The impact of the COMT genotype and cognitive demands on facets of intra-subject variability.

Intra-Subject Variability (ISV), a potential index of catecholaminergic regulation, is elevated in several disorders linked with altered dopamine function. ISV has typically been defined as reaction time standard deviation. However, the ex-Gaussian and spectral measures capture different aspects and may delineate different underlying sources of ISV; thus reflecting different facets of the construct. We examined the impact of factors associated with dopamine metabolism, namely, Catechol-O-Methyltransferase Val158Met (COMT) genotype and Working Memory (WM) and response-switching on ISV facets in young healthy adults. The Met allele was associated with overall increased variability. The rather exclusive sensitivity of ex-Gaussian tau to frequencies below 0.025 Hz and the quasi-periodic structure of particularly slow responses support the interpretation of tau as low frequency fluctuations of neuronal networks. Sigma, by contrast, may reflect neural noise. Regarding cognitive demands, a WM load-related increase in variability was present for all genotypes and all ISV facets. Contrastingly, ISV facets reacted differently to variations in response-switching as, across genotypes, sigma was elevated for rare target trials whereas tau was elevated for frequent standard trials, particularly for Met homozygotes. Our findings support the significant role of COMT in regulating behavioural ISV with its facetted structure and presumed underlying neural processes.

Mindfulness vs psychoeducation in adult ADHD: a randomized controlled trial.

BACKGROUND: Mindfulness training is a promising treatment approach in adult ADHD. However, there has not yet been a randomized controlled trial comparing mindfulness to an active control condition. In this study, we assessed the efficacy of a mindfulness training program (MAP) compared to structured psychoeducation (PE). METHODS: After randomization 81 medication-free adult ADHD patients participated either in an 8-week MAP or PE group program. At baseline (T1), after 8 weeks (T2) and after 8 months (T3), severity of ADHD and associated symptoms (depression, general psychopathology, quality of life) were measured with the Conner's ADHD Rating Scales (CAARS), the Beck Depression Inventory (BDI), the Brief Symptom Inventory (BSI) and the SF-36 by self and blind observer ratings. RESULTS: Both groups showed significant pre-post improvements in observer-rated Inattention scale (p < .001, partial η2 = 0.18) and in associated symptomatology, which persisted through 6 months of follow-up. There were no significant differences regarding symptom reduction between the treatment groups. Women benefited more compared to men irrespective of treatment group. Men showed the most pronounced changes under MAP. CONCLUSIONS: In the current study, MAP was not superior to PE regarding symptom reduction in adult ADHD. Both interventions, mindfulness meditation and PE, were efficacious in reducing symptom load in adult ADHD. Furthermore in exploratory post hoc tests the study provides evidence for a potential gender-specific treatment response in adult ADHD.

Empathy training in medical students - a randomized controlled trial.

AIM: Empathy is a core element in the doctor-patient relationship. This study examined whether empathy in medical students can be improved by specific training. METHODS: 158 medical students were randomized into two groups. The intervention group participated in an empathy skills training with simulated patients (SPs). The control group participated in a history course. After the intervention, empathy was assessed by blinded SPs and experts in an Objective Structured Clinical Examination (OSCE). Students also filled out a self-assessment concerning their attitude on empathy (Jefferson Scale of Physician Empathy Student Version, JSPE-S-S). RESULTS AND CONCLUSIONS: Participants of the intervention group showed significantly higher levels of empathy when rated by SPs and experts than the control group. In contrast to that, no significant group differences were observed in self-rated empathy. The results underpin the value of empathy skills trainings in medical school study programs.

COMT Val158Met genotype is associated with fluctuations in working memory performance: converging evidence from behavioural and single-trial P3b measures.

Intra-subject variability in reaction times (ISV) is a promising endophenotype for several psychiatric conditions, but its neural underpinnings are not yet established. Converging evidence from neuroimaging, molecular genetics, and psychopharmacology suggests that ISV could index catecholaminergically-mediated neural noise. The fine-grained temporal resolution of electroencephalography is ideal for investigating ISV, but only if potential neural correlates of ISV can be assessed in single trials. Based on evidence that ISV is associated with dopaminergic functioning, we apply a recently developed method of single-trial P3b analysis to investigate the association of COMT Val(158)Met genotype with measures of ISV on the behavioural and neural levels at different working memory loads. Greater number of Met alleles was associated with poorer and more intra-individually variable performance on the tasks, and greater latency jitter in single-trial P3bs. These converging results at the behavioural and neurophysiological levels confirm previous observations that prefrontal dopamine availability is associated with stability and accuracy of cognitive performance. Together with previous studies, these data imply pleiotropic cognitive effects of COMT genotype.

