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Introduction: In Major Depressive (MDD) and Bipolar Disorders (BD), there are well-documented changes in sleep and biological rhythms. However, how sleep and biological rhythm disruptions impact functioning and quality of life (QOL) in these populations, and how these disruptions affect perinatal mood and anxiety remains little-known. In this thesis, we aimed to compare sleep and biological rhythms in individuals with and without mood disorders, and to investigate whether these measures can account for worsened functional impairment and QOL in these populations. We investigated whether clinical variables combined with sleep and biological rhythms during pregnancy can be used to predict depressive and anxiety symptom severity postpartum. Finally, we investigated longitudinal changes in sleep, and biological rhythms over the perinatal period. Results: Subjective and objective sleep and biological rhythm disruptions, and light exposure differences are wide-spread in MDD and BD. Regression analyses showed that subjective and objective sleep and biological rhythm disruptions can explain 43% of variance in QOL scores, and 52% of variance in functional impairment in MDD, BD and healthy controls. Clinical and demographic variables, objective and subjective sleep and biological rhythm measures collected during pregnancy accounted for 50% of postpartum depression and 49% of postpartum anxiety symptom severity variance, in regression analyses. Numerous sleep and biological rhythm changes occurred across multiple domains from pregnancy to postpartum. Conclusion: Results suggest that sleep and biological rhythm disruptions occur across many domains in mood disorders, including sleep, light exposure, daily activity rhythms and melatonin. These disruptions are associated with worse QOL and functioning in BD, MDD and healthy controls. Biological rhythms and sleep changes across the perinatal period can be used to predict severity of postpartum depressive and anxiety symptoms. This work highlights the importance of sleep and biological rhythms as intervention targets across different outcomes, and across different mood diagnoses. / Thesis / Doctor of Philosophy (PhD) / Sleep and biological rhythms are often disrupted in individuals with depression and bipolar disorder. In this thesis, we aimed to compare sleep and biological rhythms in individuals with depression or bipolar disorder, against individuals without these disorders. We investigated whether sleep and biological rhythms contribute to functioning and quality of life in these individuals. As sleep and biological rhythms are disrupted in pregnancy and following childbirth, we assessed whether sleep and biological rhythms during pregnancy can be used to predict postpartum depression and anxiety severity. Finally, we investigated changes in sleep, biological rhythms and light exposure from pregnancy to postpartum. Results indicate that disruptions in sleep, biological rhythms, and changes in light exposure are widespread in mood disorders. These disruptions are linked to worse quality of life and functioning. Sleep and biological rhythms change from pregnancy to postpartum, and can be used to predict severity of postpartum depression and anxiety.

