EEG Data Quality: Determinants and Impact in a Multicenter Study of Children, Adolescents, and Adults with Attention-Deficit/Hyperactivity Disorder (ADHD)

Electroencephalography (EEG) represents a widely established method for assessing altered and typically developing brain function. However, systematic studies on EEG data quality, its correlates, and consequences are scarce. To address this research gap, the current study focused on the percentage of artifact-free segments after standard EEG pre-processing as a data quality index. We analyzed participant-related and methodological influences, and validity by replicating landmark EEG effects. Further, effects of data quality on spectral power analyses beyond participant-related characteristics were explored. EEG data from a multicenter ADHD-cohort (age range 6 to 45 years), and a non-ADHD school-age control group were analyzed (ntotal = 305). Resting-state data during eyes open, and eyes closed conditions, and task-related data during a cued Continuous Performance Task (CPT) were collected. After pre-processing, general linear models, and stepwise regression models were fitted to the data. We found that EEG data quality was strongly related to demographic characteristics, but not to methodological factors. We were able to replicate maturational, task, and ADHD effects reported in the EEG literature, establishing a link with EEG-landmark effects. Furthermore, we showed that poor data quality significantly increases spectral power beyond effects of maturation and symptom severity. Taken together, the current results indicate that with a careful design and systematic quality control, informative large-scale multicenter trials characterizing neurophysiological mechanisms in neurodevelopmental disorders across the lifespan are feasible. Nevertheless, results are restricted to the limitations reported. Future work will clarify predictive value

A cellular model for human daily behaviour

All the biochemical, physiological or behavioural processes whose period is about 24 hours possess a circadian rhythm. In mammals circadian rhythms control almost all aspects of human daily behaviour and physiology. Dysregulation of circadian rhythms leads to several pathologies, such as depression, cancer and metabolic syndromes. Mammalian circadian system is organized in a hierarchic fashion: suprachiasmatic nucleus (SCN) is master clock and governs the circadian rhythms of all peripheral oscillators, virtually all the other cells of the body. The study of human circadian rhythms in subjects in vivo is expensive, time consuming and invading. However, since SCN and peripheral oscillators share the same circadian molecular machinery, it is possible to use peripheral oscillator as model to study molecular mechanisms of circadian rhythms. To visualize in real-time cellular circadian rhythms, fibroblasts were infected with a lentivirus coding for the circadian reporter firefly luciferase under a clock gene promoter (Bmal1). After the synchronization of circadian rhythms, the measurement of the light emitted by the cells gave a representation of fibroblast circadian oscillations. The aim of the thesis was to establish the use of human primary skin fibroblasts as a valuable model to study different aspects of human circadian rhythms. To address these questions three projects were designed. A first set of experiments aimed at validating human skin fibroblast model, ascertaining that this in vitro model parallels in vivo human circadian parameters. We found a very good correlation between the in vivo and the in vitro period length in the three groups of subjects (two sighted and one blind) recruited for this study. Interestingly, although the in vivo period obtained from the blind group was longer than the in vivo period obtained from the sighted groups, the in vitro period length from the three groups of subjects was similar, revealing that human skin fibroblasts are insensitive to the after-effects caused by light. In summary, human circadian period can be approximated by measurement in fibroblasts. In a second project human age-related circadian impairments were studied in the cellular skin fibroblasts model. Indeed sleep-wake cycle alterations and phase advancing of gene expression and behaviour can be found in elder individuals. To better understand the rebound of ageing on the circadian rhythms we characterized the period length of skin fibroblasts from young and elder persons. No differences in amplitude, phase and period length were found between cells from the two groups. However, in the presence of sera from older donors human fibroblasts showed a reduced period length and a shorter phase of entrainment compared to the same cells measured in the presence of sera from young donors. These differences are likely due to one or more thermolabile substances, since heat-inactivation of sera from older donors almost undid the reduction of the circadian period length. Thus, these results suggest that during ageing the molecular machinery of peripheral circadian clocks does not change per se, but some age-related circadian changes observed in vivo might be caused by circulating molecules. Human fibroblasts were also used to investigate the role of melatonin as zeitgeber on peripheral oscillators. Melatonin is secreted in a circadian fashion and was demonstrated to regulate the SCN firing rate and to entrain the sleep-wake cycle of most mammals and humans. The circadian presence of melatonin is well conserved in all biological fluids, suggesting that melatonin may be one of the molecules that the master clock uses to synchronize peripheral oscillators. This hypothesis was tested in damped fibroblasts, using a wide range of concentrations of melatonin to restore the amplitude of the rhythms. However, no increase of amplitude or phase shift of the rhythms was observed after treating cells with melatonin. Moreover, the application of the hormone to newly synchronized oscillators decreased their bioluminescence. In summary, the experiments demonstrated that melatonin does not play a direct role as peripheral oscillator zeitgeber. In conclusion, the studies of the present thesis succeeded in revealing three primary findings: first, fibroblast circadian rhythms parallel human circadian physiology, such as circadian period length. Second, apparently, during ageing the molecular components of peripheral circadian clocks in skin fibroblasts do not change per se, but some age-related circadian changes observed in vivo might be caused by one or more heat-sensitive substances present in the blood of older subjects. Finally, melatonin does not possess direct synchronizing properties on peripheral oscillators like fibroblasts. In total, the present thesis revealed that primary human skin fibroblasts are an easily accessible, cheap and reliable model to enlighten our understanding of human circadian mechanisms

