Psychiatric complications in Graves' disease.

Background: Mood disorders are common in Graves' disease despite treatment. The pathogenic mechanisms involved are unknown and so is whether previous psychiatric disease influences these symptoms. Methods: This is a longitudinal study conducted in Sweden on 65 women with newly diagnosed Graves' disease and 65 matched controls. Participants were examined during hyperthyroidism and after 15 months of treatment. Examinations included blood sampling, and psychiatric testing with the Comprehensive Psychopathological Rating Scale for Affective Syndromes and the Structured Clinical Interview for DSM-IV - Axis I Disorders. We also performed two analyses of a national population-based registry to determine previous psychiatric diagnoses and previous prescriptions of psychoactive drugs in (i) all patients we asked to participate and (ii) all Swedish women given a diagnosis of hyperthyroidism during 2013-2018, comparing them to matched controls. Results: There was no increased previous psychiatric comorbidity in Graves' patients compared to controls. There was no higher prevalence of psychiatric diagnoses and prescriptions of psychoactive drugs between (i) included GD patients compared to those who declined participation and (ii) women with a hyperthyroidism diagnosis in 5 years prior to their diagnosis, compared to matched controls. Depression scores and anxiety scores were higher in patients compared to controls both during hyperthyroidism (depression (median (IQR): 7.5 (5.0-9.5) vs 1.0 (0.5-2.5) P < 0.001), anxiety: 7.7 (5.0-11) vs 2.5 (1.0-4.0) P < 0.001) and after treatment (depression: 2.5 (1.5-5.0) vs 1.5 (0.5-3.5) P < 0.05), anxiety: 4.0 (2.5-7.5) vs 3.0 (1.5-5.0) P < 0.05). Patients with a previous psychiatric condition, mild eye symptoms, and a younger age had more anxiety at 15 months compared to patients without these symptoms and a higher age (all p<0.05). Conclusion: Graves' disease affects patients' mood despite treatment. A previous psychiatric condition, mild eye symptoms, and a younger age increase the vulnerability for long-lasting symptoms and require specific attention.

The relationship between mental fatigue, depression, and cognition in Graves' disease.

Objective: Mental fatigue, depression, anxiety, and cognitive complaints are common in Graves' disease (GD). Our aims were to assess the relationship between these variables in patients with GD during both hyperthyroidism and a long stable euthyroidism. Methods: A prospective longitudinal case-control study where 65 premenopausal women diagnosed with GD and 65 matched controls were assessed twice with 15 months in between. The first visit for patients was in overt hyperthyroidism and the second after treatment. Results: During the hyperthyroid phase, mental fatigue, depression, and anxiety were significantly increased for GD patients compared to controls (all P < 0.001). Among GD patients, 89% reported mental fatigue and among controls 14%. No difference in cognitive tests was found. After 15 months, significant improvements for GD patients after treatment were found for the items of mental fatigue, depression, and anxiety (all P < 0.001), but these were unchanged in controls. GD patients reported residual mental fatigue (38%), 23% without depression, and 15% mental fatigue combined with depression. Self-reported cognitive complaints were pronounced while cognitive tests did not reveal any deficiencies. Conclusion: Mental fatigue and emotional distress are common in the hyperthyroid phase. These improve with treatment but are still more common in GD patients after 15 months of therapy than in controls. The residual mental fatigue is shown to be a phenomenon distinct from depression in this study. This indicates the importance of assessing mental fatigue in GD patients and underlines the need for rehabilitation and healthcare support as fatigue will have consequences for work ability.

A Longitudinal Study of Medial Temporal Lobe Volumes in Graves Disease.

