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Evoked responses and oscillations represent two major electrophysiological phenomena in the human brain yet the link between them remains rather obscure. Here we show how most frequently studied EEG signals: the P300-evoked response and alpha oscillations (8-12 Hz) can be linked with the baseline-shift mechanism. This mechanism states that oscillations generate evoked responses if oscillations have a non-zero mean and their amplitude is modulated by the stimulus. Therefore, the following predictions should hold: (1) the temporal evolution of P300 and alpha amplitude is similar, (2) spatial localisations of the P300 and alpha amplitude modulation overlap, (3) oscillations are non-zero mean, (4) P300 and alpha amplitude correlate with cognitive scores in a similar fashion. To validate these predictions, we analysed the data set of elderly participants (N=2230, 60-82 years old), using (a) resting-state EEG recordings to quantify the mean of oscillations, (b) the event-related data, to extract parameters of P300 and alpha rhythm amplitude envelope. We showed that P300 is indeed linked to alpha rhythm, according to all four predictions. Our results provide an unifying view on the interdependency of evoked responses and neuronal oscillations and suggest that P300, at least partly, is generated by the modulation of alpha oscillations., Competing Interests: AS, CF, TH, CS, NM, UH, ML, AV, VN No competing interests declared, DE D.E. is a full-time employee of F. Hoffmann-La Roche Ltd, (© 2023, Studenova et al.)

While many structural and biochemical changes in the brain have previously been associated with older age, findings concerning functional properties of neuronal networks, as reflected in their electrophysiological signatures, remain rather controversial. These discrepancies might arise due to several reasons, including diverse factors determining general spectral slowing in the alpha frequency range as well as amplitude mixing between the rhythmic and non-rhythmic parameters. We used a large dataset (N = 1703, mean age 70) to comprehensively investigate age-related alterations in multiple EEG biomarkers taking into account rhythmic and non-rhythmic activity and their individual contributions to cognitive performance. While we found strong evidence for an individual alpha peak frequency (IAF) decline in older age, we did not observe a significant relationship between theta power and age while controlling for IAF. Not only did IAF decline with age, but it was also positively associated with interference resolution in a working memory task primarily in the right and left temporal lobes suggesting its functional role in information sampling. Critically, we did not detect a significant relationship between alpha power and age when controlling for the 1/f spectral slope, while the latter one showed age-related alterations. These findings thus suggest that the entanglement of IAF slowing and power in the theta frequency range, as well as 1/f slope and alpha power measures, might explain inconsistencies reported previously in the literature. Finally, despite the absence of age-related alterations, alpha power was negatively associated with the speed of processing in the right frontal lobe while 1/f slope showed no consistent relationship to cognitive performance. Our results thus demonstrate that multiple electrophysiological features, as well as their interplay, should be considered for the comprehensive assessment of association between age, neuronal activity, and cognitive performance., Competing Interests: Declaration of Competing Interest Authors declare no competing financial or non-financial interests in relation to the work., (Copyright © 2022. Published by Elsevier Inc.)

Background: The heartbeat-evoked potential (HEP) is a brain response to each heartbeat, which is thought to reflect cardiac signaling to central autonomic areas and suggested to be a marker of internal body awareness (eg, interoception)., Objectives: Because cardiac communication with central autonomic circuits has been shown to be impaired in patients with atrial fibrillation (AF), we hypothesized that HEPs are attenuated in these patients., Methods: By simultaneous electroencephalography and electrocardiography recordings, HEP was investigated in 56 individuals with persistent AF and 56 control subjects matched for age, sex, and body mass index., Results: HEP in control subjects was characterized by right frontotemporal negativity peaking around 300 to 550 ms after the R-peak, consistent with previous studies. In comparison with control subjects, HEP amplitudes were attenuated, and HEP amplitude differences remained significant when matching the samples for heart frequency, stroke volume (assessed by echocardiography), systolic blood pressure, and the amplitude of the T-wave. Effect sizes for the group differences were medium to large (Cohen's d between 0.6 and 0.9). EEG source analysis on HEP amplitude differences pointed to a neural representation within the right insular cortex, an area known as a hub for central autonomic control., Conclusions: The heartbeat-evoked potential is reduced in AF, particularly in the right insula. We speculate that the attenuated HEP in AF may be a marker of impaired heart-brain interactions. Attenuated interoception might furthermore underlie the frequent occurrence of silent AF., Competing Interests: Funding Support and Author Disclosures The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Based on Eysenck's biopsychological trait theory, brain arousal has long been considered to explain individual differences in human personality. Yet, results from empirical studies remained inconclusive. However, most published results have been derived from small samples and, despite inherent limitations, EEG alpha power has usually served as an exclusive indicator for brain arousal. To overcome these problems, we here selected N = 468 individuals of the LIFE-Adult cohort and investigated the associations between the Big Five personality traits and brain arousal by using the validated EEG- and EOG-based analysis tool VIGALL. Our analyses revealed that participants who reported higher levels of extraversion and openness to experience, respectively, exhibited lower levels of brain arousal in the resting state. Bayesian and frequentist analysis results were especially convincing for openness to experience. Among the lower-order personality traits, we obtained the strongest evidence for neuroticism facet 'impulsivity' and reduced brain arousal. In line with this, both impulsivity and openness have previously been conceptualized as aspects of extraversion. We regard our findings as well in line with the postulations of Eysenck and consistent with the recently proposed 'arousal regulation model'. Our results also agree with meta-analytically derived effect sizes in the field of individual differences research, highlighting the need for large (collaborative) studies.

