Why ��Willusionism�� Leads to ��Bad Results��: Comments on Baumeister, Crescioni, and Alquist

Drawing on results discussed in the target article by Baumeister et al. (1), I argue that the claim that the modern mind sciences are discovering that free will is an illusion (“willusionism”) is ambiguous and depends on how ordinary people understand free will. When interpreted in ways that the evidence does not justify, the willusionist claim can lead to ‘bad results.’ That is, telling people that free will is an illusion leads people to cheat more, help less, and behave more aggressively, but these responses may be based on people’s interpreting willusionist claims to mean that they lack the powers of rational choice and self-control.     

Revisiting Arieti's ��Listening Attitude�� and Hallucinated Voices

Silvano Arieti proposed that auditory/verbal hallucinations (AVHs) are triggered by momentary states of heightened auditory attention that he identified as a “listening attitude.” Studies and clinical observations by our group support this view. Patients enrolled in our repetitive transcranial magnetic stimulation trials, if experiencing a significant curtailment of these hallucinations, often report an episodic sense that their voices are still occurring even if they no longer can be heard, suggesting episodic states of heightened auditory expectancy. Moreover, a functional magnetic resonance study reported by our group detected activation in the left insula prior to hallucination events. This finding is suggestive of activation in the same region detected in healthy subjects during “auditory search” in response to ambiguous sounds when anticipating meaningful speech. AVHs often are experienced with a deep emotional salience and may occur in the context of dramatic social isolation that together could reinforce heightened auditory expectancy. These findings and clinical observations suggest that Arieti''s original formulation deserves further study.     

Patientenverf��gungsgesetz

Current legal regulations concerning the right of self-determination of subjects who are not competent to give consent have been in force since 2009. According to the new regulations, such subjects can exercise their right of self-determination through a legal guardian who will assess and impose their will. If there is an operative advance directive covering the specific case, the guardian is bound by the provisions laid down in it. Although primarily intended for end-of-life decisions, the law applies in all cases of a subject's inability to give consent, including the context of mental illness. It allows the persons concerned to define certain aspects of medical treatment in advance. On the one hand, the right of self-determination of mentally ill people is thus strengthened. On the other hand, the new regulations can also cause significant ethical conflict involving patients and their representatives as well as family members and practitioners. The present contribution presents the consequences of the amendment for the treatment of mentally ill people. Case studies are described in order to illustrate the new regulations in clinical situations.     

Neuronal estrogen receptor-�� mediates neuroprotection by 17��-estradiol

17β-Estradiol (E₂) was shown to exert neuroprotective effects both in in vitro and in vivo models of stroke. Although these effects of E₂ are known to require estrogen receptor-α (ERα), the cellular target of estrogen-mediated neuroprotection remains unknown. Using cell type-specific ER mutant mice in an in vivo model of stroke, we specifically investigated the role of ERα in neuronal cells versus its role in the microglia in the mediation of neuroprotection by estrogens. We generated and analyzed two different tissue-specific knockout mouse lines lacking ERα either in cells of myeloid lineage, including microglia, or in the neurons of the forebrain. Both E₂-treated and E₂-untreated mutant and control mice were subjected to a permanent middle cerebral artery occlusion for 48 h, and the infarct volume was quantified. Although the infarct volume of E₂-treated female myeloid-specific ERα knockout mice was similar to that of E₂-treated control mice, both male and female neuron-specific ERα mutant mice had larger infarcts than did control mice after E₂ treatment. We conclude that neuronal ERα in female and male mice mediates neuroprotective estrogen effects in an in vivo mouse model of stroke, whereas microglial ERα is dispensable.     

Alzheimer��s disease is not ��brain aging��: neuropathological, genetic, and epidemiological human studies

Human studies are reviewed concerning whether "aging"-related mechanisms contribute to Alzheimer's disease (AD) pathogenesis. AD is defined by specific neuropathology: neuritic amyloid plaques and neocortical neurofibrillary tangles. AD pathology is driven by genetic factors related not to aging per se, but instead to the amyloid precursor protein (APP). In contrast to genes involved in APP-related mechanisms, there is no firm connection between genes implicated in human "accelerated aging" diseases (progerias) and AD. The epidemiology of AD in advanced age is highly relevant but deceptively challenging to address given the low autopsy rates in most countries. In extreme old age, brain diseases other than AD approximate AD prevalence while the impact of AD pathology appears to peak by age 95 and decline thereafter. Many distinct brain diseases other than AD afflict older human brains and contribute to cognitive impairment. Additional prevalent pathologies include cerebrovascular disease and hippocampal sclerosis, both high-morbidity brain diseases that appear to peak in incidence later than AD chronologically. Because of these common brain diseases of extreme old age, the epidemiology differs between clinical "dementia" and the subset of dementia cases with AD pathology. Additional aging-associated mechanisms for cognitive decline such as diabetes and synapse loss have been linked to AD and these hypotheses are discussed. Criteria are proposed to define an "aging-linked" disease, and AD fails all of these criteria. In conclusion, it may be most fruitful to focus attention on specific pathways involved in AD rather than attributing it to an inevitable consequence of aging.     

