Bernd Saletu

Cognitive dysfunction in psychiatric disorders: characteristics, causes and the quest for improved therapy

Studies of psychiatric disorders have traditionally focused on emotional symptoms such as depression, anxiety and hallucinations. However, poorly controlled cognitive deficits are equally prominent and severely compromise quality of life, including social and professional integration. Consequently, intensive efforts are being made to characterize the cellular and cerebral circuits underpinning cognitive function, define the nature and causes of cognitive impairment in psychiatric disorders and identify more effective treatments. Successful development will depend on rigorous validation in animal models as well as in patients, including measures of real-world cognitive functioning. This article critically discusses these issues, highlighting the challenges and opportunities for improving cognition in individuals suffering from psychiatric disorders.

An E-Health Solution for Automatic Sleep Classification according to Rechtschaffen and Kales: Validation Study of the Somnolyzer 24 × 7 Utilizing the Siesta Database

To date, the only standard for the classification of sleep-EEG recordings that has found worldwide acceptance are the rules published in 1968 by Rechtschaffen and Kales. Even though several attempts have been made to automate the classification process, so far no method has been published that has proven its validity in a study including a sufficiently large number of controls and patients of all adult age ranges. The present paper describes the development and optimization of an automatic classification system that is based on one central EEG channel, two EOG channels and one chin EMG channel. It adheres to the decision rules for visual scoring as closely as possible and includes a structured quality control procedure by a human expert. The final system (Somnolyzer 24 × 7™) consists of a raw data quality check, a feature extraction algorithm (density and intensity of sleep/wake-related patterns such as sleep spindles, delta waves, SEMs and REMs), a feature matrix plausibility check, a classifier designed as an expert system, a rule-based smoothing procedure for the start and the end of stages REM, and finally a statistical comparison to age- and sex-matched normal healthy controls (Siesta Spot Report™). The expert system considers different prior probabilities of stage changes depending on the preceding sleep stage, the occurrence of a movement arousal and the position of the epoch within the NREM/REM sleep cycles. Moreover, results obtained with and without using the chin EMG signal are combined. The Siesta polysomnographic database (590 recordings in both normal healthy subjects aged 20–95 years and patients suffering from organic or nonorganic sleep disorders) was split into two halves, which were randomly assigned to a training and a validation set, respectively. The final validation revealed an overall epoch-by-epoch agreement of 80% (Cohen’s kappa: 0.72) between the Somnolyzer 24 × 7 and the human expert scoring, as compared with an inter-rater reliability of 77% (Cohen’s kappa: 0.68) between two human experts scoring the same dataset. Two Somnolyzer 24 × 7 analyses (including a structured quality control by two human experts) revealed an inter-rater reliability close to 1 (Cohen’s kappa: 0.991), which confirmed that the variability induced by the quality control procedure, whereby approximately 1% of the epochs (in 9.5% of the recordings) are changed, can definitely be neglected. Thus, the validation study proved the high reliability and validity of the Somnolyzer 24 × 7 and demonstrated its applicability in clinical routine and sleep studies.

Sleep spindle-related activity in the human EEG and its relation to general cognitive and learning abilities.

Stage 2 sleep spindles have been previously viewed as useful markers for the development and integrity of the CNS and were more currently linked to ‘offline re‐processing’ of implicit as well as explicit memory traces. Additionally, it had been discussed if spindles might be related to a more general learning or cognitive ability. In the present multicentre study we examined the relationship of automatically detected slow (<u200313u2003Hz) and fast (>u200313u2003Hz) stage 2 sleep spindles with: (i) the Ravens Advanced Progressive Matrices (testing ‘general cognitive ability’); as well as (ii) the Wechsler Memory scale‐revised (evaluating memory in various subdomains). Forty‐eight healthy subjects slept three times (separated by 1u2003week) for a whole night in a sleep laboratory with complete polysomnographic montage. Whereas the first night only served adaptation and screening purposes, the two remaining nights were preceded either by an implicit mirror‐tracing or an explicit word‐pair association learning or (corresponding) control task. Robust relationships of slow and fast sleep spindles with both cognitive as well as memory abilities were found irrespectively of whether learning occurred before sleep. Based on the present findings we suggest that besides being involved in shaping neuronal networks after learning, sleep spindles do reflect important aspects of efficient cortical‐subcortical connectivity, and are thereby linked to cognitive‐ and memory‐related abilities alike.