Background and Purpose: The ENIGMA-EEG working group was established to enable large-scale international collaborations among cohorts that investigate the genetics of brain function measured with electroencephalography (EEG). In this perspective, we will discuss why analyzing the genetics of functional brain activity may be crucial for understanding how neurological and psychiatric liability genes affect the brain., Methods: We summarize how we have performed our currently largest genome-wide association study of oscillatory brain activity in EEG recordings by meta-analyzing the results across five participating cohorts, resulting in the first genome-wide significant hits for oscillatory brain function located in/near genes that were previously associated with psychiatric disorders. We describe how we have tackled methodological issues surrounding genetic meta-analysis of EEG features. We discuss the importance of harmonizing EEG signal processing, cleaning, and feature extraction. Finally, we explain our selection of EEG features currently being investigated, including the temporal dynamics of oscillations and the connectivity network based on synchronization of oscillations., Results: We present data that show how to perform systematic quality control and evaluate how choices in reference electrode and montage affect individual differences in EEG parameters., Conclusion: The long list of potential challenges to our large-scale meta-analytic approach requires extensive effort and organization between participating cohorts; however, our perspective shows that these challenges are surmountable. Our perspective argues that elucidating the genetic of EEG oscillatory activity is a worthwhile effort in order to elucidate the pathway from gene to disease liability., (© 2021 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

Background: The concept of alexithymia is characterized by difficulties identifying and describing one's emotions. Alexithymic individuals are impaired in the recognition of others' emotional facial expressions. Alexithymia is quite common in patients suffering from major depressive disorder. The face-in-the-crowd task is a visual search paradigm that assesses processing of multiple facial emotions. In the present eye-tracking study, the relationship between alexithymia and visual processing of facial emotions was examined in clinical depression. Materials and Methods: Gaze behavior and manual response times of 20 alexithymic and 19 non-alexithymic depressed patients were compared in a face-in-the-crowd task. Alexithymia was empirically measured via the 20-item Toronto Alexithymia-Scale. Angry, happy, and neutral facial expressions of different individuals were shown as target and distractor stimuli. Our analyses of gaze behavior focused on latency to the target face, number of distractor faces fixated before fixating the target, number of target fixations, and number of distractor faces fixated after fixating the target. Results: Alexithymic patients exhibited in general slower decision latencies compared to non-alexithymic patients in the face-in-the-crowd task. Patient groups did not differ in latency to target, number of target fixations, and number of distractors fixated prior to target fixation. However, after having looked at the target, alexithymic patients fixated more distractors than non-alexithymic patients, regardless of expression condition. Discussion: According to our results, alexithymia goes along with impairments in visual processing of multiple facial emotions in clinical depression. Alexithymia appears to be associated with delayed manual reaction times and prolonged scanning after the first target fixation in depression, but it might have no impact on the early search phase. The observed deficits could indicate difficulties in target identification and/or decision-making when processing multiple emotional facial expressions. Impairments of alexithymic depressed patients in processing emotions in crowds of faces seem not limited to a specific affective valence. In group situations, alexithymic depressed patients might be slowed in processing interindividual differences in emotional expressions compared with non-alexithymic depressed patients. This could represent a disadvantage in understanding non-verbal communication in groups., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Suslow, Günther, Hensch, Kersting and Bodenschatz.)

