Somatosensory function is impaired in patients with idiopathic REM sleep behaviour disorder.

BACKGROUND: Idiopathic REM sleep behaviour disorder (iRBD) has been recognised as a significant biomarker for developing a neurodegenerative alpha-synucleinopathy, which is why iRBD is considered to be a prodromal state for alpha-synucleinopathies including Parkinson's disease (PD). Many patients with PD suffer from complaints of pain and present impaired somatosensory function. We hypothesized that pain perception and somatosensory function could be altered already in a preclinical stage of PD including iRBD. Hence, the objective of this study was to investigate pain perception and somatosensory function in patients with iRBD. METHODS: Quantitative sensory testing (QST), laser evoked potentials (LEPs), and conditioned pain modulation (CPM) testing were performed in 13 iRBD patients without any clinical signs of PD or narcolepsy (11 males, 2 females, mean age 65.2 years) and 15 gender- and age-matched healthy control subjects (12 males, 3 females, mean age 65.8 years). RESULTS: Thermal detection thresholds were higher in the iRBD group compared with the control group (cold detection threshold (CDT) p = 0.020, thermal sensory limen (TSL) p = 0.001), indicating an impaired temperature sensation in iRBD patients. The N2/P2 LEPs amplitude was smaller in iRBD patients than controls, but not statistically significant (p = 0.053). CONCLUSIONS: This study found an impaired somatosensory function in iRBD patients, suggesting that somatosensory impairment might be an early feature in the neurodegenerative process of PD.

Dimensional anxiety scales for DSM-5: sensitivity to clinical severity.

PURPOSE: Psychometric properties and clinical sensitivity of brief self-rated dimensional scales to supplement categorical diagnoses of anxiety disorders in the DSM-5 were recently demonstrated in a German treatment seeking sample of adults. The present study aims to demonstrate sensitivity of these scales to clinical severity levels. METHODS: The dimensional scales were administered to 102 adults at a university outpatient clinic for psychotherapy. Diagnostic status was assessed using the Munich-Composite International Diagnostic Interview. To establish a wide range of clinical severity, we considered subthreshold (n=83) and threshold anxiety disorders (n=49, including Social Phobia, Specific Phobia, Agoraphobia, Panic Disorder, and Generalized Anxiety Disorder). RESULTS: Individuals with either subthreshold or threshold anxiety disorder scored higher on all dimensional scales relative to individuals without anxiety. In addition, individuals with a threshold anxiety disorder scored higher on the dimensional scales than individuals with a subthreshold anxiety disorder (except for specific phobia). Disorder-related impairment ratings, global functioning assessments and number of panic attacks were associated with higher scores on dimensional scales. Findings were largely unaffected by the number of anxiety disorders and comorbid depressive disorders. CONCLUSION: The self-rated dimensional anxiety scales demonstrated sensitivity to clinical severity, and a cut-off based on additional assessment of impairment and distress may assist in the discrimination between subthreshold and threshold anxiety disorders. Findings suggest further research in various populations to test the utility of the scales for use in DSM-5.

[Visual self-assessment with the ACTO test during follow-up of AMD patients after intravitreal injections]. / Eigenerhebung der Leseleistung mit dem ACTO-Selbsttest bei AMD-Patienten nach intravitrealen Injektionen.

INTRODUCTION: Monthly controls are necessary after injections of vascular endothelial growth factor (VEGF) to enable timely recognition of a renewed decrease in vision. However, these monthly control intervals are not realistic for many older patients with age-related macular degeneration (AMD), and outpatient clinics often reach their logistical limits because of inadequate funding for the additional medical work. Against this background, we conceived the ACTO self-test as a novel screening method for patients to discover unnoticed visual changes outside the routinely scheduled ophthalmic examination. MATERIAL AND METHODS: The paper version of the ACTO self-test consists of a reading chart gradated in decimal steps as well as six questions regarding the quality of the Amsler grid. The patient uses a self-screening test to examine each eye separately and then transfers the results to a table. Along with the self-examination, the Action Eyesight Service Center is available to the patient by phone to motivate the patient and schedule a new appointment if improved test results occur. If decreased values or suspected decreased visual function occur, these are verified immediately by the referring physician. RESULTS: There is a good correlation between the steps of the ACTO self-test and standard visual acuity at 4 m (r(2)=0.9). Altogether, 1,444 patients were followed by phone and 745 participated in repeated regular audits, for a total of 3,003 phone contacts. The treating physician was informed about decreased visual acuity or increased Amsler distortion in the ACTO test in 137 cases, and immediate verification was done. We had 699 dropouts; the reasons were decreased visual acuity below the limits of the ACTO test in 39%, additional monthly examinations by the local ophthalmologist in 29%, and a desire for no more telephone follow-up (despite initial written consent) in 32%. Decreased vision when reading or an increased score on the Amsler test within the ACTO screening test was observed in 18% of AMD patients during the maintenance phase. CONCLUSION: Monthly screening by the ACTO screening test in combination with phone audits offers a new way to test visual acuity, with the Amsler score helping to detect changes in visual function. For patients with visual changes, confirmation by the ophthalmic physician can be achieved in time. Self-assessment cannot replace qualified ophthalmologic examination, but monthly self-controls enhance safety, reduce the number of physician contacts, and improve the detection of visual changes, with the option of immediate ophthalmic retreatment.

