Browsing by Subject " physiology"

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  • Tokariev, Anton (Helsingin yliopisto, 2015)
    In humans the few months surrounding birth comprise a developmentally critical period characterised by the growth of major neuronal networks as well as their initial tuning towards more functionally mature large-scale constellations. Proper wiring in the neonatal brain, especially during the last trimester of pregnancy and the first weeks of postnatal life, relies on the brain’s endogenous activity and remains critical throughout one’s life. Structural or functional abnormalities at the stage of early network formation may result in a neurological disorder later during maturation. Functional connectivity measures based on an infant electroencephalographic (EEG) time series may be used to monitor these processes. A neonatal EEG is temporally discrete and consists of events (e.g., spontaneous activity transients (SATs)) and the intervals between them (inter-SATs). During early maturation, communication between areas of the brain may be transmitted through two distinct mechanisms: synchronisation between neuronal oscillations and event co-occurrences. In this study, we proposed a novel algorithm capable of assessing the coupling on both of these levels. Our analysis of real data from preterm neonates using the proposed algorithm demonstrated its ability to effectively detect functional connectivity disruptions caused by brain lesions. Our results also suggest that SAT synchronisation represents the dominant means through which inter-areal cooperation occurs in an immature brain. Structural disturbances of the neuronal pathways in the brain carry a frequency selective effect on the functional connectivity decreasing at the event level. Next, we used mathematical models and computational simulations combined with real EEG data to analyse the propagation of electrical neuronal activity within the neonatal head. Our results show that the conductivity of the neonatal skull is much higher than that found in adults. This leads to greater focal spread of cortical signals towards the scalp and requires high-density electrode meshes for quality monitoring of neonatal brain activity. Additionally, we show that the specific structure of the neonatal skull fontanel does not represent a special pathway for the spread of electrical activity because of the overall high conductivity of the skull. Finally, we demonstrated that the choice of EEG recording montage may strongly affect the fidelity of non-redundant neuronal information registration as well as the output of functional connectivity analysis. Our simulations suggest that high-density EEG electrode arrays combined with mathematical transformations, such as the global average or current source density (CSD), provide more spatially accurate details about the underlying cortical activity and may yield results more robust against volume conduction effects. Furthermore, we provide clear instruction regarding how to optimise recording montages for different numbers of sensors.
  • Chapman, Hugh (Helsingin yliopisto, 2016)
    The human ether á-go-go related gene (hERG1 or KCNH2) encodes the pore forming subunit of the cardiac delayed rectifier potassium (IKr) channel. Its unique kinetics result in a resurgent current crucial for the repolarisation of the cardiac action potential and a capability to suppress premature excitation. hERG1 is widely expressed with roles e.g. in neuronal firing, intestinal and uterine contractility, and insulin secretion. Furthermore overexpression and ectopic expression of hERG1 occurs in cancer where it is involved in proliferation, migration, chemotherapy resistance etc. The long QT syndrome (LQTS) often presents as sudden cardiac death in children and young adults. LQTS is characterised by electrocardiogram abnormalities with arrhythmia that can lead to palpitations, syncope, seizure, cardiac arrest and death. Underlying the congenital form of LQTS are mutations in ion channel proteins (including hERG1, the loss-of-function of which gives rise to LQT2) and their interacting proteins. Carriers of a particular mutation may be symptomatic (to varying extents) or asymptomatic, with the deleterious effects only emerging due to the presence of other factors. This is analogous to drug-induced LQTS where arrhythmia may occur in 1 of 120,000 users of certain non-cardiac drugs. Virtually all drug-induced LQTS is caused by inhibition of hERG1. Consequently in the field of safety pharmacology the hERG1 channel has for the last 20 years and continues to have a huge impact as the primary in vitro predictor of the proarrhythmic risk for a drug. Various aspects of the hERG1 channel are investigated in the studies presented in this thesis. The effect of prucalopride, a gastrointestinal prokinetic drug, on hERG1 was examined. Prucalopride exhibited rapid state and concentration dependent inhibition of hERG1 however, at therapeutic concentrations block is insignificant (hERG safety margin of ≥300). This in vitro prediction has translated to the clinical studies of this drug and the market. The heterogeneous phenotype associated with LQTS may arise from genetic modifiers such polymorphisms and mutations. Heterologous expression of the prevalent hERG1 K897T polymorphism identified a reduced hERG1 current density as the primary difference from wild-type, a result of decreased protein expression. Additionally a slowing of deactivation and alteration of inactivation was evident. Also studied but using induced pluripotent stem cell (iPSC) derived cardiomyocytes was hERG1 R176W. Unlike previous LQT2 iPSC models the origin here was a relatively asymptomatic individual. The phenotypic characteristics of LQT2 were however still reproduced in vitro (i.e. a decrease in IKr and action potential prolongation) though as a milder version. Finally the effect of ceramide, a sphingolipid which accumulates in heart failure and is involved in lipotoxicity, on hERG1 was investigated. Ceramide was found to reduce hERG1 current in a time dependent manner through tagging (ubiquitination) of the cell surface protein for internalisation and targeting to lysosomes.
  • Kulashekhar, Shrikanth (2017)
    Working memory is used to maintain information for cognitive operations, and its deficits are associated with several neuropsychological disorders. Human functional magnetic resonance imaging (fMRI) f isolated key brain areas associated with the maintenance of sensory and duration information. However, the systems-level mechanisms coordinating the collective neuronal activity in these brain areas have remained elusive. It has been suggested that synchronized oscillations could regulate communication in neuronal networks and could hence serve such coordination, but their role in the maintenance of sensory and duration information has remained largely unknown. In this thesis, combined magnetoencephalography (MEG) and electroencephalography (EEG) together with minimum norm estimate (MNE) based source modelling was used to study the oscillatory dynamics underlying visual and temporal working memory. In Publication I, we developed a neuro-informatics approach to understand the anatomical and dynamic structures of network synchrony supporting visual working memory (VWM). VWM was associated with a sustained and stable inter-areal phase synchrony among frontoparietal and visual areas in alpha- (10 13 Hz), beta- (18 24 Hz), and gamma- (30 40 Hz) frequency bands. In this study, the subjects' individual behavioural VWM capacity was predicted by synchrony in a network in which the intraparietal sulcus was the most central hub. In Publication II, we characterised the oscillatory amplitude dynamics associated with the VWM maintenance. Increasing VWM load was associated with strengthened oscillation amplitudes in the occipital and occipitotemporal cortical areas, in the alpha (8 14 Hz) beta- (15 30 Hz), gamma- (30-50 Hz), and high-gamma- (50 150 Hz) frequency bands. In Publication III, we addressed the functional significance of local neuronal synchronization, as indexed by the amplitudes of cortical oscillations, in the estimation and maintenance of duration information. The estimation of durations in the seconds range was associated with stronger beta-band (14 30 Hz) oscillations in cortical regions that have earlier been associated with temporal processing. The encoding of duration information was associated with strengthened gamma- (30 120 Hz), and the retrieval and comparison with alpha-band (8 14 Hz) oscillations. Further, the maintenance of stimulus duration was associated with stronger theta- and alpha-band (5 14Hz) frequencies. These data suggested that both local and large-scale phase synchrony in the alpha-, beta-, and gamma-frequency bands in the frontoparietal and visual regions could be a systems level mechanism for coordinating and regulating the maintenance of visual information in VWM. In addition, it suggested that beta-band oscillations may provide a mechanism for estimating short temporal durations, while gamma, alpha and theta-alpha oscillations support their encoding, retrieval, and maintenance in working memory, respectively.