[Ethical Considerations of Including Minors in Clinical Trials Using the Example of the Indicated Prevention of Psychotic Disorders]. / Minderjährige in klinischen Prüfungen: Ethische Abwägungen ihres Einbezugs am Beispiel der indizierten Prävention psychotischer Erkrankungen.

Ethical Considerations of Including Minors in Clinical Trials Using the Example of the Indicated Prevention of Psychotic Disorders Abstract: As a vulnerable group, minors require special protection in studies. For this reason, researchers are often reluctant to initiate studies, and ethics committees are reluctant to authorize such studies. This often excludes minors from participating in clinical studies. This exclusion can lead to researchers and clinicians receiving only incomplete data or having to rely on adult-based findings in the treatment of minors. Using the example of the study "Computer-Assisted Risk Evaluation in the Early Detection of Psychotic Disorders" (CARE), which was conducted as an 'other clinical investigation' according to the Medical Device Regulation, we present a line of argumentation for the inclusion of minors which weighs the ethical principles of nonmaleficence (especially regarding possible stigmatization), beneficence, autonomy, and fairness. We show the necessity of including minors based on the development-specific differences in diagnostics and early intervention. Further, we present specific protective measures. This argumentation can also be transferred to other disorders with the onset in childhood and adolescence and thus help to avoid excluding minors from appropriate evidence-based care because of insufficient studies.

Premorbid body weight predicts weight loss in both anorexia nervosa and atypical anorexia nervosa: Further support for a single underlying disorder.

OBJECTIVE: For adolescents, DSM-5 differentiates anorexia nervosa (AN) and atypical AN with the 5th BMI-centile-for-age. We hypothesized that the diagnostic weight cut-off yields (i) lower weight loss in atypical AN and (ii) discrepant premorbid BMI distributions between the two disorders. Prior studies demonstrate that premorbid BMI predicts admission BMI and weight loss in patients with AN. We explore these relationships in atypical AN. METHOD: Based on admission BMI-centile < or ≥5th, participants included 411 female adolescent inpatients with AN and 49 with atypical AN from our registry study. Regression analysis and t-tests statistically addressed our hypotheses and exploratory correlation analyses compared interrelationships between weight loss, admission BMI, and premorbid BMI in both disorders. RESULTS: Weight loss in atypical AN was 5.6 kg lower than in AN upon adjustment for admission age, admission height, premorbid weight and duration of illness. Premorbid BMI-standard deviation scores differed by almost one between both disorders. Premorbid BMI and weight loss were strongly correlated in both AN and atypical AN. DISCUSSION: Whereas the weight cut-off induces discrepancies in premorbid weight and adjusted weight loss, AN and atypical AN overall share strong weight-specific interrelationships that merit etiological consideration. Epidemiological and genetic associations between AN and low body weight may reflect a skewed premorbid BMI distribution. In combination with prior findings for similar psychological and medical characteristics in AN and atypical AN, our findings support a homogenous illness conceptualization. We propose that diagnostic subcategorization based on premorbid BMI, rather than admission BMI, may improve clinical validity. PUBLIC SIGNIFICANCE: Because body weights of patients with AN must drop below the 5th BMI-centile per DSM-5, they will inherently require greater weight loss than their counterparts with atypical AN of the same sex, age, height and premorbid weight. Indeed, patients with atypical AN had a 5.6 kg lower weight loss after controlling for these variables. In comparison to the reference population, we found a lower and higher mean premorbid weight in patients with AN and atypical AN, respectively. Considering previous psychological and medical comparisons showing little differences between AN and atypical AN, we view a single disorder as the most parsimonious explanation. Etiological models need to particularly account for the strong relationship between weight loss and premorbid body weight.

Movement initiation and preparation in subjects with schizophrenia - The amplitude of the readiness potential as a biological marker for negative symptom severity.

OBJECTIVE: Despite extensive research, the etiology of negative symptoms is not well understood. Preliminary findings are linking motor disturbances to negative symptom severity. We aimed to further the understanding to what extent motor movement preparation influences negative symptom severity. METHODS: In a cohort of 31 subjects with schizophrenia and 20 control subjects we recorded the readiness potential amplitude over Cz during spontaneous movements of the right and left thumb. We further assessed negative and positive symptom severity (scale for the assessment of negative and positive symptoms) as well as neurological soft signs (NSS). RESULTS: In subjects with schizophrenia the severity of negative symptoms was best predicted by the readiness potential amplitude and the NSS subdomain motor coordination. The correlation between deficits in motor coordination and negative symptom severity was partially mediated by the readiness potential amplitude in subjects with schizophrenia. CONCLUSIONS: Deficits in motor processing are linked to negative symptom severity in schizophrenia. The readiness potential may represent a biological marker of these basal deficits. In combination with the assessment of NSS, the readiness potential may be a marker of the course of negative symptom severity and help clarifying interdependencies between (pre)frontal networks for action initiation and coordination, as well as negative symptoms.