Background: The amygdala and the hippocampus are two limbic structures that play a critical role in cognition and behavior, however their manual segmentation and that of their smaller nuclei/subfields in multicenter datasets is time consuming and difficult due to the low contrast of standard MRI. Here, we assessed the reliability of the automated segmentation of amygdalar nuclei and hippocampal subfields across sites and vendors using FreeSurfer in two independent cohorts of older and younger healthy adults., Methods: Sixty-five healthy older (cohort 1) and 68 younger subjects (cohort 2), from the PharmaCog and CoRR consortia, underwent repeated 3D-T1 MRI (interval 1-90 days). Segmentation was performed using FreeSurfer v6.0. Reliability was assessed using volume reproducibility error (ε) and spatial overlapping coefficient (DICE) between test and retest session., Results: Significant MRI site and vendor effects (p ​< ​.05) were found in a few subfields/nuclei for the ε, while extensive effects were found for the DICE score of most subfields/nuclei. Reliability was strongly influenced by volume, as ε correlated negatively and DICE correlated positively with volume size of structures (absolute value of Spearman's r correlations >0.43, p ​< ​1.39E-36). In particular, volumes larger than 200 ​mm 3 (for amygdalar nuclei) and 300 ​mm 3 (for hippocampal subfields, except for molecular layer) had the best test-retest reproducibility (ε ​< ​5% and DICE ​> ​0.80)., Conclusion: Our results support the use of volumetric measures of larger amygdalar nuclei and hippocampal subfields in multisite MRI studies. These measures could be useful for disease tracking and assessment of efficacy in drug trials., Competing Interests: Declaration of competing interest None., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

The term fatigue is not only used to describe a sleepy state with a lack of drive, as observed in patients with chronic physical illnesses, but also a state with an inhibition of drive and central nervous system (CNS) hyperarousal, as frequently observed in patients with major depression. An electroencephalogram (EEG)-based algorithm has been developed to objectively assess CNS arousal and to disentangle these pathophysiologically heterogeneous forms of fatigue. The aim of this study was to test the hypothesis that fatigued patients with CNS hyperarousal score higher on depressive symptoms than those without this neurophysiological pattern., Methods: Subjects with fatigue (Multidimensional Fatigue Inventory sum-score > 40) in the context of cancer, neuroinflammatory, or autoimmune diseases were drawn from the 60+ cohort of the Leipzig Research Center for Civilization Diseases. CNS arousal was assessed by automatic EEG-vigilance stage classification using the Vigilance Algorithm Leipzig (VIGALL 2.1) based on 20 min EEG recordings at rest with eyes closed. Depression was assessed by the Inventory of Depressive Symptomatology (IDS-SR)., Results: Sixty participants (33 female; median age: 67.5 years) were included in the analysis. As hypothesized, fatigued patients with CNS hyperarousal had higher IDS-SR scores than those without hyperarousal (F 1,58 = 18.34; p < 0.0001, η 2 = 0.240)., Conclusion: hyperaroused fatigue in patients with chronic physical illness may be a sign of comorbid depression.

Sleep impairments are a hallmark of acute bipolar disorder (BD) episodes and are present even in the euthymic state. Studying healthy subjects who are vulnerable to BD can improve our understanding of whether sleep impairment is a predisposing factor. Therefore, we investigated whether vulnerability to BD, dimensionally assessed by the hypomanic personality scale (HPS), is associated with sleep disturbances in healthy subjects. We analyzed participants from a population-based cohort who had completed the HPS and had either a 7-day actigraphy recording or a Pittsburgh sleep quality index (PSQI) assessment. In addition, subjects had to be free of confounding diseases or medications. This resulted in 771 subjects for actigraphy and 1766 for PSQI analyses. We found strong evidence that higher HPS scores are associated with greater intraindividual sleep variability, more disturbed sleep and more daytime sleepiness. In addition, factor analyses revealed that core hypomanic features were especially associated with self-reported sleep impairments. Results support the assumption of disturbed sleep as a possibly predisposing factor for BD and suggest sleep improvement as a potential early prevention target.