Altered cingulate and amygdala response towards threat and safe cues in attention deficit hyperactivity disorder.

BACKGROUND: Emotional dysregulation is becoming increasingly recognized as an important feature of attention deficit hyperactivity disorder (ADHD). In this study, two experiments were conducted investigating the neural response to either verbally instructed fear (IF) or uninstructed (classically conditioned) fear (UF) using the skin conductance response (SCR) and functional magnetic resonance imaging (fMRI). METHOD: In the conditioning phase of the UF experiment (17 ADHD and 17 healthy controls), subjects experienced an unconditioned stimulus (UCS, unpleasant electrodermal stimulation) paired with a former neutral conditioned stimulus (CS+), whereas a control stimulus (CS-) was never paired with the UCS. In the subsequent test phase, only the CS+ and the CS- were presented. In the IF experiment (13 ADHD and 17 healthy controls), subjects were only told that an independently experienced UCS might occur together with the CS+ but not the CS- during testing. No UCS was presented. RESULTS: Groups did not detectably differ in SCR or neural responses to UF. In IF, ADHD patients showed a trend-line decreased SCR and significantly decreased activation of the dorsal anterior cingulate cortex (dACC), a region prominently involved in fear responding, to the CS+. This was accompanied by higher amygdala activation to the CS-. CONCLUSIONS: During IF, ADHD patients showed deficits in regions centrally involved in fear learning and expression in terms of diminished CS+-related dACC and increased CS--related amygdala signals. This suggests an impaired processing of verbally transmitted aversive information, which is central for conveying fear information in social contexts. This result extends the growing literature on emotional alterations in ADHD.

The influence of 8 and 16 mg nicotine patches on sleep in healthy non-smokers.

AIM AND METHODS: The purpose of this study was to determine whether sleep changes are a consequence of nicotine presence or withdrawal during the night, we examined 66 healthy non-smokers (33 males, 33 females, age: 20-25 years) after an adaptation night in a sleep laboratory setting. Subjects were randomized to receive placebo or either 8 or 16 mg nicotine patches during the day or during the night in a double blind, parallel group design. RESULTS: The 16 mg nicotine patch applied during the night caused a reduced sleep period time and sleep efficiency as well as an increased wake time. A reduced REM-sleep latency and subjective sleep quality rating were found in subjects receiving nicotine during the night. Arousals, apneas and periodic leg movements were not affected by nicotine. DISCUSSION: This study documents insomnia-like sleep changes in healthy non-smokers caused by nicotine in a dose-dependent manner. There was no evidence for sleep-related withdrawal symptoms after 13 h of nicotine application.

[Insomnia--state of the science]. / Insomnien--Stand der Forschung.

Diagnostic systems such as the international classification of diseases (ICD-10) or the diagnostic and statistical manual of mental disorders (DSM IV) have frequently been criticized as not adequately reflecting the complexity and heterogeneity of insomnia. Progress was made through the introduction of the international classification of sleep disorders (ICSD-2) and the research diagnostic criteria (RDC). The DSM-5 introduced the new category of insomnia disorder, thus relinquishing the traditional dichotomy of primary versus secondary insomnia. Recent basic research indicates that genetic and epigenetic factors are involved in the etiology of insomnia; the so-called three P model (i.e. predisposing, precipitating and perpetuating factors) and the hyperarousal concept have gained much attention in trying to explain the pathophysiology of insomnia. With respect to the cognitive-behavioral therapy of insomnia (CBT-I), a plethora of empirical evidence supports the first-line character of this type of treatment for insomnia. Unfortunately, CBT-I is still administered to only a minority of afflicted patients, probably due to a lack of resources in the healthcare system. As a consequence, stepped-care models to improve insomnia therapy encompass self-help programs, internet-based treatment avenues, community-centered activities (specially trained nurses) and as a last resort medical specialists/psychotherapists and sleep experts to deal with insomnia.

Disentangling common and specific neural subprocesses of response inhibition.