A functional dopamine-beta-hydroxylase gene promoter polymorphism is associated with impulsive personality styles, but not with affective disorders.

Dopamine-beta-hydroxylase (DbetaH) catalyzes the conversion of dopamine to norepinephrine in central noradrenergic and adrenergic neurons and thus is critically involved in the biosynthesis of catecholamines. There are equivocal findings concerning the question whether or not DssH activity levels are altered in affective disorders or in subtypes of affective disorders. Moreover, information about the role of dopamine beta-hydroxylase (DBH) genotype, which explains a large part of the variance of enzymatic activity, in affective disorders and personality dimensions is limited. To resolve these inconsistencies, association tests were performed using four independent samples, healthy volunteers (N = 387), patients with affective disorders (N = 182), adult attention deficit hyperactivity disorder (ADHD) patients (N = 407), and patients with personality disorders (N = 637). In the latter two samples, the revised NEO personality inventory (NEO-PI-R) was administered. All participants were genotyped for a putatively functional single nucleotide polymorphism (C-1021T, rs1611115). No differences in DBH C-1021T genotype distribution were observed between patients with affective disorders and healthy control subjects. Also when the patient sample was divided into uni- and bipolar patients versus controls, no significant differences emerged. Furthermore, no clear-cut association was detected between the TT genotype and personality disorder clusters while there was a significant association with adult ADHD. However, personality disorder patients carrying the DBH TT genotype exhibited higher neuroticism and novelty seeking scores as compared to individuals with the CC or CT genotype. Analyses on the level of the neuroticism and novelty seeking subscales revealed that the DBH TT genotype was primarily associated with personality features related to impulsiveness and aggressive hostility. Also adult ADHD patients carrying the homozygous TT genotypes displayed by significantly increased neuroticism scores; when both personality disorder and adult ADHD patient were analyzed together, TT carriers also displayed by significantly lower conscientiousness levels. Our results thus do not implicate the DBH C-1021T polymorphism in the pathophysiology of depressive disorders or personality disorders, yet homozygosity at this locus appears to increase the risk towards personality traits related to impulsiveness, aggression and related disease states, namely adult ADHD. These data argue for a dimensional rather than categorical effect of genetic variance in DBH activity; accordingly, the inconsistency of previous findings concerning DbetaH levels in affective disorders might be caused by the underlying association of the TT genotype at DBH-1021 with impulsive personality traits.

FZD3 is not a risk gene for schizophrenia: a case-control study in a Caucasian sample.

BACKGROUND: Polymorphisms in the human frizzeled-3 (FZD3) gene have been associated with schizophrenia in an Asian population sample. However, this finding could not be confirmed in subsequent studies investigating other populations. Here we attempted to replicate this finding in a sample of 192 German chronically ill schizophrenic subjects. METHODS: Three single nucleotide polymorphisms in the FZD3 gene have been genotyped by primer extension and MALDI-TOF measurement. Subsequently, associations for single markers as well as haplotypes were tested. RESULTS: In German patients, neither single markers nor haplotypes in FZD3 were associated with schizophrenia. Further exploratory analyses using a different diagnostic approach did also not yield significant results. CONCLUSIONS: FZD3 is unlikely to play a role in the genetic predisposition towards schizophrenia in the Caucasian population.

NO synthase-positive striatal interneurons are decreased in schizophrenia.