Reciprocal Induction Between ��-Synuclein and ��-Amyloid in Adult Rat Neurons

In spite of definite roles for ??-amyloid (A??) in familial Alzheimer??s disease (AD), the cause of sporadic AD remains unknown. Amyloid senile plaques and Lewy body pathology frequently coexist in neocortical and hippocampal regions of AD and Parkinson??s diseases. However, the relationship between A?? and ??-synuclein (??-Syn), the principle components in the pathological structures, in neuronal toxicity and the mechanisms of their interaction are not well studied. As A?? and ??-Syn accumulate in aging patients, the biological functions and toxicity of these polypeptides in the aging brain may be different from those in young brain. We examined the neurotoxicity influences of A??1-42 or ??-Syn on mature neurons and the effects of A??1-42 or ??-Syn on the production of endogenous ??-Syn or A??1-40 reciprocally using a model of culture enriched with primary neurons from the hippocampus of adult rats. Treatment of neurons with high concentrations of A??1-42 or ??-Syn caused significant apoptosis of neurons. Following A??1-42 treatment at sub apoptotic concentrations, both intra- and extra-cellular ??-Syn levels were significantly increased. Reciprocally, the non-toxic levels of ??-Syn treatment also increased intra- and extra-cellular A??1-40 levels. The phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002, suppressed ??-Syn-induced A??1-40 elevation, as well as A??1-42-induced ??-Syn elevation. Thus, high concentrations of A??1-42 and ??-Syn exert toxic effects on mature neurons; however, non-toxic concentration treatment of these polypeptides induced the production of each other reciprocally with possible involvement of PI3K pathway.     

Lateralisierte ?Out-of-body experience��

The authors report 2 patients with an out-of-body experience (OBE) as an epileptic phenomenon. The autoscopic illusion was constantly lateralized. One patient had a contralateral lesion, while in the other patient a contralateral lesion was suspected. Patients with autoscopic phenomena should be asked for a lateralization as this might be an indication of a contralateral brain pathology. Generally, patients should explicitly be asked for autoscopic perceptions, as these are probably only rarely mentioned spontaneously. Limitations of the hypothesis of a cerebral lesion which is located contralaterally to the autoscopic illusion are the retrospective nature of data collection and the small number of published reports in the literature on lateralization of autoscopic phenomena.     

Oxidative stress increases phosphorylation of I��B kinase-�� by enhancing NF-��B-inducing kinase after transient focal cerebral ischemia

The IκB kinase (IKK) complex is a central component in the classic activation of the nuclear factor-κB (NF-κB) pathway. It has been reported to function in physiologic responses, including cell death and inflammation. We have shown that IKK is regulated by oxidative status after transient focal cerebral ischemia (tFCI) in mice. However, the mechanism by which oxidative stress influences IKKs after tFCI is largely unknown. Nuclear accumulation and phosphorylation of IKKα (pIKKα) were observed 1 h after 30 mins of tFCI in mice. In copper/zinc-superoxide dismutase knockout mice, levels of NF-κB-inducing kinase (NIK) (an upstream kinase of IKKα), pIKKα, and phosphorylation of histone H3 (pH3) on Ser10 were increased after tFCI and were higher than in wild-type mice. Immunohistochemistry showed nuclear accumulation and pIKKα in mouse brain endothelial cells after tFCI. Nuclear factor-κB-inducing kinase was increased, and it enhanced pH3 by inducing pIKKα after oxygen–glucose deprivation (OGD) in mouse brain endothelial cells. Both NIK and pH3 interactions with IKKα were confirmed by coimmunoprecipitation. Treatment with IKKα small interfering RNA significantly reduced cell death after OGD. These results suggest that augmentation of NIK, IKKα, and pH3 in response to oxidative stress is involved in cell death after cerebral ischemia (or stroke).     