Immunohistochemical and electrophysiological investigation of E/I balance alterations in animal models of frontotemporal dementia

Behavioural variant frontotemporal dementia (bvFTD) is a neurodegenerative disease characterised by changes in behaviour. Apathy, behavioural disinhibition and stereotyped behaviours are the first symptoms to appear and all have a basis in reward and pleasure deficits. The ventral striatum and ventral regions of the globus pallidus are involved in reward and pleasure. It is therefore reasonable to suggest alterations in these regions may underpin bvFTD. One postulated contributory factor is alteration in E/I balance in striatal regions. GABAergic interneurons play a role in E/I balance, acting as local inhibitory brakes, they are therefore a rational target for research investigating early biological predictors of bvFTD. To investigate this, we will carry out immunohistochemical staining for GABAergic interneurons (parvalbumin and neuronal nitric oxide synthase) in striatal regions of brains taken from CHMP2B mice, a validated animal model of bvFTD. We hypothesise that there will be fewer GABAergic interneurons in the striatum which may lead to ‘reward-seeking’ behaviour in bvFTD. This will also enable us to investigate any preclinical alterations in interneuron expression within this region. Results will be analysed using a mixed ANOVA and if significant, post hoc t-tests will be used. The second part of our study will involve extracellular recordings from CHMP2B mouse brains using a multi-electrode array (MEA). This will enable us to determine if there are alterations in local field potentials (LFP) in preclinical and symptomatic animals. We will also be able to see if neuromodulators such as serotonin and dopamine effect LFPs after bath application. We will develop slice preparations to preserve pathways between the ventral tegmental area and the ventral pallidum, an output structure of the striatum, and the dorsal raphe nucleus and the VP. Using the MEA we will stimulate an endogenous release of dopamine and serotonin using the slice preparations as described above. This will enable us to see if there are any changes in LFPs after endogenous release of neuromodulators. We hypothesise there will be an increase in LFPs due to loss of GABAergic interneurons