CONTEXT: Neuropsychiatric symptoms are common features of Graves disease (GD) in hyperthyroidism and after treatment. The mechanism behind these symptoms is unknown, but reduced hippocampal volumes have been observed in association with increased thyroid hormone levels. OBJECTIVE: This work aimed at investigating GD influence on regional medial temporal lobe (MTL) volumes. METHODS: Sixty-two women with newly diagnosed GD underwent assessment including magnetic resonance (MR) imaging in hyperthyroidism and 48 of them were followed up after a mean of 16.4 ±â€…4.2 SD months of treatment. Matched thyroid-healthy controls were also assessed twice at a 15-month interval. MR images were automatically segmented using multiatlas propagation with enhanced registration. Regional medial temporal lobe (MTL) volumes for amygdalae and hippocampi were compared with clinical data and data from symptom questionnaires and neuropsychological tests. RESULTS: Patients had smaller MTL regions than controls at inclusion. At follow-up, all 4 MTL regions had increased volumes and only the volume of the left amygdala remained reduced compared to controls. There were significant correlations between the level of thyrotropin receptor antibodies (TRAb) and MTL volumes at inclusion and also between the longitudinal difference in the levels of free 3,5,3'-triiodothyronine and TRAb and the difference in MTL volumes. There were no significant correlations between symptoms or test scores and any of the 4 MTL volumes. CONCLUSION: Dynamic alterations in the amygdalae and hippocampi in GD reflect a previously unknown level of brain involvement both in the hyperthyroid state of the condition and after treatment. The clinical significance, as well as the mechanisms behind these novel findings, warrant further study of the neurological consequences of GD.

Structural brain changes in hyperthyroid Graves' disease: protocol for an ongoing longitudinal, case-controlled study in Göteborg, Sweden-the CogThy project.

INTRODUCTION: Cognitive impairment and reduced well-being are common manifestations of Graves' disease (GD). These symptoms are not only prevalent during the active phase of the disease but also often prevail for a long time after hyperthyroidism is considered cured. The pathogenic mechanisms involved in these brain-derived symptoms are currently unknown. The overall aim of the CogThy study is to identify the mechanism behind cognitive impairment to be able to recognise GD patients at risk. METHODS AND ANALYSIS: The study is a longitudinal, single-centre, case-controlled study conducted in Göteborg, Sweden on premenopausal women with newly diagnosed GD. The subjects are examined: at referral, at inclusion and then every 3.25 months until 15 months. Examinations include: laboratory measurements; eye evaluation; neuropsychiatric and neuropsychological testing; structural MRI of the whole brain, orbits and medial temporal lobe structures; functional near-infrared spectroscopy of the cerebral prefrontal cortex and self-assessed quality of life questionnaires. The primary outcome measure is the change in medial temporal lobe structure volume. Secondary outcome measures include neuropsychological, neuropsychiatric, hormonal and autoantibody variables. The study opened for inclusion in September 2012 and close for inclusion in October 2019. It will provide novel information on the effect of GD on medial temporal lobe structures and cerebral cortex functionality as well as whether these changes are associated with cognitive and affective impairment, hormonal levels and/or autoantibody levels. It should lead to a broader understanding of the underlying pathogenesis and future treatment perspectives. ETHICS AND DISSEMINATION: The study has been reviewed and approved by the Regional Ethical Review Board in Göteborg, Sweden. The results will be actively disseminated through peer-reviewed journals, national and international conference presentations and among patient organisations after an appropriate embargo time. TRIAL REGISTRATION NUMBER: 44321 at the public project database for research and development in Västra Götaland County, Sweden (https://www.researchweb.org/is/vgr/project/44321).

Role of iodine-containing multivitamins during pregnancy for children's brain function: protocol of an ongoing randomised controlled trial: the SWIDDICH study.