Arousal affects cognition, emotion, and behavior and has been implicated in the etiology of psychiatric disorders. Although environmental conditions substantially contribute to the level of arousal, stable interindividual characteristics are well-established and a genetic basis has been suggested. Here we investigated the molecular genetics of brain arousal in the resting state by conducting a genome-wide association study (GWAS). We selected N = 1877 participants from the population-based LIFE-Adult cohort. Participants underwent a 20-min eyes-closed resting state EEG, which was analyzed using the computerized VIGALL 2.1 (Vigilance Algorithm Leipzig). At the SNP-level, GWAS analyses revealed no genome-wide significant locus (p < 5E-8), although seven loci were suggestive (p < 1E-6). The strongest hit was an expression quantitative trait locus (eQTL) of TMEM159 (lead-SNP: rs79472635, p = 5.49E-8). Importantly, at the gene-level, GWAS analyses revealed significant evidence for TMEM159 (p = 0.013, Bonferroni-corrected). By mapping our SNPs to the GWAS results from the Psychiatric Genomics Consortium, we found that all corresponding markers of TMEM159 showed nominally significant associations with Major Depressive Disorder (MDD; 0.006 ≤ p ≤ 0.011). More specifically, variants associated with high arousal levels have previously been linked to an increased risk for MDD. In line with this, the MetaXcan database suggests increased expression levels of TMEM159 in MDD, as well as Autism Spectrum Disorder, and Alzheimer's Disease. Furthermore, our pathway analyses provided evidence for a role of sodium/calcium exchangers in resting state arousal. In conclusion, the present GWAS identifies TMEM159 as a novel candidate gene which may modulate the risk for psychiatric disorders through arousal mechanisms. Our results also encourage the elaboration of the previously reported interrelations between ion-channel modulators, sleep-wake behavior, and psychiatric disorders.

Background: Autonomic nervous system (ANS) activity has been shown to vary with the state of brain arousal. In a previous study, this association of ANS activity with distinct states of brain arousal was demonstrated using 15-min EEG data, but without directly controlling for possible time-on-task effects. In the current study we examine ANS-activity in fine-graded EEG-vigilance stages (indicating states of brain arousal) during two conditions of a 2-h oddball task while controlling for time-on-task. In addition, we analyze the effect of time-on-task on ANS-activity while holding the level of brain arousal constant., Methods: Heart rate and skin conductance level of healthy participants were recorded during a 2-h EEG with eyes closed under simultaneous presentation of stimuli in an ignored (N = 39) and attended (N = 39) oddball condition. EEG-vigilance stages were classified using the Vigilance Algorithm Leipzig (VIGALL 2.1). The time-on-task effect was tested by dividing the EEG into four 30-min consecutive time blocks. ANS-activity was compared between EEG-vigilance stages across the entire 2 h and within each time block., Results: We found a coherent decline of ANS-activity with declining brain arousal states, over the 2-h recording and in most cases within each 30-min block in both conditions. Furthermore, we found a significant time-on-task effect on heart rate, even when arousal was kept constant. It was most pronounced between the first and all subsequent blocks and could have been a consequence of postural change at the beginning of the experiment., Conclusion: Our findings contribute to the validation of VIGALL 2.1 using ANS parameters in 2-h EEG recording under oddball conditions.

Maintaining temporal coordination across physiological systems is crucial at the wake-sleep transition. As shown in recent studies, the degree of coordination between brain and autonomic arousal influences attention, which highlights a previously unrecognised point of potential failure in the attention system. To investigate how cortical and autonomic dynamics are linked to the attentive process we analysed electroencephalogram, electrocardiogram and skin conductance data of 39 healthy adults recorded during a 2-h resting-state oddball experiment. We related cross-correlations to fluctuation periods of cortical and autonomic signals and correlated obtained measures to event-related potentials N1 and P2, reflecting excitatory and inhibitory processes. Increasing alignment of cortical and autonomic signals and longer periods of vigilance fluctuations corresponded to a larger and earlier P2; no such relations were found for N1. We compared two groups, with (I) and without measurable (II) delay in cortico-autonomic correlations. Individuals in Group II had more stable vigilance fluctuations, larger and earlier P2 and fell asleep more frequently than individuals in Group I. Our results support the hypothesis of a link between cortico-autonomic coupling and dynamics and central inhibition. Quantifying this link could help refine classification in psychiatric disorders with attention and sleep-related symptoms, particularly in ADHD, depression, and insomnia.

