Stefanie C. Linden

Real-Time Self-Regulation of Emotion Networks in Patients with Depression

Many patients show no or incomplete responses to current pharmacological or psychological therapies for depression. Here we explored the feasibility of a new brain self-regulation technique that integrates psychological and neurobiological approaches through neurofeedback with functional magnetic resonance imaging (fMRI). In a proof-of-concept study, eight patients with depression learned to upregulate brain areas involved in the generation of positive emotions (such as the ventrolateral prefrontal cortex (VLPFC) and insula) during four neurofeedback sessions. Their clinical symptoms, as assessed with the 17-item Hamilton Rating Scale for Depression (HDRS), improved significantly. A control group that underwent a training procedure with the same cognitive strategies but without neurofeedback did not improve clinically. Randomised blinded clinical trials are now needed to exclude possible placebo effects and to determine whether fMRI-based neurofeedback might become a useful adjunct to current therapies for depression.

Mortality in schizophrenia and related psychoses: data from two cohorts, 1875–1924 and 1994–2010

Objective To investigate death rates in schizophrenia and related psychoses. Design Data from two epidemiologically complete cohorts of patients presenting for the first time to mental health services in North Wales for whom there are at least 1, and up to 10-year follow-up data have been used to calculate survival rates and standardised death rates for schizophrenia and related psychoses. Setting The North Wales Asylum Denbigh (archived patient case notes) and the North West Wales District General Hospital psychiatric unit. Population Cohort 1: The North Wales Asylum Denbigh (archived patient case notes). Of 3168 patients admitted to the North Wales Asylum Denbigh 1875–1924, 1074 had a schizophrenic or related psychosis. Cohort 2: Patients admitted between 1994 and 2010 to the North West Wales District General Hospital psychiatric unit, of whom 355 had first admissions for schizophrenia or related psychoses. Results We found a 10-year survival probability of 75% in the historical cohort and a 90% survival probability in the contemporary cohort with a fourfold increase in standardised death rates in schizophrenia and related psychoses in both historical and contemporary periods. Suicide is the commonest cause of death in schizophrenia in the contemporary period (SMR 35), while tuberculosis was the commonest cause historically (SMR 9). In the contemporary data, deaths from cardiovascular causes arise in the elderly and deaths from suicide in the young. Conclusions Contemporary death rates in schizophrenia and related psychoses are high but there are particular hazards and windows of risk that enable interventions. The data point to possible interventions in the incident year of treatment that could give patients with schizophrenia a normal life expectancy.

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.

Sad benefit in face working memory: An emotional bias of melancholic depression

Emotion biases feature prominently in cognitive theories of depression and are a focus of psychological interventions. However, there is presently no stable neurocognitive marker of altered emotion–cognition interactions in depression. One reason may be the heterogeneity of major depressive disorder. Our aim in the present study was to find an emotional bias that differentiates patients with melancholic depression from controls, and patients with melancholic from those with non-melancholic depression. We used a working memory paradigm for emotional faces, where two faces with angry, happy, neutral, sad or fearful expression had to be retained over one second. Twenty patients with melancholic depression, 20 age-, education- and gender-matched control participants and 20 patients with non-melancholic depression participated in the study. We analysed performance on the working memory task using signal detection measures. We found an interaction between group and emotion on working memory performance that was driven by the higher performance for sad faces compared to other categories in the melancholic group. We computed a measure of “sad benefit”, which distinguished melancholic and non-melancholic patients with good sensitivity and specificity. However, replication studies and formal discriminant analysis will be needed in order to assess whether emotion bias in working memory may become a useful diagnostic tool to distinguish these two syndromes.

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.

The incidence of admissions for schizophrenia and related psychoses in two cohorts: 1875–1924 and 1994–2010

Objective To investigate changes in incidence of admissions for schizophrenia and related non-affective psychoses in North Wales. Design Data from two epidemiologically complete cohorts of patients presenting for the first time to mental health services in North Wales between 1875–1924 and 1994–2010 are used in this study to map the incidence of hospital admissions for schizophrenia and non-affective psychoses. Setting The North Wales Asylum Denbigh (archived patient case notes) and the North West Wales District General Hospital psychiatric unit. Population 3168 patients admitted to the North Wales Asylum Denbigh between 1875 and 1924 and 355 patients admitted to the District General Hospital psychiatric unit between 1994 and 2010. Results There was an increasing admission incidence for schizophrenia between 1875 and 1900, a higher admission rate in the 1990s for men, followed by a drop in rates of admission for both genders since 2006. Admission incidences switch from parity between the sexes in the historical period to a doubling of the admission rates for men compared with women in the modern period. This admission pattern differs from the admission patterns for affective psychoses or organic disorders. Conclusion There have been changes in the incidence of admissions for schizophrenia in North Wales.

'Shell shock' Revisited: An Examination of the Case Records of the National Hospital in London

During the First World War the National Hospital for the Paralysed and Epileptic, in Queen Square, London, then Britain’s leading centre for neurology, took a key role in the treatment and understanding of shell shock. This paper explores the case notes of all 462 servicemen who were admitted with functional neurological disorders between 1914 and 1919. Many of these were severe or chronic cases referred to the National Hospital because of its acknowledged expertise and the resources it could call upon. Biographical data was collected together with accounts of the patient’s military experience, his symptoms, diagnostic interpretations and treatment outcomes. Analysis of the notes showed that motor syndromes (loss of function or hyperkinesias), often combined with somato-sensory loss, were common presentations. Anxiety and depression as well as vegetative symptoms such as sweating, dizziness and palpitations were also prevalent among this patient population. Conversely, psychogenic seizures were reported much less frequently than in comparable accounts from German tertiary referral centres. As the war unfolded the number of physicians who believed that shell shock was primarily an organic disorder fell as research failed to find a pathological basis for its symptoms. However, little agreement existed among the Queen Square doctors about the fundamental nature of the disorder and it was increasingly categorised as functional disorder or hysteria.

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.

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 and developmental delay 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. 21 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 quantitative T1 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 mid-line 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 mid-line white-matter structures constitutes a common neurodevelopmental aberration contributing to risk for schizophrenia and intellectual disability.

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 (HNF1β) 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.