Attention for Emotion-How Young Adults With Neurodevelopmental Disorders Look at Facial Expressions of Affect.

While Autism Spectrum Disorder (ASD), Attention-Deficit/Hyperactivity Disorder (ADHD) and Schizophrenia (SCZ) differ in many clinically relevant features such as symptomatology and course, they may also share genetic underpinnings, affective problems, deviancies in social interactions, and are all characterized by some kind of cognitive impairment. This situation calls for a joint investigation of the specifics of cognitive (dys-)functions of the three disorders. Such endeavor should focus, among other domains, on the inter-section of processing cognitive, affective and social information that is crucial in effective real-life interactions and can be accomplished when attentional preferences for human facial expressions of emotions is studied. To that end, attention to facial expressions of basic emotions was examined in young adults with ASD, ADHD, or SCZ in the present study. The three clinical groups were compared with an age-matched group of typically-developing participants (TD) during the free contemplation of five different facial emotions presented simultaneously, by varying identities, through the registration of eye movements. We showed, that dwell times and fixation counts differed for the different emotions in TD and in a highly similar way in ADHD. Patients with ASD differed from TD by showing a stronger differentiation between emotions and partially different attentional preferences. In contrast, the SCZ group showed an overall more restricted scanning behavior and a lack of differentiation between emotions. The ADHD group, showed an emotion-specific gazing pattern that was highly similar to that of controls. Thus, by analyzing eye movements, we were able to differentiate three different viewing patterns that allowed us to distinguish between the three clinical groups. This outcome suggests that attention for emotion may not tap into common pathophysiological processes and argues for a multi-dimensional approach to the grouping of disorders with neurodevelopmental etiology.

An German Short-Version of the "Sensory Perception Quotient" for Adults With Autism Spectrum Disorder.

Sensory features in autism spectrum disorder (ASD) have received increasing interest in clinical work and research during the recent years. With the Sensory Perception Quotient (SPQ), Tavasolli and colleagues have produced a self-rating scale for adults with ASD that measures sensory hyper-sensitivity in different sensory modalities, without also tapping cognitive or motivational aspects that precede or follow autistic sensory experiences. Here, we present the results of a translation of the SPQ to German and its short version as well as their validation in samples of autistic or neuro-typical participants. We, furthermore, present the psychometric properties and validities of Tavasolli's original SPQ-short version as well as an alternative short version based on different psychometric item-selection criteria. We can show here that our alternative SPQ-short version, overlapping with the original short-version in 61% of its items, exhibits superior reliabilities, reasonable concurrent validities with other related measures. It, furthermore, exhibits excellent differentiation between autistic and non-autistic samples, underscoring its utility as a screening instrument in research and a clinical instrument to supplement the ASD diagnostic process.

Bereitschaftspotential and lateralized readiness potential in children with attention deficit hyperactivity disorder: altered motor system activation and effects of methylphenidate.

Attention deficit hyperactivity disorder (ADHD) has been linked to abnormal functioning of cortical motor areas such as the supplementary motor area, the premotor cortex and primary motor cortex (MI). The Bereitschaftspotential (BP) and lateralized readiness potential (LRP) are movement-related potentials generated by cortical motor areas. We hypothesized that the BP and LRP would be altered in children with ADHD. A group of 17 children with ADHD (mean age: 11.5 ±â€¯1.9 years) and a control group of 16 typically developing children (mean age: 12.2 ±â€¯2.0 years) performed movements at self-chosen irregular intervals while a 64-channel DC-EEG was registered. BP and LRP were calculated from the EEG. The ADHD group had significantly lower and on average positive BP amplitudes at Cz. In agreement with age-dependent maturation effects the LRP had a positive polarity in both groups, but lower amplitudes were found in the ADHD group without medication. The control group showed a mid-central negativity and a positivity over motor areas contra-lateral to the side of movement, whereas no negativity over Cz and a more diffuse positivity was found in the ADHD group. LRP group differences diminished after MPH administration as indicated by an interaction between group and time of measurement/medication. The cortical motor system shows altered functioning during movement preparation and initiation in children affected by ADHD. Positive Bereitschaftspotential polarities may represent delayed cortical maturation. Group differences of LRP were pharmacologically modulated by the catecholaminergic agent MPH.