Background: Previous studies compared evoked potentials (EPs) between several sleep stages but only one uniform wake state. However, using electroencephalography (EEG), several arousal states can be distinguished before sleep onset. Recently, the Vigilance Algorithm Leipzig (VIGALL 2.0) has been developed, which automatically attributes one out of seven EEG-vigilance stages to each 1-s EEG segment, ranging from stage 0 (associated with cognitively active wakefulness), to stages A1, A2 and A3 (associated with relaxed wakefulness), to stages B1 and B2/3 (associated with drowsiness) up to stage C (indicating sleep onset). Applying VIGALL, we specified the effects of these finely differentiated EEG-vigilance stages (indicating arousal states) on EPs (P1, N1, P2, N300, MMN and P3) and behavioral performance. Subjects underwent an ignored and attended condition of a 2-h eyes-closed oddball-task. Final analysis included 43 subjects in the ignored and 51 subjects in the attended condition. First, the effect of brain arousal states on EPs and performance parameters were analyzed between EEG-vigilance stages A (i.e. A1, A2 and A3 combined), B1 and B2/3&C (i.e. B2/3 and C combined). Then, in a second step, the effects of the finely differentiated EEG-vigilance stages were further specified., Results: Comparing stages A versus B1 versus B2/3&C, a significant effect of EEG-vigilance stages on all behavioral parameters and all EPs, with exception of MMN and P3, was found. By applying VIGALL, a more detailed view of arousal effects on EP and performance was possible, such as the finding that the P2 showed no further significant increase in stages deeper than B1. Stage 0 did not differ from any of the A-stages. Within more fine-graded stages, such as the A-substages, EPs and performance only partially differed. However, these analyses were partly based on small sample sizes and future studies should take effort to get enough epochs of rare stages (such as A3 and C)., Conclusions: A clear impact of arousal on EPs and behavioral performance was obtained, which emphasize the necessity to consider arousal effects when interpreting EPs.

Understanding how to reduce the influence of physiological noise in resting state fMRI data is important for the interpretation of functional brain connectivity. Limited data is currently available to assess the performance of physiological noise correction techniques, in particular when evaluating longitudinal changes in the default mode network (DMN) of healthy elderly participants. In this 3T harmonized multisite fMRI study, we investigated how different retrospective physiological noise correction (rPNC) methods influence the within-site test-retest reliability and the across-site reproducibility consistency of DMN-derived measurements across 13 MRI sites. Elderly participants were scanned twice at least a week apart (five participants per site). The rPNC methods were: none (NPC), Tissue-based regression, PESTICA and FSL-FIX. The DMN at the single subject level was robustly identified using ICA methods in all rPNC conditions. The methods significantly affected the mean z-scores and, albeit less markedly, the cluster-size in the DMN; in particular, FSL-FIX tended to increase the DMN z-scores compared to others. Within-site test-retest reliability was consistent across sites, with no differences across rPNC methods. The absolute percent errors were in the range of 5-11% for DMN z-scores and cluster-size reliability. DMN pattern overlap was in the range 60-65%. In particular, no rPNC method showed a significant reliability improvement relative to NPC. However, FSL-FIX and Tissue-based physiological correction methods showed both similar and significant improvements of reproducibility consistency across the consortium (ICC = 0.67) for the DMN z-scores relative to NPC. Overall these findings support the use of rPNC methods like tissue-based or FSL-FIX to characterize multisite longitudinal changes of intrinsic functional connectivity. Hum Brain Mapp 37:2114-2132, 2016. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Recently, there has been an increased interest in the use of automatically segmented subfields of the human hippocampal formation derived from magnetic resonance imaging (MRI). However, little is known about the test-retest reproducibility of such measures, particularly in the context of multisite studies. Here, we report the reproducibility of automated Freesurfer hippocampal subfields segmentations in 65 healthy elderly enrolled in a consortium of 13 3T MRI sites (five subjects per site). Participants were scanned in two sessions (test and retest) at least one week apart. Each session included two anatomical 3D T1 MRI acquisitions harmonized in the consortium. We evaluated the test-retest reproducibility of subfields segmentation (i) to assess the effects of averaging two within-session T1 images and (ii) to compare subfields with whole hippocampus volume and spatial reliability. We found that within-session averaging of two T1 images significantly improved the reproducibility of all hippocampal subfields but not that of the whole hippocampus. Volumetric and spatial reproducibility across MRI sites were very good for the whole hippocampus, CA2-3, CA4-dentate gyrus (DG), subiculum (reproducibility error∼2% and DICE > 0.90), good for CA1 and presubiculum (reproducibility error ∼ 5% and DICE ∼ 0.90), and poorer for fimbria and hippocampal fissure (reproducibility error ∼ 15% and DICE < 0.80). Spearman's correlations confirmed that test-retest reproducibility improved with volume size. Despite considerable differences of MRI scanner configurations, we found consistent hippocampal subfields volumes estimation. CA2-3, CA4-DG, and sub-CA1 (subiculum, presubiculum, and CA1 pooled together) gave test-retest reproducibility similar to the whole hippocampus. Our findings suggest that the larger hippocampal subfields volume may be reliable longitudinal markers in multisite studies., (© 2015 Wiley Periodicals, Inc.)

