prevalence of ASD in child carriers of deletions and duplications was similar (22% versus 26%). Comparison of the two CNV groups indicated a higher frequency of ADHD in children with the duplication than deletion (OR = 2.7, p = 0.04) as well as a higher frequency of overall psychiatric disorders (OR = 2.8, p = 0.02) and psychotic symptoms (OR = 4.7, p = 0.02). However, no differences between deletion and duplications carriers in the prevalence of ASD were found. Both deletion and duplication are associated with an increased risk of psychiatric disorder, supporting the importance of early recognition, diagnosis, and intervention in these groups.

The relationship between the First World War and neurology: 100 years of "Shell Shock".

The First World War was a global war, beginning on 28 July 1914, until 11 November 1918. Soon after the beginning of the war, there was an "epidemic" of neurological conversion symptoms. Soldiers on both sides started to present in large numbers with neurological symptoms, such as dizziness, tremor, paraplegia, tinnitus, amnesia, weakness, headache and mutism of psychosomatic origin. This condition was known as shell shock, or "war neurosis". Because medically unexplained symptoms remain a major challenge, and considering the close relationship of symptoms described in shell shock with clinical neurology, we should study their history in order to improve future care.