��berlegungen zur Wirksamkeit von Psychopharmaka

Current systematic reviews yielded relatively small efficacy effect sizes of different psychopharmacological agents compared to placebo. It seems that these effect sizes have decreased compared to earlier meta-analyses. We speculate about factors explaining the decrease of effect size such as lower methodological requirements for earlier randomised controlled trials, but in particular enormous methodological problems of current trials such as chronic patient populations, exclusion of severely ill patients by the protocols, sponsoring by the pharmaceutical industry and so-called professional patients. A few examples from general medicine are used to illustrate that the effect sizes of other medications are often also surprisingly small. Psychotropic drugs are efficacious, but they need to be prudently applied according to evidence-based criteria.     

Von der ?Schizophrenie�� zur ?St?rung der Einheit des Selbst��

In August 2002 the Japanese Society of Psychiatry and Neurology decided to rename the Japanese expression for schizophrenia from Sêshin Bunretsu By? to T?g? Shicch? Sh?. Currently the psychiatric classification systems ICD-10 and DSM-IV are under revision. Against this background the Japanese process of renaming a psychiatric disorder is of high interest as far as the clinical, social and cultural implications of the new name are concerned.The authors give an overview of the Japanese process of renaming schizophrenia. Its background and realization are explained and the expectations of Japanese physicians, patients and their families related to the new name are analysed. Furthermore, its effects are evaluated. The aim of the paper is to clarify in how far the Japanese example may serve as a model for evaluating the possible implications that a renaming or nosological redefinition of schizophrenia might have in the course of the revision process of ICD 10 and DSM IV.     

Changes in the solubility and phosphorylation of ��-synuclein over the course of Parkinson��s disease

Lewy bodies are made from insoluble, phosphorylated α-synuclein, but the earliest changes that precipitate such pathology still remain conjecture. In this study, we quantify and identify relationships between the levels of the main pathologic form of phosphorylated α-synuclein over the course of Parkinson's disease in regions affected early through to end-stage disease. Brain tissue samples from 33 cases at different disease stages and 13 controls were collected through the Australian Network of Brain Banks. 500 mg of frozen putamen (affected preclinically) and frontal cortex (affected late) was homogenized, fractionated and α-synuclein levels evaluated using specific antibodies (syn-1, BD Transduction Laboratories; S129P phospho-α-synuclein, Elan Pharmaceuticals) and quantitative western blotting. Statistical analyses assessed the relationship between the different forms of α-synuclein, compared levels between groups, and determined any changes over the disease course. Soluble S129P was detected in controls with higher levels in putamen compared with frontal cortex. In contrast, insoluble α-synuclein occurred in Parkinson's disease with a significant increase in soluble and lipid-associated S129P, and a decrease in soluble frontal α-synuclein over the disease course. Increasing soluble S129P in the putamen correlated with increasing S129P in other fractions and regions. These data show that soluble non-phosphorylated α-synuclein decreases over the course of Parkinson's disease, becoming increasingly phosphorylated and insoluble. The finding that S129P α-synuclein normally occurs in vulnerable brain regions, and in Parkinson's disease has the strongest relationships to the pathogenic forms of α-synuclein in other brain regions, suggests a propagating role for putamenal phospho-α-synuclein in disease pathogenesis.     

Peroxisomal alterations in Alzheimer��s disease

In Alzheimer's disease (AD), lipid alterations are present early during disease progression. As some of these alterations point towards a peroxisomal dysfunction, we investigated peroxisomes in human postmortem brains obtained from the cohort-based, longitudinal Vienna-Transdanube Aging (VITA) study. Based on the neuropathological Braak staging for AD on one hemisphere, the patients were grouped into three cohorts of increasing severity (stages I-II, III-IV, and V-VI, respectively). Lipid analyses of cortical regions from the other hemisphere revealed accumulation of C22:0 and very long-chain fatty acids (VLCFA, C24:0 and C26:0), all substrates for peroxisomal β-oxidation, in cases with stages V-VI pathology compared with those modestly affected (stages I-II). Conversely, the level of plasmalogens, which need intact peroxisomes for their biosynthesis, was decreased in severely affected tissues, in agreement with a peroxisomal dysfunction. In addition, the peroxisomal volume density was increased in the soma of neurons in gyrus frontalis at advanced AD stages. Confocal laser microscopy demonstrated a loss of peroxisomes in neuronal processes with abnormally phosphorylated tau protein, implicating impaired trafficking as the cause of altered peroxisomal distribution. Besides the original Braak staging, the study design allowed a direct correlation between the biochemical findings and the amount of neurofibrillary tangles (NFT) and neuritic plaques, quantified in adjacent tissue sections. Interestingly, the decrease in plasmalogens and the increase in VLCFA and peroxisomal volume density in neuronal somata all showed a stronger association with NFT than with neuritic plaques. These results indicate substantial peroxisome-related alterations in AD, which may contribute to the progression of AD pathology.     

