Hypoarousal as indicated by skin conductance and electroencephalography (EEG) has been discussed as a pathogenetic factor in attention-deficit/hyperactivity disorder (ADHD). The aim of this paper was to review these arousal-related pathogenetic concepts and to present the more recently proposed vigilance regulation model of affective disorders and ADHD. The latter builds on methodological advances in classifying short EEG segments into vigilance stages (Vigilance Algorithm Leipzig, VIGALL), indicating different states of global brain function ("brain arousal"). VIGALL allows the objective assessment of vigilance regulation under defined conditions, e.g. how fast vigilance declines to lower vigilance stages associated with drowsiness during 15-20-min EEG recordings under resting conditions with eyes closed. According to the vigilance regulation model, the hyperactivity and sensation seeking observed in overtired children, ADHD and mania may be interpreted as an autoregulatory attempt to create a stimulating environment in order to stabilize vigilance. The unstable regulation of vigilance observed in both mania and ADHD may thus explain the attention deficits, which become especially prominent in monotonous sustained attention tasks. Among the arguments supporting the vigilance regulation model are the facts that destabilizing vigilance (e.g., via sleep deprivation) can trigger or exacerbate symptoms of ADHD or mania, whereas stabilizing vigilance (e.g., via psychostimulants, reducing sleep deficits) alleviates these symptoms. The potential antimanic effects of methylphenidate are presently being studied in an international randomized controlled trial. We propose vigilance regulation as a converging biomarker, which could be useful for identifying treatment responders to psychostimulants and forming pathophysiologically more homogeneous ADHD subgroups for research purposes.
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.
Large-scale longitudinal multi-site MRI brain morphometry studies are becoming increasingly crucial to characterize both normal and clinical population groups using fully automated segmentation tools. The test-retest reproducibility of morphometry data acquired across multiple scanning sessions, and for different MR vendors, is an important reliability indicator since it defines the sensitivity of a protocol to detect longitudinal effects in a consortium. There is very limited knowledge about how across-session reliability of morphometry estimates might be affected by different 3T MRI systems. Moreover, there is a need for optimal acquisition and analysis protocols in order to reduce sample sizes. A recent study has shown that the longitudinal FreeSurfer segmentation offers improved within session test-retest reproducibility relative to the cross-sectional segmentation at one 3T site using a nonstandard multi-echo MPRAGE sequence. In this study we implement a multi-site 3T MRI morphometry protocol based on vendor provided T1 structural sequences from different vendors (3D MPRAGE on Siemens and Philips, 3D IR-SPGR on GE) implemented in 8 sites located in 4 European countries. The protocols used mild acceleration factors (1.5-2) when possible. We acquired across-session test-retest structural data of a group of healthy elderly subjects (5 subjects per site) and compared the across-session reproducibility of two full-brain automated segmentation methods based on either longitudinal or cross-sectional FreeSurfer processing. The segmentations include cortical thickness, intracranial, ventricle and subcortical volumes. Reproducibility is evaluated as absolute changes relative to the mean (%), Dice coefficient for volume overlap and intraclass correlation coefficients across two sessions. We found that this acquisition and analysis protocol gives comparable reproducibility results to previous studies that used longer acquisitions without acceleration. We also show that the longitudinal processing is systematically more reliable across sites regardless of MRI system differences. The reproducibility errors of the longitudinal segmentations are on average approximately half of those obtained with the cross sectional analysis for all volume segmentations and for entorhinal cortical thickness. No significant differences in reliability are found between the segmentation methods for the other cortical thickness estimates. The average of two MPRAGE volumes acquired within each test-retest session did not systematically improve the across-session reproducibility of morphometry estimates. Our results extend those from previous studies that showed improved reliability of the longitudinal analysis at single sites and/or with non-standard acquisition methods. The multi-site acquisition and analysis protocol presented here is promising for clinical applications since it allows for smaller sample sizes per MRI site or shorter trials in studies evaluating the role of potential biomarkers to predict disease progression or treatment effects.
The German Association for Psychiatry and Psychotherapy (DGPPN) has committed itself to establish a prospective national cohort of patients with major psychiatric disorders, the so-called DGPPN-Cohort. This project will enable the scientific exploitation of high-quality data and biomaterial from psychiatric patients for research. It will be set up using harmonised data sets and procedures for sample generation and guided by transparent rules for data access and data sharing regarding the central research database. While the main focus lies on biological research, it will be open to all kinds of scientific investigations, including epidemiological, clinical or health-service research.
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.
Prepulse inhibition (PPI) is the attenuation of the startle response towards an instantaneous and intense stimulus when preceded by a weaker non-startling stimulus. Deficits in this sensorimotor gating process have been associated with the pathophysiology of schizophrenia and other psychiatric disorders. Among the neurotransmitters involved in PPI modulation, serotonin (5-HT) has so far received comparably little attention. While a recent pharmacological study suggests an important role of different 5-HT receptor (5-HTR) subtypes in PPI modulation, the mechanisms by which 5-HTR impact on PPI remain to be further elucidated. Therefore, we employed a molecular genetic approach in order to examine whether PPI is associated with two functional 5-HTR gene polymorphisms, 5-HTR1A C-1019G and 5-HTR2A T102C. In a sample of 81 healthy volunteers, we found no significant main effects of the polymorphisms, but a significant interaction effect on PPI at short (50 ms) and mid-long (150 ms) pulse-prepulse intervals. The presence of the 5-HTR2A T allele (reported to result in higher 5-HTR2A expression) led to attenuated PPI only in the absence of the 5-HTR1A G allele (reported to result in reduced 5-HTR1A autoreceptor expression). Our results may indicate that a higher 5-HTR2A expression together with a reduced 5-HTR1A autoreceptor expression and consequently, elevated firing rates of serotonergic neurons results in elevated 5-HTR2A activation by serotonin which could potently attenuate PPI. While further research into the molecular mechanisms underlying this interaction is needed, our results underscore the role of 5-HTR in PPI modulation and further implicate the 5-HTR1A G-1019C and the 5-HTR2A T102C polymorphisms in the pathophysiology of schizophrenia.
According to the recently proposed vigilance model of affective disorders (vigilance in the sense of "brain arousal"), manic behaviour is partly interpreted as an autoregulatory attempt to stabilise vigilance by creating a stimulating environment, and the sensation avoidance and withdrawal in Major Depressive Disorder (MDD) is seen as an autoregulatory reaction to tonically increased vigilance. Indeed, using a newly developed EEG-based algorithm, hyperstable vigilance was found in MDD, and the contrary, with rapid drops to sleep stages, in mania. Furthermore, destabilising vigilance (e.g. by sleep deprivation) triggers (hypo)mania and improves depression, whereas stabilising vigilance, e.g. by prolonged sleep, improves mania. ADHD and mania have common symptoms, and the unstable vigilance might be a common pathophysiology. There is even evidence that psychostimulants might ameliorate both ADHD and mania. Hyperactivity of the noradrenergic system could explain both the high vigilance level in MDD and, as recently argued, anhedonia and behavioural inhibition. Interestingly, antidepressants and electroconvulsions decrease the firing rate of neurons in the noradrenergic locus coeruleus, whereas many antimanic drugs have opposite effects.
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