INTRODUCTION: Iodine is essential for normal brain development. Moderate and severe fetal iodine deficiency results in substantial to serious developmental delay in children. Mild iodine deficiency in pregnancy is associated with neurodevelopmental deficits in the offspring, but evidence from randomised trials is lacking. The aim of the Swedish Iodine in Pregnancy and Development in Children study is to determine the effect of daily supplementation with 150 µg iodine during pregnancy on the offspring's neuropsychological development up to 14 years of age. METHODS AND ANALYSIS: Thyroid healthy pregnant women (n=1275: age range 18-40 years) at ≤12 weeks gestation will be randomly assigned to receive multivitamin supplements containing 150 µg iodine or non-iodine-containing multivitamin daily throughout pregnancy. As a primary outcome, IQ will be measured in the offspring at 7 years (Wechsler Intelligence Scale for Children-V). As secondary outcomes, IQ will be measured at 3.5 and 14 years, psychomotor development at 18 months and 7 years, and behaviour at 3.5, 7 and 14 years. Iodine status (urinary iodine concentration) will be measured during pregnancy and in the offspring at 3.5, 7 and 14 years. Thyroid function (thyroid hormones, thyroglobulin), and deiodinase type 2 polymorphisms will be measured during pregnancy and in the offspring at 7 and 14 years. Structural MRI or other relevant structural or functional brain imaging procedures will be performed in a subgroup of children at 7 and 14 years. Background and socioeconomic information will be collected at all follow-up times. ETHICS AND DISSEMINATION: This study is approved by the Ethics Committee in Göteborg, Sweden (Diary numbers: 431-12 approved 18 June 2012 (pregnancy part) and 1089-16 approved 8 February 2017 (children follow-up)). According to Swedish regulations, dietary supplements are governed by the National Food Agency and not by the Medical Product Agency. Therefore, there is no requirement for a monitoring committee and the National Food Agency does not perform any audits of trial conduct. The trial will be conducted in accordance with the Declaration of Helsinki. The participating sites will be contacted regarding important protocol changes, both orally and in writing, and the trial registry database will be updated accordingly. Study results will be presented at relevant conferences, and submitted to peer-reviewed journals with open access in the fields of endocrinology, paediatrics and nutrition. After the appropriate embargo period, the results will be communicated to participants, healthcare professionals at the maternal healthcare centres, the public and other relevant groups, such as the national guideline group for thyroid and pregnancy and the National Food Agency. TRIAL REGISTRATION NUMBER: NCT02378246; Pre-results.

Delineation of two intracranial areas and the perpendicular intracranial width is sufficient for intracranial volume estimation.

OBJECTIVES: The aim of the present study is to determine if the delineation of one or two optimally chosen intracranial areas (ICA) is enough to achieve adequate estimates of intracranial volume (ICV) in magnetic resonance imaging. METHODS: The correlations of 62 fully delineated ICVs with four types of ICV estimates were calculated. The estimate types were: (1) a single midsagittal ICA, (2) single ICA multiplied by the intracranial width perpendicular to the ICA, (3) sum of two ICAs multiplied by the perpendicular intracranial width and (4) shape-preserving piecewise cubic interpolation using two ICAs. For methods 2-4, the fully delineated ICVs were randomly separated into an evaluation and a validation set of equal size. Method 1 was validated against all of the fully delineated ICVs. RESULTS: Estimates from method 1 had a Pearson correlation of 0.904 with fully delineated ICV. For method 2, the correlation was 0.986 when delineating the sagittal ICA at 31% of the sagittal intracranial width. For methods 3 and 4, the correlations were both 0.997 when delineating the sagittal ICAs at 17.5 and 64% and at 12 and 64% respectively. CONCLUSIONS: Delineation of two specific intracranial areas is sufficient for intracranial volume estimation. MAIN MESSAGES: • Delineation of two specific intracranial areas is sufficient for intracranial volume estimation. • The estimates had a Pearson correlation of 0.997 with intracranial volume. • The estimation should take no more than 5 min.

Effects of a Curricular Physical Activity Intervention on Children's School Performance, Wellness, and Brain Development.