Response inhibition is disturbed in several disorders sharing impulse control deficits as a core symptom. Since response inhibition is a cognitively and neurally multifaceted function which has been shown to rely on differing neural subprocesses and neurotransmitter systems, further differentiation to define neurophysiological endophenotypes is essential. Response inhibition may involve at least three separable cognitive subcomponents, i.e. interference inhibition, action withholding, and action cancelation. Here, we introduce a novel paradigm - the Hybrid Response Inhibition task - to disentangle interference inhibition, action withholding and action cancelation and their neural subprocesses within one task setting during functional magnetic resonance imaging (fMRI). To validate the novel task, results were compared to a battery of separate, standard response inhibition tasks independently capturing these subcomponents and subprocesses. Across all subcomponents, mutual activation was present in the right inferior frontal cortex (rIFC), pre-supplementary motor area (pre-SMA) and parietal regions. Interference inhibition revealed stronger activation in pre-motor and parietal regions. Action cancelation resulted in stronger activation in fronto-striatal regions. Our results show that all subcomponents share a common neural network and thus all constitute different subprocesses of response inhibition. Subprocesses, however, differ to the degree of regional involvement: interference inhibition relies more pronouncedly on a fronto-parietal-pre-motor network suggesting its close relation to response selection processes. Action cancelation, in turn, is more strongly associated with the fronto-striatal pathway implicating it as a late subcomponent of response inhibition. The new paradigm reliably captures three putatively subsequent subprocesses of response inhibition and might be a promising tool to differentially assess disturbed neural networks in disorders showing impulse control deficits.

REM sleep instability--a new pathway for insomnia?

Chronic insomnia afflicts approximately 10% of the adult population and is associated with daytime impairments and an elevated risk for developing somatic and mental disorders. Current pathophysiological models propose a persistent hyperarousal on the cognitive, emotional and physiological levels. However, the marked discrepancy between minor objective alterations in standard parameters of sleep continuity and the profound subjective impairment in patients with insomnia is unresolved. We propose that "instability" of REM sleep contributes to the experience of disrupted and non-restorative sleep and to the explanation of this discrepancy. This concept is based on evidence showing increased micro- and macro-arousals during REM sleep in insomnia patients. As REM sleep represents the most highly aroused brain state during sleep it seems particularly prone to fragmentation in individuals with persistent hyperarousal. The continuity hypothesis of dream production suggests that pre-sleep concerns of patients with insomnia, i. e., worries about poor sleep and its consequences, dominate their dream content. Enhanced arousal during REM sleep may render these wake-like cognitions more accessible to conscious perception, memory storage and morning recall, resulting in the experience of disrupted and non-restorative sleep. Furthermore, chronic fragmentation of REM sleep might lead to dysfunction in a ventral emotional neural network, including limbic and paralimbic areas that are specifically activated during REM sleep. This dysfunction, along with attenuated functioning in a dorsal executive neural network, including frontal and prefrontal areas, might contribute to emotional and cognitive alterations and an elevated risk of developing depression.

Local area network inhibition: a model of a potentially important paraepileptic pathomechanism in neuropsychiatric disorders.

Electroencephalographic abnormalities in the absence of any other major laboratory or imaging findings are a frequently encountered phenomenon in many psychiatric disorders. In some cases, clear-cut interictal epileptiform EEG abnormalities in patients with classic primary psychiatric disorders lead to referrals to epilepsy departments for diagnostic evaluation. Although video/EEG telemetry in these cases generally proves that there is no direct temporal link between the EEG pathologies and psychiatric symptoms, and therefore the psychiatric syndrome cannot be regarded as epilepsy, the relevance of the EEG abnormalities remains open to discussion. In this article we put forward the model of a paraepileptic pathomechanism, which might explain the pathogenetic role of such EEG pathologies, at least in subgroups of such patients. We propose that ictal or nonictal epileptic neurophysiological activity can lead to local area neuronal network inhibition (LANI). In this model clinical symptoms are related not to the excitatory epileptiform abnormalities themselves, but to the extent, site, and dynamics of the resulting local neuronal network inhibition. The LANI hypothesis is capable of explaining the complex relationship between EEG abnormalities and clinical symptoms in different neuropsychiatric syndromes and can be verified and falsified in empirical research.

Examining the Overlap Between ADHD and Autism Spectrum Disorder (ASD) Using Candidate Endophenotypes of ADHD.

Objective: Recent discussions of aetiological overlap between ADHD and Autism Spectrum Disorder (ASD) require comparative studying of these disorders. METHOD: We examined performance of ASD patients with (ASD+) and without (ASD-) comorbid ADHD, ADHD patients, and controls for selected putative endophenotypes of ADHD: Intrasubject Variability (ISV) of reaction times, working memory (WM), inhibition, and temporal processing. RESULTS: We found that patients with ADHD or ASD+, but not ASD-, had elevated ISV across the entire task battery and temporal processing deficits, and that none of the groups were impaired in WM or inhibition. High levels of ISV and generally poor performance in ASD+ patients were only partially due to additive effects of the pure disorders. CONCLUSION: Overall, we conclude that, within our limited but heterogeneous task battery, ISV and temporal processing deficits are most sensitive to ADHD symptomatology and that controlling for ADHD comorbidity is mandatory when assessing ISV in autism.