The gaseous messenger NO has repeatedly been suggested to play a role in the pathogenesis of psychoses. Following a pilot study, we investigated whether the number of nitrinergic neurons in the putamen of patients suffering from schizophrenia, bipolar disorder or major depression is altered. Post-mortem striatum sections of 15 brains from patients with either disease were examined by NADPH-diaphorase staining, which selectively labels NO synthase-positive interneurons. Quantification of these cells revealed significantly lower numbers of NO synthase-containing neurons in the putamen of schizophrenic patients. Our results suggest that striatal nitrinergic interneurons are involved in the pathophysiology of at least some forms of schizophrenia, such as e.g. catatonic schizophrenia.

[Retained foreign bodies from the surgical point of view]. / Belassene Fremdkörper--aus der Sicht des Chirurgen.

The number of foreign bodies remaining in the patient after a surgical procedure is presumably higher than mentioned in the literature. According to US insurance statistics, the incidence amounts to 1 in 1,500 surgical procedures. As a basic principle--also from the legal aspect--it is necessary to determine whether a foreign body was left in situ accidentally (i.e. due to a material fault) or if it was simply forgotten. In 70% of cases, fabric items (e.g. swabs etc.) are left behind, while around 30% are metal objects. A particularly high risk is seen in emergency settings, in unexpected changes in the surgical procedure, or for patients with a high body mass index. The outcome for the patient differs depending on the nature of the object left behind and the individual patient's situation. Usually, metal items cause more acute clinical symptoms at an earlier time after the operation. Fabric items tend to induce, in the absence of primary contamination, a chronic progression of symptoms over several years. Reoperation has a high mortality (between 11% and 35%). Precautions in terms of risk management have to be established and need to be strictly respected, especially in high risk settings. Visually or acoustically controlled monitoring before wound-closure are recommended to eliminate "human error" as thoroughly as possible.

Serotonin transporter gene variation impacts innate fear processing: Acoustic startle response and emotional startle.

Anxiety-related behaviors are closely linked to neural circuits relaying fear-specific information to the amygdala. Many of these circuits, like those underlying processing of innate fear, are remarkably well understood. Recent imaging studies have contributed to this knowledge by discriminating more detailed corticoamygdalar associations mediating processing fear and anxiety. However, little is known about the underlying molecular mechanisms. We used the acoustic startle paradigm to investigate the impact of molecular genetic variation of serotonergic function on the acoustic startle response and its fear potentiation. Startle magnitudes to noise bursts as measured with the eye blink response were recorded in 66 healthy volunteers under four conditions: presenting unpleasant and pleasant affective pictures as well as neutral pictures, and presenting the startle stimulus without additional stimuli as a baseline. Subjects were genotyped for functional polymorphism in the transcriptional control region of the serotonin transporter gene (5-hydroxytryptamine transporter gene-linked region: 5-HTTLPR). Analyses of variance revealed a significant effect of 5-HTTLPR on overall startle responses across conditions. Carriers of the short (s) allele exhibited stronger startle responses than l/l homozygotes. However, we could not confirm our hypothesis of enhanced fear potentiation of the startle in s allele carriers. In conclusion, the results provide first evidence that the startle response is sensitive to genetic variation in the serotonin pathway. Despite some issues remaining to be resolved, the startle paradigm may provide a valuable endophenotype of fear processing and underlying serotonergic influences.

A neuronal nitric oxide synthase (NOS-I) haplotype associated with schizophrenia modifies prefrontal cortex function.

Nitric oxide (NO) is a gaseous neurotransmitter thought to play important roles in several behavioral domains. On a neurobiological level, NO acts as the second messenger of the N-methyl-D-aspartate receptor and interacts with both the dopaminergic as well as the serotonergic system. Thus, NO is a promising candidate molecule in the pathogenesis of endogenous psychoses and a potential target in their treatment. Furthermore, the chromosomal locus of the gene for the NO-producing enzyme NOS-I, 12q24.2, represents a major linkage hot spot for schizophrenic and bipolar disorder. To investigate whether the gene encoding NOS-I (NOS1) conveys to the genetic risk for those diseases, five NOS1 polymorphisms as well as a NOS1 mini-haplotype, consisting of two functional polymorphisms located in the transcriptional control region of NOS1, were examined in 195 chronic schizophrenic, 72 bipolar-I patients and 286 controls. Single-marker association analysis showed that the exon 1c promoter polymorphism was linked to schizophrenia (SCZ), whereas synonymous coding region polymorphisms were not associated with disease. Long promoter alleles of the repeat polymorphism were associated with less severe psychopathology. Analysis of the mini-haplotype also revealed a significant association with SCZ. Mutational screening did not detect novel exonic polymorphisms in patients, suggesting that regulatory rather than coding variants convey the genetic risk on psychosis. Finally, promoter polymorphisms impacted on prefrontal functioning as assessed by neuropsychological testing and electrophysiological parameters elicited by a Go-Nogo paradigm in 48 patients (continuous performance test). Collectively these findings suggest that regulatory polymorphisms of NOS1 contribute to the genetic risk for SCZ, and modulate prefrontal brain functioning.