Topographic distribution of sleep spindles in young healthy subjects

The application of an automatic sleep spindle detection procedure allowed the documentation of the topographic distribution of spindle characteristics, such as number, amplitude, frequency and duration, as a function of sleep depth and of recording time. Multichannel all‐night EEG recordings were performed in 10 normal healthy subjects aged 20–35 years. Although the interindividual variability in the number of sleep spindles was very high (2.7±2.1 spindles per minute stage 2 sleep), all but two subjects showed maximal spindle activity in centro‐parietal midline leads. Moreover, this topography was seen in all sleep stages and changed only slightly – to a more central distribution – towards the end of the night. On the other hand, slow (11.5–14 Hz) and fast (14–16 Hz) spindles showed a completely different topography, with slow spindles distributed anteriorly and fast spindles centro‐parietally. The number of sleep spindles per min was significant depending on sleep stages, with the expected highest occurrence in stage 2, and on recording time, with a decrease in spindle density from the beginning towards the end of the night. However, spindle amplitude, frequency and individual duration was not influenced by sleep depth or time of the night.

Interrater reliability for sleep scoring according to the Rechtschaffen & Kales and the new AASM standard

Interrater variability of sleep stage scorings has an essential impact not only on the reading of polysomnographic sleep studies (PSGs) for clinical trials but also on the evaluation of patients’ sleep. With the introduction of a new standard for sleep stage scorings (AASM standard) there is a need for studies on interrater reliability (IRR). The SIESTA database resulting from an EU‐funded project provides a large number of studies (nu2003=u200372; 56 healthy controls and 16 subjects with different sleep disorders, mean ageu2003±u2003SD: 57.7u2003±u200318.7, 34 females) for which scorings according to both standards (AASM and R&K) were done. Differences in IRR were analysed at two levels: (1) based on quantitative sleep parameter by means of intraclass correlations; and (2) based on an epoch‐by‐epoch comparison by means of Cohen’s kappa and Fleiss’ kappa. The overall agreement was for the AASM standard 82.0% (Cohen’s kappau2003=u20030.76) and for the R&K standard 80.6% (Cohen’s kappau2003=u20030.68). Agreements increased from R&K to AASM for all sleep stages, except N2. The results of this study underline that the modification of the scoring rules improve IRR as a result of the integration of occipital, central and frontal leads on the one hand, but decline IRR on the other hand specifically for N2, due to the new rule that cortical arousals with or without concurrent increase in submental electromyogram are critical events for the end of N2.

Interindividual sleep spindle differences and their relation to learning-related enhancements.

We reported earlier that overnight change in explicit memory is positively related to the change in sleep spindle activity (between a control and a learning night). However, it remained unclear whether this effect was restricted to good memory performers and whether a general association of sleep spindles and a sleep-related learning trait may not account for this effect. Here we now present a secondary and more detailed analysis of our randomized multicenter study. Subjects were studied over a 4-week study period (including actigraphy and daily sleep diaries), including three overnight stays in the sleep laboratory. In the course of the study, subjects completed test-batteries of memory (Wechsler-Memory-Scale-revised; WMS) and other cognitive abilities (Ravens Advanced-Progressive-Matrices; APM) and were asked to study 160 word pairs in the evening before being tested by cued-recall. Afterwards, subjects went to bed in the laboratory with full polysomnographic montages. Additionally, subjects participated on another occasion in a non-learning control (perceptual priming) task that was counterbalanced either before or after the learning condition. Slow as well as fast spindle activities were analyzed at frontopolar and central topographies. Although it was found that spindle activity is generally (in learning as well as control nights) elevated in highly gifted subjects, spindle analyses revealed that spindle increase (control to learning night) is specifically related to explicit memory improvement overnight, independent of individual learning traits. Together these findings suggest that the spindle increase after learning is related to elaborate encoding before sleep, whereas an individuals general learning ability is well reflected in interindividual (and trait-like) differences of absolute sleep spindle activity.