BACKGROUND: Physical activity and structural differences in the hippocampus have been linked to educational outcome. We investigated whether a curriculum-based physical activity intervention correlates positively with children's academic achievement, psychological well-being, health-related quality of life (HRQoL), fitness, and structural development of the brain. METHODS: The study had a quasi-experimental design and a control group. National test results were gathered from 545 students, 122 in the intervention school, and 423 in 3 control schools. HRQoL and socioemotional data were collected with child and proxy versions of KIDSCREEN and the Strength and Difficulties Questionnaire. Overall, 79 students in grades 5 and 6 were recruited for an in-depth study, consisting of a submaximal oxygen consumption test and magnetic resonance imaging of the brain. HRQoL and socioemotional data were collected from 349 students (65%), 182 (52%) in the intervention school, and 167 (48%) in one of the control schools. RESULTS: Girls attending the intervention school were more likely to pass national tests in Swedish (odds ratio 5.7) and Mathematics (odds ratio 3.2). The fourth to sixth graders in the intervention school reported lower levels of conduct problems (p < .05), and the girls were also less likely to report hyperactivity (p < .05). Girls reported higher levels of emotional problems (p < .05) than boys. Boys in the intervention group had significantly higher levels of estimated maximal oxygen uptake (p < .05) than controls. No difference in hippocampal structure was seen. CONCLUSIONS: Curriculum-based physical activity in school may improve the academic achievement and psychological health of children, particularly for girls.

Valid and efficient manual estimates of intracranial volume from magnetic resonance images.

BACKGROUND: Manual segmentations of the whole intracranial vault in high-resolution magnetic resonance images are often regarded as very time-consuming. Therefore it is common to only segment a few linearly spaced intracranial areas to estimate the whole volume. The purpose of the present study was to evaluate how the validity of intracranial volume estimates is affected by the chosen interpolation method, orientation of the intracranial areas and the linear spacing between them. METHODS: Intracranial volumes were manually segmented on 62 participants from the Gothenburg MCI study using 1.5 T, T1-weighted magnetic resonance images. Estimates of the intracranial volumes were then derived using subsamples of linearly spaced coronal, sagittal or transversal intracranial areas from the same volumes. The subsamples of intracranial areas were interpolated into volume estimates by three different interpolation methods. The linear spacing between the intracranial areas ranged from 2 to 50 mm and the validity of the estimates was determined by comparison with the entire intracranial volumes. RESULTS: A progressive decrease in intra-class correlation and an increase in percentage error could be seen with increased linear spacing between intracranial areas. With small linear spacing (≤15 mm), orientation of the intracranial areas and interpolation method had negligible effects on the validity. With larger linear spacing, the best validity was achieved using cubic spline interpolation with either coronal or sagittal intracranial areas. Even at a linear spacing of 50 mm, cubic spline interpolation on either coronal or sagittal intracranial areas had a mean absolute agreement intra-class correlation with the entire intracranial volumes above 0.97. CONCLUSION: Cubic spline interpolation in combination with linearly spaced sagittal or coronal intracranial areas overall resulted in the most valid and robust estimates of intracranial volume. Using this method, valid ICV estimates could be obtained in less than five minutes per patient.

Erratum: Music structure determines heart rate variability of singers.

[This corrects the article on p. 334 in vol. 4, PMID: 23847555.].

Music structure determines heart rate variability of singers.

Choir singing is known to promote wellbeing. One reason for this may be that singing demands a slower than normal respiration, which may in turn affect heart activity. Coupling of heart rate variability (HRV) to respiration is called Respiratory sinus arrhythmia (RSA). This coupling has a subjective as well as a biologically soothing effect, and it is beneficial for cardiovascular function. RSA is seen to be more marked during slow-paced breathing and at lower respiration rates (0.1 Hz and below). In this study, we investigate how singing, which is a form of guided breathing, affects HRV and RSA. The study comprises a group of healthy 18 year olds of mixed gender. The subjects are asked to; (1) hum a single tone and breathe whenever they need to; (2) sing a hymn with free, unguided breathing; and (3) sing a slow mantra and breathe solely between phrases. Heart rate (HR) is measured continuously during the study. The study design makes it possible to compare above three levels of song structure. In a separate case study, we examine five individuals performing singing tasks (1-3). We collect data with more advanced equipment, simultaneously recording HR, respiration, skin conductance and finger temperature. We show how song structure, respiration and HR are connected. Unison singing of regular song structures makes the hearts of the singers accelerate and decelerate simultaneously. Implications concerning the effect on wellbeing and health are discussed as well as the question how this inner entrainment may affect perception and behavior.

