Detecting Slow Wave Sleep Using a Single EEG Signal Channel

Background: In addition to the cost and complexity of processing multiple signal channels, manual sleep staging is also tedious, time consuming, and error-prone. The aim of this paper is to propose an automatic slow wave sleep (SWS) detection method that uses only one channel of the electroencephalography (EEG) signal. New Method: The proposed approach distinguishes itself from previous automatic sleep staging methods by using three specially designed feature groups. The first feature group characterizes the waveform pattern of the EEG signal. The remaining two feature groups are developed to resolve the difficulties caused by interpersonal EEG signal differences. Results and comparison with existing methods: The proposed approach was tested with 1,003 subjects, and the SWS detection results show kappa coefficient at 0.66, an accuracy level of 0.973, a sensitivity score of 0.644 and a positive predictive value of 0.709. By excluding sleep apnea patients and persons whose age is older than 55, the SWS detection results improved to kappa coefficient, 0.76; accuracy, 0.963; sensitivity, 0.758; and positive predictive value, 0.812. Conclusions: With newly developed signal features, this study proposed and tested a single-channel EEG-based SWS detection method. The effectiveness of the proposed approach was demonstrated by applying it to detect the SWS of 1003 subjects. Our test results show that a low SWS ratio and sleep apnea can degrade the performance of SWS detection. The results also show that a large and accurately staged sleep dataset is of great importance when developing automatic sleep staging methods

Trypanosoma brucei brucei invasion and T-cell infiltration of the brain parenchyma in experimental sleeping sickness: timing and correlation with functional changes

Background: The timing of Trypanosoma brucei entry into the brain parenchyma to initiate the second, meningoencephalitic stage of human African trypanosomiasis or sleeping sickness is currently debated and even parasite invasion of the neuropil has been recently questioned. Furthermore, the relationship between neurological features and disease stage are unclear, despite the important diagnostic and therapeutic implications. Methodology: Using a rat model of chronic Trypanosoma brucei brucei infection we determined the timing of parasite and T-cell neuropil infiltration and its correlation with functional changes. Parasite DNA was detected using trypanosome-specific PCR. Body weight and sleep structure alterations represented by sleep-onset rapid eye movement (SOREM) periods, reported in human and experimental African trypanosomiasis, were monitored. The presence of parasites, as well as CD4+ and CD8+ T-cells in the neuropil was assessed over time in the brain of the same animals by immunocytochemistry and quantitative analyses. Principal findings: Trypanosome DNA was present in the brain at day 6 post-infection and increased more than 15-fold by day 21. Parasites and T-cells were observed in the parenchyma from day 9 onwards. Parasites traversing blood vessel walls were observed in the hypothalamus and other brain regions. Body weight gain was reduced from day 7 onwards. SOREM episodes started in most cases early after infection, with an increase in number and duration after parasite neuroinvasion. Conclusion: These findings demonstrate invasion of the neuropil over time, after an initial interval, by parasites and lymphocytes crossing the blood-brain barrier, and show that neurological features can precede this event. The data thus challenge the current clinical and cerebrospinal fluid criteria of disease staging

Down-phase auditory stimulation is not able to counteract pharmacologically or physiologically increased sleep depth in traumatic brain injury rats

Modulation of slow-wave activity, either via pharmacological sleep induction by administering sodium oxybate or sleep restriction followed by a strong dissipation of sleep pressure, has been associated with preserved posttraumatic cognition and reduced diffuse axonal injury in traumatic brain injury rats. Although these classical strategies provided promising preclinical results, they lacked the specificity and/or translatability needed to move forward into clinical applications. Therefore, we recently developed and implemented a rodent auditory stimulation method that is a scalable, less invasive and clinically meaningful approach to modulate slow-wave activity by targeting a particular phase of slow waves. Here, we assessed the feasibility of down-phase targeted auditory stimulation of slow waves and evaluated its comparative modulatory strength in relation to the previously employed slow-wave activity modulators in our rat model of traumatic brain injury. Our results indicate that, in spite of effectively reducing slow-wave activity in both healthy and traumatic brain injury rats via down-phase targeted stimulation, this method was not sufficiently strong to counteract the boost in slow-wave activity associated with classical modulators, nor to alter concomitant posttraumatic outcomes. Therefore, the usefulness and effectiveness of auditory stimulation as potential standalone therapeutic strategy in the context of traumatic brain injury warrants further exploration

The Effectiveness of Background Noise During a Sleep Deprived EEG: a Randomised Control Trial