Time-resolved neuroimaging of visual short term memory consolidation by post-perceptual attention shifts.

Post-perceptual cues can enhance visual short term memory encoding even after the offset of the visual stimulus. However, both the mechanisms by which the sensory stimulus characteristics are buffered as well as the mechanisms by which post-perceptual selective attention enhances short term memory encoding remain unclear. We analyzed late post-perceptual event-related potentials (ERPs) in visual change detection tasks (100ms stimulus duration) by high-resolution ERP analysis to elucidate these mechanisms. The effects of early and late auditory post-cues (300ms or 850ms after visual stimulus onset) as well as the effects of a visual interference stimulus were examined in 27 healthy right-handed adults. Focusing attention with post-perceptual cues at both latencies significantly improved memory performance, i.e. sensory stimulus characteristics were available for up to 850ms after stimulus presentation. Passive watching of the visual stimuli without auditory cue presentation evoked a slow negative wave (N700) over occipito-temporal visual areas. N700 was strongly reduced by a visual interference stimulus which impeded memory maintenance. In contrast, contralateral delay activity (CDA) still developed in this condition after the application of auditory post-cues and was thereby dissociated from N700. CDA and N700 seem to represent two different processes involved in short term memory encoding. While N700 could reflect visual post processing by automatic attention attraction, CDA may reflect the top-down process of searching selectively for the required information through post-perceptual attention.

The optic radiation and the cerebellar peduncles in adolescents with first-admission schizophrenia--a diffusion tensor imaging study.

BACKGROUND AND PURPOSE: Previous studies have found gray matter alterations in the cerebellum and in the visual system in both adults and adolescents with schizophrenia. The present study was conducted to investigate whether white matter tracts associated with these regions are also affected in the early stages of the disorder. METHODS: Using a 1.5 Tesla magnetic resonance imaging (MRI) scanner and fiber tracking, the optic radiations and the middle cerebellar peduncles were examined in 13 adolescents with first-admission schizophrenia and 13 healthy controls matched for age, gender, school type, and handedness. RESULTS: Patients with schizophrenia displayed significantly decreased fractional anisotropy in the optic radiations, but no differences in the middle cerebellar peduncles compared to healthy controls. CONCLUSIONS: Our findings of altered fiber integrity in the optic radiations in adolescents with schizophrenia are in line with gray matter alterations in the visual cortices previously reported in the same sample and are in accordance with other studies that found decreased fractional anisotropy in these regions. These findings support the view that the visual system plays an important role in the pathogenesis of schizophrenia and may enhance our understanding of associations between the visual cortex and symptoms of the disorder.

Neurological soft signs and brainstem morphology in first-episode schizophrenia.

BACKGROUND: Minor motor and sensory deficits or neurological soft signs (NSS) have frequently been reported in patients with schizophrenia at any stage of their illness. NSS have been demonstrated to correlate with neuroanatomical abnormalities in various brain regions. Despite its important role in the integration and coordination of automatic motor actions, the brainstem has so far rather been ignored in previous neuroimaging studies on NSS in schizophrenia. METHOD: We investigated 21 right-handed first-episode schizophrenia patients using high-resolution magnetic resonance imaging at 3 T. The severity of NSS was measured with the Heidelberg Scale. Associations between NSS and both brainstem volume and shape changes were examined. RESULTS: Higher NSS scores were significantly associated with structural alterations in the brainstem. According to volume measurements higher NSS scores correlated with global changes of the brainstem. Using shape analyses these associations referred to regionally specific morphometric alterations predominantly in the midbrain and pons. CONCLUSION: The findings suggest that brainstem morphometric alterations are associated with the severity of NSS in patients with first-episode schizophrenia. They further indicate the involvement of the brainstem in the pathogenesis of schizophrenia.

White matter alterations in the corpus callosum of adolescents with first-admission schizophrenia.