Background: The LIFE-Adult-Study is a population-based cohort study, which has recently completed the baseline examination of 10,000 randomly selected participants from Leipzig, a major city with 550,000 inhabitants in the east of Germany. It is the first study of this kind and size in an urban population in the eastern part of Germany. The study is conducted by the Leipzig Research Centre for Civilization Diseases (LIFE). Our objective is to investigate prevalences, early onset markers, genetic predispositions, and the role of lifestyle factors of major civilization diseases, with primary focus on metabolic and vascular diseases, heart function, cognitive impairment, brain function, depression, sleep disorders and vigilance dysregulation, retinal and optic nerve degeneration, and allergies., Methods/design: The study covers a main age range from 40-79 years with particular deep phenotyping in elderly participants above the age of 60. The baseline examination was conducted from August 2011 to November 2014. All participants underwent an extensive core assessment programme (5-6 h) including structured interviews, questionnaires, physical examinations, and biospecimen collection. Participants over 60 underwent two additional assessment programmes (3-4 h each) on two separate visits including deeper cognitive testing, brain magnetic resonance imaging, diagnostic interviews for depression, and electroencephalography., Discussion: The participation rate was 33 %. The assessment programme was accepted well and completely passed by almost all participants. Biomarker analyses have already been performed in all participants. Genotype, transcriptome and metabolome analyses have been conducted in subgroups. The first follow-up examination will commence in 2016.

Background: The neuropeptide S receptor (NPSR1) and its ligand neuropeptide S (NPS) have received increased attention in the last few years, as both establish a previously unknown system of neuromodulation. Animal research studies have suggested that NPS may be involved in arousal/wakefulness and may also have a crucial role in sleep regulation. The single nucleotide polymorphism (SNP) rs324981 in NPSR1 has begun to shed light on a function of the NPS-system in human sleep regulation. Due to an amino acid exchange, the T-allele leads to an increased sensitivity of the NPSR1. In the only genome-wide association study to date on circadian sleep parameters in humans, an association was found between rs324981 and regular bedtime. However, the sleep parameters in this study were only measured by self-rating. Therefore, our study aimed to replicate these findings using an objective measure of sleep., Methods: The study included n = 393 white subjects (62-79 years) who participated in an actigraphic assessment for determining sleep duration, rest duration, sleep onset, rest onset and sleep onset latency. Genotyping of the SNP rs324981 was performed using the TaqMan OpenArray System., Results: The genotype at rs324981 was not significantly associated with rest onset (bedtime) or sleep onset (p = .146 and p = .199, respectively). However, the SNP showed a significant effect on sleep- and rest duration (p = .007 and p = .003, respectively). Subjects that were homozygous for the minor T-allele had a significantly decreased sleep- and rest duration compared to A-allele carriers., Conclusion: The results of this study indicate that the sleep pattern in humans is influenced by the NPS-system. However, the previously reported association between bedtime and rs324981 could not be confirmed. The current finding of decreased sleep duration in T/T allele carriers is in accordance with studies in rodents reporting similar results after NPS application.