Introduction Sleep Deprived Electroencephalogram’s (EEG’s) are usually carried out routinely in dedicated children’s Hospitals as they have been shown to increase the yield of the study. However, despite sleep deprivation being successfully carried out prior to the EEG the patient may fail to fall asleep. Various techniques have been developed to enhance sleep, such as the use of “white or background noise”. This study examined the use of background noise during the sleep portion of the EEG in comparison with a control group. Methodology This was a randomised control trial with two interventions (two different types of background noise) and a control group (no noise). There were 202 patients enrolled in the study over a two year period and randomly allocated to each group. They were given forty minutes for the sleep portion of the test and if still awake after forty minutes, this was noted as a “fail to sleep”. The study was performed in the Neurosciences centre, Our Lady’s children’s hospital. Literature Review The literature review was carried out after the study commenced which highlighted that as well as the use of white noise during sleep, the use of music as another technique was also frequently used to enhance sleep. Also emphasized were the various confounding factors that were present in this type of study and therefore this thesis attempted to address these issues and endeavoured to control for these influences so as not to affect the results. Results Initial results examining the three groups in terms of the data distribution showed that there was little difference in relation to whether the participants fell asleep or not or the time taken to fall asleep. This was also the case when further statistical analysis was performed. However a trend was noted between group B (CD noise) and C (No noise) which was statistically significant at p=.037. Further data was obtained regarding sleep showing that 91% of the participants fell asleep regardless of the allocated group. It was also noted that 15% of patients only had abnormalities in sleep. Conclusions In relation to the data on arousals, this information should be interpreted with caution as correlating peak noise was not measured, in order to determine if the noise was the cause of the arousal or not. There were also little differences between the groups on the other outcomes measured however there may be small differences between the CD noise and the control group as somewhat more participants fell asleep when using the CD noise. Further studies need to validate these results, particularly across various departments under strict controlled settings in order to eliminate the confounding factors outlined in this thesis

Inter-expert and intra-expert reliability in sleep spindle scoring

Objectives: To measure the inter-expert and intra-expert agreement in sleep spindle scoring, and to quantify how many experts are needed to build a reliable dataset of sleep spindle scorings. Methods: The EEG dataset was comprised of 400 randomly selected 115 s segments of stage 2 sleep from 110 sleeping subjects in the general population (57 ± 8, range: 42–72 years). To assess expert agreement, a total of 24 Registered Polysomnographic Technologists (RPSGTs) scored spindles in a subset of the EEG dataset at a single electrode location (C3-M2). Intra-expert and inter-expert agreements were calculated as F_1-scores, Cohen’s kappa (κ), and intra-class correlation coefficient (ICC). Results: We found an average intra-expert F_1-score agreement of 72 ± 7% (κ: 0.66 ± 0.07). The average inter-expert agreement was 61 ± 6% (κ: 0.52 ± 0.07). Amplitude and frequency of discrete spindles were calculated with higher reliability than the estimation of spindle duration. Reliability of sleep spindle scoring can be improved by using qualitative confidence scores, rather than a dichotomous yes/no scoring system. Conclusions: We estimate that 2–3 experts are needed to build a spindle scoring dataset with ‘substantial’ reliability (κ: 0.61–0.8), and 4 or more experts are needed to build a dataset with ‘almost perfect’ reliability (κ: 0.81–1). Significance: Spindle scoring is a critical part of sleep staging, and spindles are believed to play an important role in development, aging, and diseases of the nervous system

The development of imaging biomarkers for the diagnosis of human prion disease

Future therapeutic trials in human prion disease will require the use of biomarkers of disease activity such as MRI in order to assess efficacy of treatment. Whilst the development of biomarkers is of importance it is also necessary to be able to understand and interpret what imaging findings characterise at post-mortem and furthermore how they correlate with clinical symptoms. In this thesis I investigate whether both conventional and quantitative imaging parameters can act as biomarkers to predict disease progression in symptomatic patients. I also assess what conventional MRI findings represent on a microstructural level and how imaging findings correlate with clinical symptoms of prion disease such as sleep disturbance. This work is detailed in four projects, the first of which I investigate if abnormalities found on conventional MRI brain scans, PRNP genotype and prion strain can act as predictors of disease progression in patients with the sporadic form of prion disease. I was unable to show that conventional MR brain imaging helps to predict disease progression in this patient group, but I was able to show that codon 129 remains the main predictor of disease progression and strain subtype has an additional effect. In the second project I test the hypothesis that MTR, a quantitative imaging parameter can predict disease progression in symptomatic patients. I found that both on cross-sectional and longitudinal analysis there were significant differences in symptomatic patients and that there was a strong correlation with the MRC Scale score, clinical outcome measure, and MTR value in patients with symptomatic disease which could be used as a clinical biomarker in combination to predict response to therapeutics in future clinical trials. In the third project I focus on investigating the prevalence of sleep disturbance and its association with other features of disease and imaging findings. I found that sleep disturbance was highly prevalent in all forms of prion disease. I also found that there was a significant association found between thalamic signal change seen on MRI scan and sleep symptomatology. In order to capture more data on the diversity of sleep symptoms in this population I constructed the Prion Disease Sleep Questionnaire a bedside screening tool that can be used to both record and monitor the incidence and severity of sleep disturbance. In the final project I assess if specific histopathological findings on post-mortem correlate with cortical imaging abnormalities seen on DWI in patients diagnosed with sporadic CJD. I found that there were significant difference between patients with and without cortical ribboning present on their MRI brain scans those with DWI signal change had more frontal cortex spongiosis than those that didn’t. There was also a modest correlation identified between the 3 histopathological parameters: PrPSc, deposition, gliosis and spongiosis