A combination of neuropsychological, neuroimaging, and cerebrospinal fluid markers predicts conversion from mild cognitive impairment to dementia.

BACKGROUND: Mild cognitive impairment (MCI) is a condition with increased risk for further cognitive decline. A considerable challenge lies in predicting which patients will eventually convert to dementia. OBJECTIVE: To study prediction of dementia in MCI using neuropsychological tests, commonly used cerebrospinal fluid (CSF) biomarkers, and hippocampal volume. METHODS: Twenty-one MCI patients converting to dementia, 21 stable MCI patients, and 26 controls were included in the study with a follow-up time of two years. The study participants underwent comprehensive examinations at inclusion: a neuropsychological assessment comprising 20 tests, MRI scanning with subsequent hippocampal volumetry, and CSF analyses of T-tau, P-tau, and Aß42. RESULTS: Neuropsychological tests, hippocampal volume, and the CSF markers Aß42, P-tau, and T-tau all predicted conversion from MCI to dementia. A combination of all classes of markers was the most successful at predicting dementia (AUC 0.96) with a memory test (RAVLT) as the best individual predictor (AUC 0.93). Similar findings are reported for the prediction of Alzheimer's disease. CONCLUSION: Neuropsychological tests were the best individual predictors of dementia. A combination of markers improved the predictive ability with the combination of neuropsychological tests, CSF, and hippocampal volume as the best predictors of dementia.

White Matter Lesion Assessment in Patients with Cognitive Impairment and Healthy Controls: Reliability Comparisons between Visual Rating, a Manual, and an Automatic Volumetrical MRI Method-The Gothenburg MCI Study.

Age-related white matter lesions (WML) are a risk factor for stroke, cognitive decline, and dementia. Different requirements are imposed on methods for the assessment of WML in clinical settings and for research purposes, but reliability analysis is of major importance. In this study, WML assessment with three different methods was evaluated. In the Gothenburg mild cognitive impairment study, MRI scans from 152 participants were used to assess WML with the Fazekas visual rating scale on T2 images, a manual volumetric method on FLAIR images, and FreeSurfer volumetry on T1 images. Reliability was acceptable for all three methods. For low WML volumes (2/3 of the patients), reliability was overall lower and nonsignificant for the manual volumetric method. Unreliability in the assessment of patients with low WML with manual volumetry may mainly be due to intensity variation in the FLAIR sequence used; hence, intensity standardization and normalization methods must be used for more accurate assessments. The FreeSurfer segmentations resulted in smaller WML volumes than the volumes acquired with the manual method and showed deviations from visible hypointensities in the T1 images, which quite likely reduces validity.

Hippocampal volumes in patients exposed to low-dose radiation to the basal brain. A case-control study in long-term survivors from cancer in the head and neck region.

BACKGROUND: An earlier study from our group of long time survivors of head and neck cancer who had received a low radiation dose to the hypothalamic-pituitary region, with no signs of recurrence or pituitary dysfunction, had their quality of life (QoL) compromised as compared with matched healthy controls. Hippocampal changes have been shown to accompany several psychiatric conditions and the aim of the present study was to test whether the patients' lowered QoL was coupled to a reduction in hippocampal volume. METHODS: Patients (11 men and 4 women, age 31-65) treated for head and neck cancer 4-10 years earlier and with no sign of recurrence or pituitary dysfunction, and 15 matched controls were included. The estimated radiation doses to the basal brain including the hippocampus (1.5 - 9.3 Gy) had been calculated in the earlier study. The hippocampal volumetry was done on coronal sections from a 1.5 T MRI scanner. Measurements were done by two independent raters, blinded to patients and controls, using a custom method for computer assisted manual segmentation. The volumes were normalized for intracranial volume which was also measured manually. The paired t test and Wilcoxon's signed rank test were used for the main statistical analysis. RESULTS: There was no significant difference with respect to left, right or total hippocampal volume between patients and controls. All mean differences were close to zero, and the two-tailed 95% confidence interval for the difference in total, normalized volume does not include a larger than 8% deficit in the patients. CONCLUSION: The study gives solid evidence against the hypothesis that the patients' lowered quality of life was due to a major reduction of hippocampal volume.