Genetic variation of the serotonin transporter (5-HTT) has been associated with fear- and anxiety-related behaviours. The amygdala is considered crucial in emotional modulation and stronger amygdala reactivity in response to fearful stimuli has been found in carriers of the short (S) allele of the 5-HTT gene in imaging studies. Additionally, reactivity of amygdala-innervated effectory systems is also of particular interest. We recently reported the impact of a functional polymorphism in the transcriptional control region of the serotonin transporter gene (5-HTTLPR) on the acoustic startle reflex. Here, we attempted to replicate and extend these findings. Startle magnitudes to intense noise bursts as measured with the eyeblink response were recorded in 106 healthy volunteers during baseline without additional stimulation and while they viewed pictures of three valence conditions: unpleasant, pleasant and neutral. Subjects were genotyped for the tri-allelic functional polymorphism 5-HTTLPR. In replication of our previous findings we found that carriers of the low-expressing S or LG alleles exhibited stronger overall startle responses across conditions than LA/LA homozygotes, while there were no differences in emotional startle modulation between the two genetic groups. In addition, we found that the recent experience of stressful life events resulted in overall higher startle responses and less startle habituation across blocks. The results replicate and emphasize the role of 5-HTTLPR and stress on the overall startle response as a possible genetically driven endophenotype for anxiety-related behaviour.

Intensity dependence of auditory-evoked potentials (IAEP) has been suggested as an indicator of central serotonergic neurotransmission. Two recent studies investigated a possible association of IAEP with a functional polymorphism in the transcriptional control region of the serotonin transporter gene (5-HTTLPR) that has a short (s) and a long (l) variant. Although both studies found an association between 5-HTTLPR and IAEP, Gallinat et al found l/l individuals to exhibit lower IAEP, whereas Strobel et al observed stronger IAEP in l/l individuals. These conflicting results require further evaluation and more attention needs to be paid to variables that are known to be confounded with the effects of IAEP and 5-HTTLPR. Using a paradigm comparable to Strobel et al, the present study analyzes the effect of 5-HTTLPR on IAEP in a healthy male student sample (N=91; age=23 years, SD=1.9) that was homogenous for most significant confounding variables. A stronger IAEP was shown in l/l individuals, irrespective of the method of IAEP parametrization. This also held at retest after 3 weeks in a subsample (N=18). Given the successful replication of Strobel et al, several possible reasons for conflicting results with regard to Gallinat et al are discussed. It is argued that the most significant difference between Gallinat et al on the one hand, and Strobel et al and this study on the other, is that different intensity ranges are used which impact IAEP. Therefore, this study encourages further analysis of dose dependence of results.

Neuronal activity elicits a rapid increase in the expression of several immediate early genes (IEGs). To clarify a role for IEG response in activity-dependent development, we examined the contribution of the egr1/zif268 gene during visual cortical processing and plasticity in mice. We first analyzed the expression of egr1 mRNA in wild-type (WT) mice using Northern blot hybridization. In the visual cortex, expression of egr1 mRNA increased dramatically after eye opening, systemic injection of kainate, or 30 min of photostimulation after a brief (5 d) period of dark adaptation. Thus, the expression of egr1 is regulated by synaptic activity in the mouse visual cortex, as it is in other species (e.g., monkeys, cats, and rats). To evaluate whether this transcription factor is directly involved in activity-dependent plasticity, mice lacking Egr1 were deprived of the use of one eye during the developmental critical period [postnatal day 24 (P24)-P34]. Extracellular in vivo single-unit recordings from the binocular zone of the visual cortex revealed that visual responses developed normally in egr1 knock-out (KO) mice. Moreover, a similarly significant shift of responsiveness in favor of the open eye was produced in both KO and WT mice by either brief (4 d) or long-term (>2 weeks) occlusion of one eye. There was no apparent compensation among egr2, egr3, or c-fos mRNA and protein expression in the visual cortex of egr1 KO mice. Taken together, these results indicate that egr1 is a useful marker of sensory input in mice but is not intrinsically necessary for the experience-dependent plasticity of the visual cortex. Our findings underscore a mechanistic distinction between sensory plasticity and long-lasting forms of synaptic potentiation in the hippocampus, for which egr1/zif268 was recently found to be essential.