Effects of dance therapy on balance, gait and neuro-psychological performances in patients with Parkinson's disease and postural instability

Postural Instability (PI) is a core feature of Parkinson’s Disease (PD) and a major cause of falls and disabilities. Impairment of executive functions has been called as an aggravating factor on motor performances. Dance therapy has been shown effective for improving gait and has been suggested as an alternative rehabilitative method. To evaluate gait performance, spatial-temporal (S-T) gait parameters and cognitive performances in a cohort of patients with PD and PI modifications in balance after a cycle of dance therapy

Role of Biomarkers for the Diagnosis of Prion Diseases : A Narrative Review

Prion diseases are progressive and irreversible neurodegenerative disorders with a low incidence (1.5-2 cases per million per year). Genetic (10-15%), acquired (anecdotal) and sporadic (85%) forms of the disease have been described. The clinical spectrum of prion diseases is very varied, although the most common symptoms are rapidly progressive dementia, cerebellar ataxia and myoclonus. Mean life expectancy from the onset of symptoms is 6 months. There are currently diagnostic criteria based on clinical phenotype, as well as neuroimaging biomarkers (magnetic resonance imaging), neurophysiological tests (electroencephalogram and polysomnogram), and cerebrospinal fluid biomarkers (14-3-3 protein and real-time quaking-induced conversion (RT-QuIC)). The sensitivity and specificity of some of these tests (electroencephalogram and 14-3-3 protein) is under debate and the applicability of other tests, such as RT-QuIC, is not universal. However, the usefulness of these biomarkers beyond the most frequent prion disease, sporadic Creutzfeldt-Jakob disease, remains unclear. Therefore, research is being carried out on new, more efficient cerebrospinal fluid biomarkers (total tau, ratio total tau/phosphorylated tau and neurofilament light chain) and potential blood biomarkers (neurofilament light chain, among others) to try to universalize access to early diagnosis in the case of prion diseases

Clinical and PET Imaging Studies in Parkinson’s Disease Motor and Non-Motor Complications: Serotonergic and Dopamimergic Mechanisms and Applications in Treatment

The clinical course of Parkinson’s disease (PD) is complicated by the development of motor and non-motor complications. This thesis, using clinical motor and non-motor assessments and positron emission tomography (PET) imaging with 11C-raclopride, 11CDASB and 18F-DOPA, aims to explore in PD the role of: (1) postsynaptic dopamine D2 receptor dysfunction, (2) serotonergic dysfunction in the development of non-motor symptoms such as depression and body weight change, (3) striatal serotonergic neurons in levodopa- and graft -induced dyskinesias (LIDs and GIDs), and (4) the efficacy of treatment with continuous dopaminergic stimulation. The main findings are as follows: (1) D2 receptor dysfunction in the hypothalamus but not in the putamen was evident in PD, possibly accounting for the development of non-motor symptoms. (2) A staging of serotonergic dysfunction throughout the clinical course of PD has been demonstrated in this thesis and showed that serotonergic system is involved early on. (3) Higher serotonin transporter availability has been found in PD patients with elevated depressive symptoms and in PD patients with significant changes in their body weight. (4) Striatal serotonergic terminals are involved in peak-dose LIDs in PD, and administration of a high bolus dose of a 5-HT1A agonist was able to normalize extracellular dopamine levels and alleviate dyskinesias. (5) Excessive serotonergic innervation was found in two PD patients with GIDs who had experienced major recovery after striatal transplantation with fetal cells. GIDs were markedly attenuated by repeated administration of low doses of a 5-HT1A agonist, which dampens transmitter release from serotonergic neurons, indicating that serotonergic hyperinnervation was the likely cause of GIDs. (6) Continuous dopaminergic stimulation with levodopa intestinal gel induced good clinical response and stable and prolonged synaptic levels of striatal dopamine release. My observations provide fundamental insight for the role and interaction of serotonergic and dopaminergic systems in the pathophysiology of PD and have key implications for the management of motor and non-motor complications with drugs or cell therapies

Clinicopathological characteristics of nigral neuron density in Lewy body spectrum diseases