Impact of escitalopram on nocturnal sleep, day-time sleepiness and performance compared to amitriptyline: a randomized, double-blind, placebo-controlled study in healthy male subjects.

INTRODUCTION: Antidepressant drugs vary in their effects on sleep, day-time sedation and performance. Up to now, no data are available for either escitalopram (ESCIT) or amitriptyline (AMI), measuring these by an objective test, such as the MULTIPLE SLEEP LATENCY TEST (MSLT). SUBJECTS AND METHODS: We therefore investigated the impact of a single evening dose of 10 mg ESCIT on polysomnographically recorded nocturnal sleep, day-time sleepiness and performance in comparison to 75 mg AMI and placebo (PLAC) in healthy male subjects. RESULTS: Both antidepressants significantly suppressed REM sleep (p<0.001). Although polysomnographically measured sleep continuity was impaired after ESCIT (p=0.006), subjective estimates of sleep parameters did not differ. Periodic limb movements (PLMS) were increased after AMI (p<0.001) but not after ESCIT. Processing speed and performance were enhanced after ESCIT compared with AMI (p=0.011), but not with PLAC. Next-day alertness was significantly impaired by AMI (p=0.012), but not by ESCIT. Mean day-time sleep onset latencies increased significantly after evening ESCIT (p<0.001). In contrast, AMI led to a pronounced increase of day-time sleepiness (p=0.007). DISCUSSION: This study demonstrates that single evening doses of either AMI or ESCIT exhibit different effects on next-day vigilance and alertness in terms of a slightly stimulating effect of ESCIT and a significant reduction after AMI.

[Nicotine. Influence on sleep and its relevance for psychiatry and psychotherapy]. / Nikotin. Einfluss auf den Schlaf und Relevanz für Psychiatrie und Psychotherapie.

BACKGROUND: Nicotine, by its impact on several neurotransmitter systems, influences sleep. Sleep disturbance is a common symptom in different psychiatric disorders and there is a high prevalence of smoking in psychiatric patients. METHODS: Systematic literature search. RESULTS: Symptoms of insomnia are observed during nicotine consumption and its withdrawal. The effects of therapeutic nicotine substitution after smoking cessation on sleep are often masked by withdrawal symptoms. Depressive non-smokers experience an improvement of mood under nicotine administration and in turn, depressive symptoms and sleep impairment during nicotine withdrawal have a negative impact on abstinence rates. CONCLUSION: Sleep disturbance is a comorbid risk factor influencing abstinence during smoking cessation. In depressive patients the complex relationship between affect, sleep, nicotine consumption and its withdrawal should be carefully monitored. In such subgroups of smokers willing to quit this has to be taken care of in therapeutic interventions.

Author Correction: Post-stroke insomnia in community-dwelling patients with chronic motor stroke: Physiological evidence and implications for stroke care.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

Electro-cortical correlates of multisensory integration using ecologically valid emotional stimuli: Differential effects for fear and disgust.

Multisensory integration (MSI) is crucial for human communication and social interaction and has been investigated in healthy populations and neurodevelopmental disorders. However, the use of stimuli with high ecological validity is sparse, especially in event-related potential (ERP) studies. The present study examined the ERP correlates of MSI in healthy adults using short (500 ms) ecologically valid professional actor-produced emotions of fear or disgust as vocal exclamation or facial expression (unimodal conditions) or both (bimodal condition). Behaviourally, our results show a general visual dominance effect (similarly fast responses following bimodal and visual stimuli) and an MSI-related speedup of responses only for fear. Electrophysiologically, both P100 and N170 showed MSI-related amplitude increases only following fear, but not disgust stimuli. Our results show for the first time that the known differential neural processing of fear and disgust also holds for the integration of dynamic auditory and visual information.

Post-stroke insomnia in community-dwelling patients with chronic motor stroke: Physiological evidence and implications for stroke care.

Questionnaire studies suggest that stroke patients experience sustained problems with sleep and daytime sleepiness, but physiological sleep studies focussing specifically on the chronic phase of stroke are lacking. Here we report for the first time physiological data of sleep and daytime sleepiness obtained through the two gold-standard methods, nocturnal polysomnography and the Multiple Sleep Latency Test. Data from community-dwelling patients with chronic right-hemispheric stroke (>12 months) were compared to sex- and age-matched controls. Behavioural and physiological measures suggested that stroke patients had poorer sleep with longer sleep latencies and lower sleep efficiency. Patients further spent more time awake during the night, and showed greater high-frequency power during nonREM sleep than controls. At the same time the Multiple Sleep Latency Test revealed greater wake efficiency in patients than controls. Importantly these findings were not due to group differences in sleep disordered breathing or periodic limb movements. Post-stroke insomnia is presently not adequately addressed within the care pathway for stroke. A holistic approach to rehabilitation and care provision, that includes targeted sleep interventions, is likely to enhance long-term outcome and quality of live in those living with chronic deficits after stroke.