Compromised quality of life in adult patients who have received a radiation dose towards the basal part of the brain. A case-control study in long-term survivors from cancer in the head and neck region.

BACKGROUND: Adult patients with hypothalamic-pituitary disorders have compromised quality of life (QoL). Whether this is due to their endocrine consequences (hypopituitarism), their underlying hypothalamic-pituitary disorder or both is still under debate. The aim of this trial was to measure quality of life (QoL) in long-term cancer survivors who have received a radiation dose to the basal part of the brain and the pituitary. METHODS: Consecutive patients (n=101) treated for oropharyngeal or epipharyngeal cancer with radiotherapy followed free of cancer for a period of 4 to10 years were identified. Fifteen patients (median age 56 years) with no concomitant illness and no hypopituitarism after careful endocrine evaluation were included in a case-control study with matched healthy controls. Doses to the hypothalamic-pituitary region were calculated. QoL was assessed using the Symptom check list (SCL)-90, Nottingham Health Profile (NHP), and Psychological Well Being (PGWB) questionnaires. Level of physical activity was assessed using the Baecke questionnaire. RESULTS: The median accumulated dose was 1.9 Gy (1.5-2.2 Gy) to the hypothalamus and 2.4 Gy (1.8-3.3 Gy) to the pituitary gland in patients with oropharyngeal cancer and 6.0-9.3 Gy and 33.5-46.1 Gy, respectively in patients with epipharyngeal cancer (n=2). The patients showed significantly more anxiety and depressiveness, and lower vitality, than their matched controls. CONCLUSION: In a group of long time survivors of head and neck cancer who hade received a low radiation dose to the hypothalamic-pituitary region and who had no endocrine consequences of disease or its treatment QoL was compromised as compared with well matched healthy controls.

Mentally disordered criminal offenders in the Swedish criminal system.

Historically, the Swedish criminal justice system conformed to other Western penal law systems, exempting severely mentally disordered offenders considered to be unaccountable. However, in 1965 Sweden enforced a radical penal law abolishing exceptions based on unaccountability. Mentally disordered offenders have since then been subjected to various forms of sanctions motivated by the offender's need for care and aimed at general prevention. Until 2008, a prison sentence was not allowed for offenders found to have committed a crime under the influence of a severe mental disorder, leaving forensic psychiatric care the most common sanction in this group. Such offenders are nevertheless held criminally responsible, liable for damages, and encumbered with a criminal record. In most cases, such offenders must not be discharged without the approval of an administrative court. Two essentially modern principles may be discerned behind the "Swedish model": first, an attempted abolishment of moral responsibility, omitting concepts such as guilt, accountability, atonement, and retribution, and, second, the integration of psychiatric care into the societal reaction and control systems. The model has been much criticized, and several governmental committees have suggested a re-introduction of a system involving the concept of accountability. This review describes the Swedish special criminal justice provisions on mentally disordered offenders including the legislative changes in 1965 along with current proposals to return to a pre-1965 system, presents current Swedish forensic psychiatric practice and research, and discusses some of the ethical, political, and metaphysical presumptions that underlie the current system.

A philosophical view on concepts in psychiatry.

This essay first outlines a philosophical theory of concepts and then applies it to two areas of relevance to psychiatrists, especially forensic psychiatrists. In the philosophical theory, the respective roles of verbal and non-verbal definitions are illuminated, and the importance of the phenomenon of division of semantic labour is stressed. It is pointed out that vagueness and ambiguity of a term often result when the term is used for several practical purposes at the same time. Such multi-purpose uses of terms may explain both the current problems associated with the Swedish forensic-psychiatric concept of a severe mental disorder and some of the shortcomings of DSM-IV.