Neuronal circuits across several systems display remarkable plasticity to sensory input during postnatal development. Experience-dependent refinements are often restricted to well-defined critical periods in early life, but how these are established remains mostly unknown. A representative example is the loss of responsiveness in neocortex to an eye deprived of vision. Here we show that the potential for plasticity is retained throughout life until an inhibitory threshold is attained. In mice of all ages lacking an isoform of GABA (gamma-aminobutyric acid) synthetic enzyme (GAD65), as well as in immature wild-type animals before the onset of their natural critical period, benzodiazepines selectively reduced a prolonged discharge phenotype to unmask plasticity. Enhancing GABA-mediated transmission early in life rendered mutant animals insensitive to monocular deprivation as adults, similar to normal wild-type mice. Short-term presynaptic dynamics reflected a synaptic reorganization in GAD65 knockout mice after chronic diazepam treatment. A threshold level of inhibition within the visual cortex may thus trigger, once in life, an experience-dependent critical period for circuit consolidation, which may otherwise lie dormant.

Sensory experience in early life shapes the mammalian brain. An impairment in the activity-dependent refinement of functional connections within developing visual cortex was identified here in a mouse model. Gene-targeted disruption of one isoform of glutamic acid decarboxylase prevented the competitive loss of responsiveness to an eye briefly deprived of vision, without affecting cooperative mechanisms of synapse modification in vitro. Selective, use-dependent enhancement of fast intracortical inhibitory transmission with benzodiazepines restored plasticity in vivo, rescuing the genetic defect. Specific networks of inhibitory interneurons intrinsic to visual cortex may detect perturbations in sensory input to drive experience-dependent plasticity during development.

Developing sensory systems are sculpted by an activity-dependent strengthening and weakening of connections. Long-term potentiation (LTP) and depression (LTD) in vitro have been proposed to model this experience-dependent circuit refinement. We directly compared LTP and LTD induction in vitro with plasticity in vivo in the developing visual cortex of a mouse mutant of protein kinase A (PKA), a key enzyme implicated in the plasticity of a diverse array of systems. In mice lacking the RIbeta regulatory subunit of PKA, we observed three abnormalities of synaptic plasticity in layer II/III of visual cortex in vitro. These included an absence of (1) extracellularly recorded LTP, (2) depotentiation or LTD, and (3) paired-pulse facilitation. Potentiation was induced, however, by pairing low-frequency stimulation with direct depolarization of individual mutant pyramidal cells. Together these findings suggest that the LTP defect in slices lacking PKA RIbeta lies in the transmission of sufficient net excitation through the cortical circuit. Nonetheless, functional development and plasticity of visual cortical responses in vivo after monocular deprivation did not differ from normal. Moreover, the loss of all responsiveness to stimulation of the originally deprived eye in most cortical cells could be restored by reverse suture of eyelids during the critical period in both wild-type and mutant mice. Such an activity-dependent increase in response would seem to require a mechanism like potentiation in vivo. Thus, the RIbeta isoform of PKA is not essential for ocular dominance plasticity, which can proceed despite defects in several common in vitro models of neural plasticity.

Occluding vision through one eye during a critical period in early life nearly abolishes responses to that eye in visual cortex. This phenomenon is mimicked by long-term depression of synaptic transmission in vitro, which may require metabotropic glutamate receptors (mGluRs) and is age-dependent. Peaks in mGluR expression and glutamate-stimulated phosphoinositide turnover during visual cortical development have been proposed as biochemical bases for the critical period. Pharmacological blockade of mGluRs specifically prevented synapse weakening in mouse visual cortical slices but did not alter kitten ocular dominance plasticity in vivo. Thus, a heightened mGluR response does not account for the critical period in development.

Neurons contain distinct compartments including dendrites, dendritic spines, axons and synaptic terminals. The molecular mechanisms that generate and distinguish these compartments, although largely unknown, may involve the small GTPases Rac and Cdc42, which appear to regulate actin polymerization. Having shown that perturbations of Rac1 activity block the growth of axons but not dendrites of Drosophila neurons, we investigated whether this also applies to mammals by examining transgenic mice expressing constitutively active human Rac1 in Purkinje cells. We found that these mice were ataxic and had a reduction of Purkinje-cell axon terminals in the deep cerebellar nuclei, whereas the dendritic trees grew to normal height and branched extensively. Unexpectedly, the dendritic spines of Purkinje cells in developing and mature cerebella were much reduced in size but increased in number. These 'mini' spines often form supernumerary synapses. These differential effects of perturbing Rac1 activity indicate that there may be distinct mechanisms for the elaboration of axons, dendrites and dendritic spines.