Structural and serum surrogate markers of cerebrovascular disease in obstructive sleep apnea (OSA): association of mild OSA with early atherosclerosis.

AbstractThere is increasingnevidence of a causal interactionnbetween obstructive sleep apnean(OSA) and cerebrovascular disease.nThe aim of the study was to elucidatenthe relationship between thenpolysomnographically (PSG) measurednseverity of OSA and carotidnatherosclerosis determined bynultrasonography and serum surrogatenmarkers. 147 patients (102nmales, 45 females) referred to ournsleep laboratory for evaluation ofnsnoring and sleep–disorderednbreathing were investigated.nCarotid atherosclerosis was evaluatednby serum analysis of high-sensitivitynC–reactive protein (hs–CRP) and fibrinogen and fournsonographic indices: intima–medianthickness (IMT) of the commonncarotid artery (CCA), IMT fromnbulb to internal carotid arteryn(Bulb–ICA), combined IMT measurementsnfrom all segments and anplaque score (PlaS). Pearson correlationnanalysis, intergroup comparisonn(ANOVA), covariance analysisnand a multiple regression werenperformed to assess the associationnbetween surrogate markers andnrespiratory variables. 44 patientsnhad no OSA (apnea–hypopneanindex AHI < 5/h), 27 mild (AHIn5–15), 25 moderate (AHI 15–30)nand 51 severe OSA (AHI > 30).nAfter adjusting for potential confounders,nsignificant differencesnbetween the controls and all threenOSA groups were observed in thenCCA–IMT (p = 0.032) and in thenPlaS between the controls and thensevere group (p = 0.034). Multiplenregression revealed the AHI as annindependent predictor of CCA–IMTn(p = 0.001) and combined IMTn(p = 0.001), whereas the percentagenof total sleep time with an oxygennsaturation below 90 % was associatednwith Bulb–ICA IMT (p = 0.018)nand hs–CRP (p = 0.015). OSA isnassociated with higher surrogatenlevels of cerebrovascular disease.nEven mild OSA seems to predisposento early atherosclerosis.

Rotigotine transdermal patch in moderate to severe idiopathic restless legs syndrome: A randomized, placebo-controlled polysomnographic study

OBJECTIVEnTo assess the efficacy of rotigotine transdermal patch in subjects with moderate to severe idiopathic restless legs syndrome (RLS) and periodic limb movement (PLM) in sleep in a double-blind, randomized, placebo-controlled, multicenter study (NCT00275236).nnnMETHODSnSixty-seven (46 rotigotine, 21 placebo) subjects applied rotigotine (maximum 3mg/24h) or placebo patches once-daily during a 4-week maintenance period; efficacy evaluations used polysomnographic measures and clinician/patient ratings.nnnRESULTSnMean PLM index (PLMI; PLM/h time in bed) decreased more with rotigotine (50.9/h to 8.1/h) than with placebo (37.4/h to 27.1/h; adjusted treatment ratio 4.25 (95% CI [2.48,7.28], p<0.0001). PLM during sleep with arousal index (PLMSAI; 8.57/h to 2.47/h under rotigotine, 6.5/h to 4.95/h under placebo; adjusted treatment difference: -3.12 (95% CI [-5.36, -0.88], p=0.0072) also improved more under rotigotine. At end of maintenance, 39% of rotigotine subjects had PLMI levels <5/h and 26% showed no RLS symptoms (IRLS=0), whereas no placebo subject met these criteria. Common drug-related adverse events for rotigotine and placebo included nausea (21.7%/4.8%), headache (17.4%/14.3%), application site reactions (17.4%/4.8%), and somnolence (10.9%/9.5%); most were mild to moderate in intensity.nnnCONCLUSIONSnRotigotine transdermal patch was efficacious and well tolerated in the short-term treatment of RLS motor symptoms and associated sleep disturbances.