The effect of decerebrate rigidity on intracranial pressure in man and animals

Patients with decerebrate rigidity frequently also show intracranial hypertension. The factors responsible for this effect and their inter -relationships were explored in cats and in patients with head injuries.Animals: The factors examined, separately and in combination, were elevation of central venous, intrathoracic, intra- abdominal and systemic arterial pressures. The baselines thus established were used for the investigation of the effects of these factors on the intracranial pressure (ICP) in cats which had been rendered decerebrate by focal stereotactic mesencephalic lesions.Little or no change occurred in the ICP when: 1) Rigidity was mainly unilateral. 2) Bilateral limb rigidity was extreme.Persistent elevation of ICP occurred when 1) Truncal rigidity resulted in the simultaneous elevation of the intrathoracic and intra- abdominal pressures 2) Elevation of the systemic arterial pressure occurred in the presence of defective cerebrovascular homeostasis.Human: The dynamics and management of the complex clinical problem posed by decerebrate rigidity were investigated in patients with head injuries who exhibited well -developed bi- lateral rigidity under conditions of altered cerebral elastance.Rigidity was quantified by measuring the resonant frequency of the wrist induced by a printed- circuit motor. The brain elastance, ICP, intrathoracic and blood pressures were measured throughout the study. The effect of pharmacological muscle paralysis on the ICP and rigidity was examined.It appeared that well- developed decerebrate rigidity increased the ICP. The relationship was direct; the greater the rigidity or cerebral elastance, the greater the rise in ICP and vice versa. The two factors mainly responsible were muscle hypertonicity and cerebral elastance. The rises in ICP were caused by the rigidity and although it may not always be possible to reduce the abnormally increased elastance, the rigidity can certainly be abolished. As long as the cerebral vascular homeostatic mechanisms were intact, spontaneous waning of the rigidity or its abolition by muscle relaxants returned the ICP to its previous resting level. Pancuronium produced much deeper and more lasting relaxation than either diazepam or chlorpromazine.During the period of mechanical ventilation, alterations in ICP were of prognostic value as regards the outcome of the injuries

Computer simulation of a neurological model of learning

A number of problems in psychology and neurology are discussed to orient the reader to a theory of neural integration. The importance is stressed of the comprehensive temporal and spatial integration of sensory, motor and motivational aspects of brain function. It is argued that an extended neural template theory could provide such an integration. Contemporary solutions to the problem of neural integration are discussed. The available knowledge concerning the structure of neural tissue leads to the description of a theory of neural integration which might provide such neural templates. Integrating Neurons are suggested to be organised in columns or pools. Sub-sets of Neurons are formed as a result of excitation and can preferentially exchange excitation. These sub-sets or Linked Constellations would act as spatial templates to be matched with subsequent states of excitation. Inhibition acts to restrict spike emission to the most highly activated sub-sets. An initial computer simulation represented a simple learning or classical conditioning situation. In a variety of test computer runs the performance confirmed the main predictions of the theoretical model. The model was then extended to include representation of instrumental, consummatory, motivational and other aspects of behaviour. The intention of these further simulations was not to demonstrate the predictions of prior formulations but rather to use the computer to develop simulations progressively able to represent behaviour. Difficulties were encountered which were remedied by incorporating rhythmic mechanisms. A number of different versions of the model were explored. It was shown that the models could be trained to produced a different response to discriminative cues, when those cues had previously signalled different contingencies of obtaining the opportunity to perform consummatory behaviour. A published experiment on the Spiral Illusion is reported, which confirmed predictions suggested by the model.<p