Neural stem cell proliferation is decreased in schizophrenia, but not in depression.

The phenomenon of adult neurogenesis (AN), that is, the generation of functional neurons from neural stem cells in the dentate gyrus of the hippocampus, has attracted remarkable attention, especially as it was shown that this process is also active in the human brain. Based on animal studies, it has been suggested that reduced AN is implicated in the etiopathology of psychiatric disorders, and that stimulation of AN contributes to the mechanism of action of antidepressant therapies. As data from human post-mortem brain are still lacking, we investigated whether the first step of AN, that is, the level of neural stem cell proliferation (NSP; as quantified by Ki-67 immunohistochemistry), is altered in tissue from the Stanley Foundation Neuropathology Consortium comprising brain specimens from patients with bipolar affective disorder, major depression, schizophrenia as well as control subjects (n=15 in each group). The hypothesis was that stem cell proliferation is reduced in affective disorders, and that antidepressant treatment increases NSP. Neither age, brain weight or pH, brain hemisphere investigated nor duration of storage had an effect on NSP. Only in bipolar disorder, post-mortem interval was a significant intervening variable. In disease, onset of the disorder and its duration likewise did not affect NSP. Also, cumulative lifetime dose of fluphenazine was not correlated with NSP, and presence of antidepressant treatment did not result in an increase of NSP. Concerning the different diagnostic entities, reduced amounts of newly formed cells were found in schizophrenia, but not in major depression. Our findings suggest that reduced NSP may contribute to the pathogenesis of schizophrenia, whereas the rate of NSP does not seem to be critical to the etiopathology of affective disorders, nor is it modified by antidepressant drug treatment.

Association between allelic variation of serotonin transporter function and neuroticism in anxious cluster C personality disorders.

OBJECTIVE: Association between the low-activity variant of a polymorphism in the transcriptional control region of the serotonin transporter (5-HTTLPR) and neuroticism or harm avoidance was found in several but not all studies. The authors analyzed the influence of 5-HTTLPR variants on personality disorders. METHOD: Patients with personality disorders (N=320) and healthy volunteers (N=281) were studied with the Revised NEO Personality Inventory and the Tridimensional Personality Questionnaire. All were genotyped for 5-HTTLPR variants. RESULTS: No differences in 5-HTTLPR genotype distribution were detected between patients with cluster B and C personality disorders and comparison subjects. In contrast, among patients with a cluster C diagnosis, carriers of the low-activity short allele of the 5-HTTLPR exhibited higher neuroticism scores than noncarriers. CONCLUSIONS: These findings support the notion that there is no general association between the 5-HTTLPR and anxiety-related traits and that differential gene effects and/or gene-by-environment interactions are likely operative in distinct clinical subpopulations.

Allelic variation in 5-HT1A receptor expression is associated with anxiety- and depression-related personality traits.

The 5-HT1A receptor plays a critical role in the pathophysiology of anxiety and depression as well as in the mode of action of anxiolytic and antidepressant drugs. Human 5-HT1A gene transcription is modulated by a common C-1016G single nucleotide polymorphism (SNP) in its upstream regulatory region. In the present study, we evaluated the role of the HTR1A-1019 polymorphism in the modulation of individual differences in personality traits by an association study of a sample of healthy volunteers. Personality traits were assessed with two different methods, NEO personality inventory (NEO-PI-R) and Tridimensional Personality Questionnaire (TPQ). There was a significant effect of the HTR1A-1019 polymorphism on NEO Neuroticism with carriers of the G allele showing higher scores than individuals homozygous for the C variant. The effect was primarily due to associations with the Neuroticism facets Anxiety and Depression. Carriers of the G allele also exhibited higher TPQ Harm Avoidance scores. Our findings indicate a role of allelic variation in 5-HT1A receptor expression in the development and modulation of anxiety- and depression-related personality traits.

Allelic variation in serotonin transporter function associated with the intensity dependence of the auditory evoked potential.