B��cher; Kongresse; Personalia

Mitteilungen der Gesellschaft

Bücher; Kongresse; Personalia     

Neuromuskul?re Signal��bertragung im Erwachsenenalter

The availability of early diagnosis and modern effective therapies has reduced mortality and disability linked to late-onset acquired or hereditary neuromuscular transmission disorders. Nevertheless, identification of the pathogenesis of these diseases remains a challenge. In addition to non-specific and fluctuating presenting symptoms current diagnostic work-up strategies include electrophysiology, antibody measurements and less frequently molecular genetics. For differential diagnostic purposes there is an increasing demand for improving awareness concerning late-onset congenital myasthenic syndromes (CMS) which are rare but nevertheless symptomatically treatable diseases. Especially in seronegative myasthenic syndromes, molecular genetic analyses of CMS genes should be integrated into the differential diagnostic work-up. Therefore, some facets of neuromuscular synaptogenesis in the context of seronegative acquired myasthenic syndromes and recently uncovered congenital myasthenic syndromes are reviewed.     

The Neuropathology of Late-Onset Friedreich��s Ataxia

Friedreich’s ataxia (FRDA) affects very young persons. In a large series, the mean ages of onset and death were 11 and 38 years, respectively. The clinical spectrum of FRDA has expanded after genetic confirmation of the mutation became a routine laboratory test. The main cause of death in juvenile-onset FRDA is cardiomyopathy whereas patients with late-onset are more likely to succumb to neurological disability or an intercurrent illness. Many patients with early onset now survive for 20 years or longer. This study made a systematic comparison of the neuropathology in 14 patients with juvenile onset and long survival, and five patients with late onset and long survival. Mean ages of onset (± standard deviation) were 10 ± 5 and 28 ± 13 years, respectively. Disease durations were 33 ± 11 and 47 ± 11 years, respectively. Cross-sectional areas of the thoracic spinal cord were greatly reduced from the normal state but did not differ between the two groups. Similarly, the neurons of dorsal root ganglia were significantly reduced in size in both juvenile- and late-onset cases of FRDA. The dentate nucleus showed severe loss of neurons as well as modification and destruction of corticonuclear terminals in all FRDA patients. Delayed atrophy of the dentate nucleus is the likely cause of the ataxic phenotype of FRDA in late-onset cases, but the reason for the delay is unknown. Frataxin levels in the dentate nucleus of two patients with late onset were similar to those of seven patients with juvenile onset.     

Clinical features and prognosis with Guillain-Barr�� syndrome

Background:

Guillain-Barré syndrome (GBS) is an acute inflammatory polyneuropathy commonly characterized by rapidly progressive, symmetric weakness and areflexia.

Materials and Methods:

We retrospectively assessed the clinical manifestations, results of electrodiagnostic tests, functional status and prognosis of 36 children diagnosed with GBS.

Results:

Based on clinical and electrophysiological findings, the patients were classified as having acute inflammatory demyelinating polyradiculoneuropathy (AIDP) (n = 25), acute motor axonal neuropathy (AMAN) (n = 10) and acute motor-sensory axonal neuropathy (AMSAN) (n = 1). Twenty (55.5%) patients were males and 16 (44.5%) patients were females. The mean age of the 36 patients was 68.1 ± 45.01 months (range, 6–180 months). Five (13.8%) patients were younger than 2 years. The most common initial symptoms were limb weakness, which was documented in 34 (94.4%) patients. In our study, 18 patients (51.4%) showed albuminocytological dissociation (raised protein concentration without pleocytosis) on cerebrospinal fluid (CSF) examination. Three patients (8.3%) required mechanical ventilation therapy during hospitalization. Unfortunately, three (8.3%) patients died; one patient had AIDP and two patients had axonal involvement (one case was AMAN and another case was AMSAN). When we compared the cases of residual sequel/dead and cases of complete recovery for neural involvement type including AIDP, AMAN and AMSAN, we did not find a statistically significant difference between the groups (P > 0.05).

Conclusion:

Our findings showed that cases of GBS was not uncommon in children younger than 2 years of age, and CSF protein level might be found high in the first week of the disease in about one half of the patients, with a higher rate of morbidity and mortality in patients with axonal involvement than in those with AIDP.