Several diffusion tensor imaging (DTI) studies involving adults and adolescents with schizophrenia have examined fractional anisotropy (FA) in the corpus callosum (CC) with conflicting findings. This may be due to confounding factors such as the chronicity of the disorder, long-term medication with psychotropics or methodological differences. To provide a clearer picture of early alterations, we examined 13 adolescents with first-admission schizophrenia and 13 healthy controls using a region-of-interest approach based on probabilistic voxel classification. We quantified FA in four subdivisions of the CC and hypothesized that adolescents with schizophrenia display a reduced FA in the genu associated with 'hypofrontality' and a reduced FA in the body of the CC linked to the heteromodal association cortex. Fiber integrity measurements revealed significant FA decreases in the genu and body of the CC in adolescents with schizophrenia compared to healthy controls. These findings emphasize the central role of the CC in even the early stages of schizophrenia and lend weight to hypotheses about frontal alterations and the central role of the heteromodal association cortex in the aetiopathogenesis of the disorder.

Cortical post-movement and sensory processing disentangled by temporary deafferentation.

Motor system calibration depends crucially on the adjustment to the consequences of a movement, which often occur when the movement itself is already completed. The mechanisms by which reafferent feedback information is compared to the programmed movement remain unclear. In the current study, the hypothesis of a short term memory trace in the motor cortex which outlasts quick movements and is generated independently from reafferent feedback was challenged by temporal deafferentation. Post-movement cortical potentials were recorded by high-resolution EEG during a reaction time task which required speeded unilateral right-hand or left-hand button presses. We analysed lateralized motor N700 (motor post-imperative negative variation), a post-movement component, under temporary deafferentation achieved through application of a blood pressure tourniquet in ten healthy adult subjects. Motor N700 persisted under deafferentation in the absence of reafferent tactile and proprioceptive feedback input into the sensorimotor cortex, which was abolished under deafferentation. Source analysis pointed towards continuing activation in the pre-/primary motor cortex. Thus, motor post-processing can be dissociated from reafferent sensory feedback. Motor cortex activation outlasts quick movements for about a second also in the absence of a reafferent signal. Continuing motor cortex activation could act as an internal motor model in motor learning and allow better adjustment of movements according to the evaluation of their consequences.

Gray matter alterations in first-admission adolescents with schizophrenia.

BACKGROUND AND PURPOSE: Imaging studies of patients with schizophrenia have described a variety of cerebral alterations. However, long-term medication and the chronicity of the disorder may have contributed substantially to these alterations. Studies examining patients in the early stages of the disorder reduce the possibility of such confounding factors but are rare. In light of this, the aim of the present study was to examine adolescents in the early stages of the disorder to observe primary structural brain abnormalities. METHODS: Gray and white matter were measured in 13 adolescents with schizophrenia and 13 healthy controls matched for age, gender, handedness, and school type using voxel-based morphometry. RESULTS: Subjects with schizophrenia displayed decreased gray matter in the cerebellar vermis, and alterations in the left putamen and in several parts of the visual system. CONCLUSIONS: These findings support cerebellar involvement in the pathogenesis of schizophrenia, and the alterations observed in several parts of the visual system may provide insights into the nature of hallucinations and delusional interpretations.

The role of a pseudocapsula in thymic epithelial tumors: outcome and correlation with established prognostic parameters. Results of a 20-year single centre retrospective analysis.

BACKGROUND: Treatment of thymoma is often based on observation of only a few patients. Surgical resection is considered to be the most important step. Role of a pseudocapsula for surgery, its clinical significance and outcome compared with established prognostic parameters is discussed which has not been reported so far. METHODS: 84 patients with thymoma underwent resection and analysis was carried out for clinical features, prognostic factors and long-term survival. RESULTS: Fifteen patients were classified in WHO subgroup A, 21 in AB, 29 in B and 19 patients in C. Forty two patients were classified in Masaoka stage I, 19 stage II, 9 stage III and 14 stage IV. Encapsulated thymoma was seen in 40, incomplete or missing capsula in 44 patients. In 71 complete resections, local recurrence was 5%. 5-year survival was 88.1%. Thymomas with pseudocapsula showed a significant better survival (94.9% vs. 61.1%, respectively) (p = 0.001) and was correlated with the absence of nodal or distant metastasis (p = 0.04 and 0.001, respectively). Presence of pseudocapsula as well as the Masaoka and WHO classification, and R-status were of prognostic significance. R-status and Masaoka stage appeared to be of independent prognostic significance in multivariate analysis. CONCLUSION: Intraoperative presence of an encapsulated tumor is a good technical marker for the surgeon to evaluate resectability and estimate prognosis. Although the presence of a capsula is of strong significance in the univariate analysis, it failed in the multivariate analysis due to its correlation with clinical Masaoka stage. Masaoka stage has a stronger relevance than WHO classification to determinate long-term outcome.