EEG Topography and Tomography (LORETA) in Diagnosis and Pharmacotherapy of Depression

Earlier investigations suggested an involvement of the right hemisphere and the left prefrontal cortex (PFC) in the pathogenesis of depression. This paper presents our own electroencephalographic (EEG) topography and low-resolution brain electromagnetic tomography (LORETA) data obtained in unmedicated depressed patients, and the effects of two representative drugs of non-sedative and sedative antidepressants, i.e., citalopram (CIT) and imipramine (IMI), as compared with placebo in normal subjects. Sixty female menopausal syndrome patients with the diagnosis of a depressive episode without psychotic symptoms as well as 30 healthy controls were investigated. Concerning the effects of antidepressants, normal healthy subjects received single oral doses of 20 mg CIT, 75 mg IMI and placebo p.o. A 3-min vigilance-controlled EEG and a 4-min resting EEG was recorded pre- and post-drug administration and analyzed by means of EEG mapping and LORETA. In the EEG mapping, depressed patients demonstrated a decrease in absolute power in all frequency bands, an augmentation of relative delta/theta and beta and a decrease in alpha activity as well as a slowing of the delta/theta centroid and an acceleration of the alpha and beta centroid, which suggests vigilance decrements. In the alpha asymmetry index, they showed right frontal hyper- and left frontal hypoactivation correlated with the Hamilton Depression Score (HAMD). LORETA predominantly revealed decreased power in the theta and alpha-1 frequency band. Negative correlations between theta power and the HAMD were observed in the ventro-medial PFC, the bilateral rostral anterior cingulate cortex (ACC) and the left insular cortex; between alpha-1 power and the HAMD in the right PFC. In the EEG mapping of antidepressants, 20 mg CIT showed mainly activating, 75 mg IMI partly sedative properties. LORETA revealed that CIT increased alpha-2, beta-1, beta-2 and beta-3 power more over the right than over the left hemisphere. However, also a left temporal and frontal delta increase was observed. In conclusion, EEG topography and tomography of depressed menopausal patients demonstrated a right frontal hyper- and left frontal hypoactivation in the alpha asymmetry index as well as a vigilance decrease, with a right-hemispheric preponderance. Within antidepressants at least 2 subtypes may be distinguished from the electrophysiological point of view, a non-sedative and a sedative. LORETA identifies cerebral generators responsible for the pathogenesis of depression as well as for the mode of action of antidepressants.

EEG mapping in patients with social phobia

Recent studies have suggested an information-processing bias in social phobia (SP). Little is known about the electrophysiological correlates of anxiety in SP. The aim of the present study was to investigate the quantitative electroencephalogram (EEG) in 25 drug-free patients with SP as compared with age- and sex-matched normal controls and to correlate anxiety and depressive symptoms with EEG data. EEG was recorded under vigilance-controlled and resting conditions. The Spielberger State and Trait Anxiety Scale (STAI) and the Beck Depression Inventory (BDI) were administered to assess anxiety and depression levels. Multivariate analysis of variance revealed significant differences between patients and controls, specifically frontopolarly and right centrally. Statistical analysis demonstrated a decrease in absolute and relative delta, theta power, alpha-adjacent slow-beta and fast beta power and an increase in absolute and relative intermediate beta power, as well as an acceleration of the total centroid and a slowing in beta centroid and its variability. Trait anxiety and depression scores correlated positively with the dominant alpha frequency and the alpha centroid, and negatively with absolute theta and slow alpha power as well as with the centroid of the delta/theta frequency band. In conclusion, EEG mapping in patients with SP revealed significant differences from normal controls suggesting a hyperarousal as a pathogenetic factor of anxiety.