The intensity dependence of the auditory evoked potential (AEP) has been suggested as an indicator of central serotonergic function, a strong intensity dependence presumably reflecting low serotonergic activity. As individual differences in serotonergic neurotransmission can be accounted for in part by genetic variation in genes of the serotonergic pathway, we investigated whether a functional polymorphism in the promoter region of the serotonin transporter gene (5-HTTLPR) is associated with the AEP intensity dependence. Because dopaminergic influences on the intensity dependence have also been reported, we furthermore explored the role of a functional polymorphism in the dopamine D4 receptor gene (DRD4 exon III) in the modulation of the AEP intensity dependence. AEPs to tones of six intensity levels were recorded from 60 healthy young individuals, and N1/P2 linear as well as median slopes at central electrode sites were computed as measures of the AEP intensity dependence. Analyses of variance showed that there was a significant effect of the 5-HTTLPR on the AEP intensity dependence. Individuals with the ll genotype exhibited a stronger intensity dependence compared to individuals with the ls genotype. This effect was even more pronounced when DRD4 exon III was considered in the analyses. In conclusion, these findings provide further evidence for a role of serotonergic neurotransmission in the modulation of the AEP intensity dependence. The results also point to possible dopaminergic influences on the AEP intensity dependence.

Association between the dopamine D4 receptor (DRD4) exon III polymorphism and measures of Novelty Seeking in a German population.

Since the observation of an association between the dopamine D4 receptor (DRD4) exon III polymorphism and the temperament trait of Novelty Seeking,1 replication studies have yielded both positive2-5 and negative6-12 results. This raised the question whether the initial findings must be regarded as false positives.13 However, demographic or methodological differences between studies may have obscured the small effect of the DRD4 polymorphism on Novelty Seeking.14 Examination of clinical or older cohorts may have led to an underestimation of possible associations due to a restricted variation of Novelty Seeking in these cohorts. The use of different questionnaires provides another source of variation. In order to replicate the initial findings as precisely as possible, a cohort of 136 healthy, young volunteers was genotyped, and Novelty Seeking was ascertained using the TPQ.15,16 In addition, further aspects of novelty seeking behavior have been ascertained through additional trait measures. We could observe the reported association between long DRD4 alleles and significantly elevated scores (age- and sex-residualized) on the TPQ-Novelty Seeking total scale as well as on two of the subscales, Exploratory Excitability and Extravagance. The results provide further confirmation for the role of the DRD4 exon III polymorphism in modulation of Novelty Seeking. In addition, the pattern of associations between the polymorphism and other scales suggests that this polymorphism has its effect on exploratory, extravagant, and extraverted, rather than on impulsive and monotony-avoidant subtypes of Novelty Seeking.

Effect of thiazolidinediones on expression of UCP2 and adipocyte markers in human PAZ6 adipocytes.

AIMS/HYPOTHESIS: Thiazolidinediones, a new class of insulin sensitizers, up-regulate the expression of uncoupling protein 2 in rodent adipocytes. It is not known, however, whether thiazolidinediones influence uncoupling protein 2 expression in human adipocytes. We therefore investigated the effect of these drugs on uncoupling protein 2 expression in the recently immortalized human PAZ6 adipocyte cell line. METHODS: Immortalized human PAZ6 preadipocytes were differentiated into adipocytes in the presence or absence of thiazolidinediones. The effect of the drugs on uncoupling protein 2 expression and adipocyte differentiation was measured by reverse transcription-polymerase chain reaction of mRNA of uncoupling protein 2 and of five adipocyte differentiation markers. RESULTS: When cells were differentiated 15 days in the presence of thiazolidinediones, uncoupling protein 2 expression was 2.1-fold higher than in the absence of the drugs. The expression of five adipocyte differentiation markers was, however, also increased by thiazolidinediones. Short-term incubation for 4 and 24 h with thiazolidinediones increased uncoupling protein 2 expression 1.35-fold and 2.3-fold, respectively. The expression of adipocyte markers studied in parallel was also augmented. CONCLUSION/INTERPRETATION: Thiazolidinediones rapidly increase the expression of uncoupling protein 2 in human PAZ6 adipocytes but the increase of uncoupling protein 2 expression is always associated with an augmentation of the expression of all adipocyte markers studied in parallel. This indicates that the effect of thiazolidinediones on uncoupling protein 2 mRNA reflects a general increase in adipocyte differentiation rather than a specific augmentation of uncoupling protein 2 gene expression.