Reduced cingulate glutamate/glutamine-to-creatine ratios in adult patients with attention deficit/hyperactivity disorder -- a magnet resonance spectroscopy study.

BACKGROUND: The dopaminergic system is thought to be essentially involved in the pathogenesis of attention deficit/hyperactivity disorder (ADHD). However, there is also evidence for abnormalities in the glutamatergic system and recent theories focus on a disturbed interaction between the two systems as the essential pathogenetic mechanism of ADHD. In the present study, we wanted to test the hypothesis that prefrontal glutamate signals indirectly indicate dopaminergic dysfunction in adult patients with ADHD. METHODS: Twenty-eight adult patients with ADHD and 28 group-matched healthy volunteers were studied clinically and using chemical-shift MR spectroscopy (MRS) of the prefrontal cortex covering the anterior cingulate gyrus. RESULTS: A significant reduction of the combined glutamate/glutamine to creatine ratio in the right anterior cingulate cortex in patients with ADHD was found. DISCUSSION: Glutamatergic alterations as measured with MRS might play a role in the pathogenesis of adult patients with ADHD.

Cognitive endophenotypes of attention deficit/hyperactivity disorder and intra-subject variability in patients with autism spectrum disorder.

Autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) have previously been studied mainly in isolation from each other. However the two conditions may be aetiologically related and thus show overlap in aetiologically relevant functions. In order to address this question of potential aetiological overlap between ADHD and ASD, the present study set out to investigate putative endophenotypes of ADHD in N=33 typically developing (TD) children and N=28 patients with ASD that were (ASD+) or were not (ASD-) co-morbid for ADHD. With regard to both the cognitive endophenotype candidates (working memory, inhibition, temporal processing) and intra-subject variability (ISV) the pattern of abnormalities was inconsistent. Furthermore, the overall profile of ASD-TD differences was extremely similar to the pattern of differences between the ASD+ and ASD- sub-groups, suggesting that any abnormalities found were due to the comorbid ASD subgroup. This held in particular for ISV, which did not show in patients with ASD the task-general increase that is common in ADHD samples. Altogether, the present results do not support the hypothesis of aetiological overlap between ASD and ADHD.

Sleep and the cholinergic rapid eye movement sleep induction test in patients with primary alcohol dependence.

BACKGROUND: The present study investigated polysomnographically assessed sleep parameters in alcohol-dependent patients after withdrawal and in healthy control subjects during baseline and after a cholinergic stimulation paradigm. The aim of the study was to test whether sleep parameters, especially rapid eye movement (REM) sleep variables, may serve as predictors for relapse in alcohol-dependent patients. METHODS: Forty patients diagnosed with alcohol dependence were admitted to a specialized ward for alcohol withdrawal and were investigated by polysomnography at three time points: 2-3 weeks after withdrawal (T0) and at follow-up investigations 6 (T1) and 12 (T2) months after discharge from the hospital. A subgroup of patients (n = 17) was studied at T0 after challenge with galanthamine, a reversible cholinesterase inhibitor (cholinergic REM induction test, CRIT). Patients were compared with two control groups: a) 30 healthy control subjects (matched for age- and gender-distribution) for comparison at baseline conditions; and b) 17 age- and gender-matched control subjects for comparison with the CRIT. RESULTS: At baseline the patients showed significant disturbances of sleep continuity and sleep architecture (decreased slow-wave sleep, SWS) and exhibited an increase of "REM sleep pressure" (a combined index of REM latency, REM density, and REM sleep percent). Galanthamine provoked significant alterations of sleep continuity, sleep architecture (reduced SWS), and increased most of the components of REM pressure, taking patients and control subjects together. Apart from SWS %SPT (sleep period time) no significant drug-group interactions occurred. Patients who remained abstinent (n = 11) for at least 6 months at follow-up exhibited significantly less abnormalities of REM sleep at T0 compared to the group of patients that relapsed at 6 months follow-up. CONCLUSIONS: It is concluded that increased REM sleep pressure after alcohol withdrawal is a robust predictor of vulnerability to relapse. Thus, a subgroup of alcoholic patients appears to exhibit distinct neurobiological abnormalities assessable by polysomnography that are related to an increased vulnerability for alcoholism and early relapse.