Circadian clocks, glucocorticoids and the gated inflammatory response

In mammals endogenous, self sustained oscillators, known as circadian clocks, have evolved as a result of day night cycles, with a period close to 24 hours, and are involved in many physiological processes; such as sleep wake cycles, metabolic and hormonal activity. The suprachiasmatic nucleus (SCN), is the central oscillator, and is synchronised to the external environment by light, via the eye. It has been demonstrated that peripheral clocks, too, contain the circadian oscillator, with tissues such as the lung, liver, heart and kidney as well as many isolated cell types remaining rhythmic, in culture, for many days. However, these peripheral oscillators require a signal from the central oscillator in order to co-ordinate a synchronised time. Leading candidates in the relay of this information are the circulating glucocorticoid hormones corticosterone (rodents) or cortisol (man), which are known to have potent effects on the peripheral clock, both in-vivo and in-vitro. Further to this, glucocorticoids have been used for many decades to suppress the symptoms of inflammation, a by product of many human diseases.This thesis aims to address the temporal regulation of the peripheral clock by the endogenous glucocorticoid, corticosterone, using a transgenic mouse harbouring a luciferase conjugated clock reporter, and circadian reporter cell lines. It also aims to address the relative contribution of the two closely related nuclear hormone receptors, the glucocorticoid and mineralocorticoid receptors. A further aim of the work with glucocorticoid signalling was to design a flow-though culture system, in order to address the effects of the endogenous pulsatile release of glucocorticoids on the peripheral oscillator. This thesis also aims to characterise the inflammatory response in relation to its circadian characteristics; its relationship with corticosterone and the effect of inflammation on the central clock components. Finally, this thesis aims to investigate a potential input/output of the clock, a member of the family of C/EBP transcription factors, C/EBP alpha, and whether it is under endogenous circadian control and regulated by glucocorticoids.Work in this thesis has shown that glucocorticoids dynamically regulate the peripheral clock at all phases of the circadian cycle and that this regulation occurs mainly through the glucocorticoid receptor; yet the mineralocorticoid receptor does have a function in the immediate response to glucocorticoid administration. Furthermore, as a result of the initial temporal profile after corticosterone addition, on the clock protein PERIOD2, I have shown transient regulation of the clock through Caveolin-1 based signalling. There is also a significant circadian component to the inflammatory response, which appears, at least in part, to be REV-ERB alpha mediated, and the inflammatory response also has profound effects on circadian gene expression in the periphery. A functional flow-through system was designed and a working model produced, albeit with technical difficulties, to address glucocorticoid pulsing and circadian timing but much more work is needed for effects to be fully understood. C/EBP alpha appears not to be under circadian regulation nor under direct glucocorticoid regulation, at least in peripheral models used here.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Functional neuroanatomy of action selection in schizophrenia

Schizophrenia remains an enigmatic disorder with unclear neuropathology. Recent advances in neuroimaging and genetic research suggest alterations in glutamate-dopamine interactions adversely affecting synaptic plasticity both intracortically and subcortically. Relating these changes to the manifestation of symptoms presents a great challenge, requiring a constrained framework to capture the most salient elements. Here, a biologically-grounded computational model of basal ganglia-mediated action selection was used to explore two pathological processes that hypothetically underpin schizophrenia. These were a drop in the efficiency of cortical transmission, reducing both the signal-to-noise ratio (SNR) and overall activity levels; and an excessive compensatory upregulation of subcortical dopamine release. It was proposed that reduced cortical efficiency was the primary process, which led to a secondary disinhibition of subcortical dopamine release within the striatum. This compensation was believed to partly recover lost function, but could then induce disorganised-type symptoms - summarised as selection ”Instability” - if it became too pronounced. This overcompensation was argued to be countered by antipsychotic medication. The model’s validity was tested during an fMRI (functional magnetic resonance imaging) study of 16 healthy volunteers, using a novel perceptual decision-making task, and was found to provide a good account for pallidal activation. Its account for striatum was developed and improved with a small number of principled model modifications: the inclusion of fast spiking interneurons within striatum, and their inhibition by the basal ganglia’s key regulatory nucleus, external globus pallidus. A key final addition was the explicit modelling of dopaminergic midbrain, which is dynamically regulated by both cortex and the basal ganglia. This enabled hypotheses concerning the effects of cortical inefficiency, compensatory dopamine release and medication to be directly tested. The new model was verified with a second set of 12 healthy controls. Its pathological predictions were compared to data from 12 patients with schizophrenia. Model simulations suggested that Instability went hand-in-hand with cortical inefficiency and secondary dopamine upregulation. Patients with high Instability scores showed a loss of SNR within decision-related cortex (consistent with cortical inefficiency); an exaggerated response to task demands within substantia nigra (consistent with dopaminergic upregulation); and had an improved fit to simulated data derived from increasingly cortically-inefficient models. Simulations representing the healthy state provided a good account for patients’ motor putamen, but only cortically-inefficient simulations representing the ill state provided a fit for ventral-anterior striatum. This fit improved as the simulated model became more medicated (increased D2 receptor blockade). The relative improvement of this account correlated with patients’ medication dosage. In summary, by distilling the hypothetical neuropathology of schizophrenia into two simplified umbrella processes, and using a computational model to consider their effects within action selection, this work has successfully related patients’ fMRI activation to particular symptomatology and antipsychotic medication. This approach has the potential to improve patient care by enabling a neurobiological appreciation of their current illness state, and tailoring their medication level appropriately