Lewy body diseases are progressive neurodegenerative disorders that are clinically and pathologically heterogeneous. The combined base of the pathophysiology in Lewy body diseases is the pathological accumulation of α- synuclein, which forms Lewy bodies and Lewy neurites. The degeneration and Lewy pathology are particularly prominent in the substantia nigra, which is a crucial part of the dopaminergic system of the central nervous system. Lewy body disease patients usually have an individual spectrum of motor and nonmotor symptoms. The nonmotor symptoms, such as depression, may precede motor symptoms by several years. Substantial dopaminergic degeneration has already occurred by the time motor signs such as rigidity, bradykinesia and rest tremor emerge. The causative disease mechanism is unclear. Lewy body diseases decrease life quality and increase mortality. This thesis focuses on the relationships between degeneration of the dopaminergic nuclei and clinical features in Lewy body disease patients. Cases were collected from neuropathologic records of the University Hospital of Turku between 2002 and 2016 retrospectively and the corresponding clinical records were then reviewed. The association between Tyrosine hydroxylase positive substantia nigra neuron or putaminal axon numbers and striatal dopamine transporter binding, depressive symptoms and height were examined in Lewy body disease patients. The number of neurons and axons were counted manually using midbrain sections, and mathematical corrections were applied in the last two studies. The numbers of dopaminergic and tyrosine hydroxylase positive neurons in the substantia nigra or neurites in the striatum did not correlate with in vivo dopamine transporter binding. The results further demonstrate that neurodegeneration in the substantia nigra pars compacta in depressed Lewy body disease patients is more severe compared to non-depressed patients. The results also suggest that the height of Lewy body disease patients may be associated with neuron density in the substantia nigra pars compacta. These results shed light on some factors which underlie the large interindividual variability of substantia nigra pars compacta degeneration.Mustatumakkeen hermosolutiheyden kliinispatologiset piirteet Lewyn kappale -kertymäsairauksissa Lewyn kappale -kertymäsairaudet ovat heterogeenisia ja eteneviä hermostorappeumasairauksia. Näiden sairauksien yhteinen patofysiologinen piirre on α-synukleiinin kertyminen, mikä muodostaa Lewyn kappaleita ja Lewyn neuriitteja. Hermorappeuma ja Lewy-patologia ovat havaittavissa erityisesti mustatumakkeessa, joka on oleellinen osa keskushermoston dopaminergistä järjestelmää. Yleensä Lewyn kappale -kertymäsairaus potilaalla on yksilöllinen kirjo motorisia ja ei-motorisia oireita. Ei-motoriset oireet, kuten masennus, saattavat edeltää motorisia oireita useilla vuosilla. Motoristen oireiden, kuten jäykkyyden, hitauden ja lepovapinan, ilmetessä on havaittavissa jo merkittävää dopaminergisen hermoston rappeumaa. Taudin aiheuttava mekanismi on yhä epäselvä. Lewyn kappale -kertymäsairaudet alentavat potilaiden elämän laatua ja lisäävät kuolleisuutta. Tässä väitöstutkimuksessa keskityttiin dopaminergisten tyvitumakkeiden ja Lewyn kappale -kertymäsairauksien kliinisten piirteiden yhteyksiin. Potilastapaukset kerättiin Turun yliopistollisen sairaalan neuropatologian arkistoista 2002 ja 2006 välillä retrospektiivisesti. Kliininen data kerättiin vastaavasti potilastietojärjestelmistä. Tyrosiinihydroksylaasi positiivisten mustatumakkeiden hermosolujen tai putamenin aksonien määrän suhdetta aivojuovion dopamiinitransportterin sitoutumiseen, masennusoireisiin ja pituuteen tutkittiin Lewyn kappale -tautia sairastavilla potilailla. Hermosolujen ja aksonien määrä laskettiin manuaalisesti keskiaivoleikkeistä, ja matemaattista korjausta hyödynnettiin jälkimmäisissä tutkimuksissa. Tulokset osoittivat, että neuromelaniini- ja tyrosiinihydroksylaasipositiivisten mustatumakkeen hermosolujen ja aivokuorukan hermohaarakkeiden määrä ei korreloi dopamiinin takaisinottajan sitovuuteen. Lisäksi tulokset viittasivat siihen, että hermostorappeuma mustatumakkeessa on vaikeampaa masentuneilla kuin eimasentuneilla potilailla. Lisäksi vaikuttaa siltä, että aikuispituus saattaisi liittyä mustatumakkeen hermosolutiheyteen. Yhteenvedettynä tulokset auttavat ymmärtämään suurta yksilökohtaista vaihtelua mustatumakkeen hermorappeumassa, eli keskeisessä Lewyn kappale - kertymäsairauksien tautimekanismissa