Rhythms of Life - An introduction using selected topics and examples

Examples for rhythms in the minute- and hour-range (chemical oscillator, glycolysis-oscillator of yeast, gravitropic pendulum, transpiration rhythms in oats, lateral leaflet movements of the telegraph plant, circumnutation, REM-sleep of mammals), for daily rhythms (sleep and wake, activity and body temperature) and consequences of their disturbances (shiftwork, jet-lag, diseases) are presented. How these rhythms function and can be influenced, is shown in mammals. Unicellulars too possess clocks (Gonyaulax, Acetabularia, cyanobacteria). In higher plants daily rhythms of photosynthesis, transpiration, leaf- and petal movements, division, growth and metabolism are known. Insects are equipped with daily rhythms. They help in orientation (time sense of bees, sun compass orientation). Tidal rhythms in organisms at the coast of the sea and lunar rhythms are presented. Annual rhythms are also common among living beings (seed germination, migration of birds, reproduction, hibernation). Photoperiodic reactions help the organisms to orient themselves during the course of the year (seed germination, flowering, diapause). Daily clocks of Drosophila are molecular biologically intensively studied. Eye clocks in marine snails, fungal rhythms, coral clocks and significance and selective advantage of these rhythms are further topics. There is finally a collection of special topics which should accentuate or illustrate certain points. In several places of this introduction into chronobiology experiments are referred to.Beispiele für Rhythmen im Minuten- und Stundenbereich (chemischer Oszillator, Glykolyse-Oszillator der Hefe, gravitropes Pendel, Transpirationsrhythmen beim Hafer, Seitenfiederbewegung der Telegrafenpflanze, Circumnutation, REM-Schlaf der Säuger), für Tageshythmen (Schlafen und Wachen, Aktivität und Körpertemperatur) und Folgen ihrer Störungen (Schichtarbeit, Jet-lag, Krankheiten) werden vorgestellt. Wie diese Rhythmen funktionieren und sich beeinflussen lassen, wird an Säugern gezeigt. Auch Einzeller haben Uhren (Gonyaulax, Acetabularia, Cyanobakterien). Bei höheren Pflanzen sind Tagesrhythmen der Photosynthese, Transpiration, Blatt- und Blütenbewegung, Teilung, Wachstum und Stoffwechsel bekannt. Insekten sind mit Tagesrhythmen ausgestattet. Sie helfen bei der Orientierung (Zeitsinn der Bienen, Sonnenkompaßorientierung). Gezeitenrhythmen bei Organismen im Küstenbereich der Meere und lunare Rhythmen werden an Beispielen vorgestellt. Auch Jahresrhythmen sind bei Lebewesen weit verbreitet (Samenkeimung, Vogelzug, Fortpflanzung, Winterschlaf). Photoperiodische Reaktionen helfen den Organismen, sich im Jahresgang zurechtzufinden (Samenkeimung, Blühen, Diapause). Tagesuhren von Drosophila sind molekularbiologisch intensiv untersucht. Augenuhren bei Meeresschnecken, Pilzrhythmen, Korallenuhren und Bedeutung und selektiver Vorteil dieser Rhythmen sind weitere Themen. Schließlich gibt es eine Sammlung von Spezialthemen, die bestimmte Dinge vertiefen oder illustrieren. In dieser Einführung in die Chronobiologie wird auch an den verschiedenen Stellen auf Versuche hingewiesen