Introduction: Sleep and biological rhythms have not been investigated in women with comorbid Bipolar and Premenstrual Dysphoric Disorder in the context of the menstrual cycle. We explored whether menstrual cycle phase causes increased disturbances in sleep, biological rhythms and mood symptoms. Additionally, we explored whether these women have worse illness outcome than women diagnosed with either Bipolar or Premenstrual Dysphoric Disorder, and healthy women. Methods: In this post-hoc analysis, participants were split into four groups: those with a Bipolar and comorbid Premenstrual Dysphoric Disorder diagnosis (n = 17, BDPMDD), those with a Bipolar Disorder diagnosis (n = 16, BD), those with a Premenstrual Dysphoric Disorder diagnosis (n = 19, PMDD), and women with no history of psychiatric diagnosis (n = 25, HC). The primary outcome variable was biological rhythm disruption as measured by the Biological Rhythms Interview and Assessment in Neuropsychiatry (BRIAN). The secondary outcome variables were depressive symptoms (Montgomery-Asberg Depression Scale, MADRS; Hamilton Depression Rating Scale, HAMD), manic symptoms (Young Mania Rating Scale, YMRS), and sleep quality (Pittsburgh Sleep Quality Index, PSQI). All variables were collected at both mid-follicular and late-luteal stages of the menstrual cycle. Results: The BDPMDD group did not have significantly higher disruptions in biological rhythms than the BD or PMDD groups at the luteal phase; however, there were significant disruptions and mood symptoms in comparison to the HC group, especially at the follicular stage, which point to markedly higher disruptions in these areas that seem to persist beyond the symptomatic luteal phase. Conclusion and Future Directions: Women diagnosed with a BD and PMDD comorbidity experience a higher illness burden then women diagnosed with either BD or PMDD. A relatively small sample size, not excluding for participants who were taking medications that affect sleep and relying solely on subjective measures of biological rhythms may explain some of the null results. Future studies should employ objective measures of sleep such as actigraphy to complement subjective measures like the BRIAN, as well as recruit a larger sample of participants. More importantly, more studies surrounding this topic must be done in order to create a robust body of evidence that can be used to compare results across studies and identify specific biological rhythms domains that can be targets for treatment. / Thesis / Master of Science (MSc) / Sleep disruptions are common in women diagnosed with Bipolar Disorder and in those diagnosed with Premenstrual Dysphoric Disorder. Illness burden has been shown to be greater in women diagnosed with a comorbidity of the above disorders in terms of clinical variables such as number of comorbidities, episode relapse, rapid cycling and mixed mood states. This thesis aims to investigate whether women diagnosed with Bipolar and comorbid Premenstrual Dysphoric Disorder have greater biological rhythms disruptions than women diagnosed with either disorder. Biological rhythms will be evaluated at both the follicular and late-luteal stages. The overall goal of this work is to add to the currently scant literature on the clinical presentation of a Bipolar and Premenstrual Dysphoric Disorder comorbidity.

The possibility that visual thresholds fluctuate in a circadian rhythmic (twenty-four hour) pattern was examined. Subjects were tested at 0400h, 1000h, 1600h and 2200h in a 30 minute dark adaptation procedure using a von Békésy tracking method. Two experiments were performed; the first tested cone functions with a red 1 degree monochromatic test stimulus located ten degrees nasally. There were no sex differences for the ten male and female subjects used in this study. However, there were time of day differences with higher thresholds at 1000h than at any other time. The second experiment examined both rod and cone thresholds with a heterochromatic test stimulus. Sex differences were found 'for the 10 male and 10 female subjects. The rods for males were found to exhibit significantly higher thresholds at 1000h than any other time. There were no significant differences for females. The null results for females may be due to an influence of the menstrual cycle on vision. The rod differences for males is thought to occur because of rod outer segment shedding which also has a circadian rhythm. A circadian rhythm questionnaire was administered to the subjects and it was found that morningness and vigorousness related to visual thresholds. / Master of Science

Fatores ambientais podem modificar o desenvolvimento dos ritmos biológicos em neonatos, como já demonstrado em ratos. Neste contexto insere-se o estudo de recém-nascidos pré-termo mantidos em unidades de cuidado neonatal. Descrevemos neste trabalho a evolução da ritmicidade no ciclo vigília/sono, atividade/repouso, temperatura do punho e alimentação na fase neonatal. Paralelamente, caracterizamos o desenvolvimento dos ritmos biológicos em ratos mantidos sob luz constante durante a lactação e a atuação da melatonina e do exercício físico nessa evolução. Em um estudo longitudinal utilizando actímetros e termistores com memória, identificamos precocemente ritmo circadiano na temperatura do punho, enquanto na atividade motora há predomínio de ritmos ultradianos, bem como no ciclo vigília/sono e no comportamento alimentar, padrão este que se modifica logo após a alta hospitalar. Em ratos sob o paradigma de luz constante, oferecemos melatonina e uma roda durante a lactação e após o desmame, encontrando modificações na emergência do ritmo circadiano em ambos os grupos. / Environmental factors can change the development of biological rhythms in neonates, as has already been demonstrated in rats. In this context is the study of preterm newborns maintained in neonatal care units. We describe in the present work the evolution of rhythmicity in sleep/wake cycle, activity/rest, wrist temperature and feeding behavior along the neonatal phase. Simultaneously, we characterize the development of biological rhythms in rats maintained under constant light during lactation and the action of melatonin and physical exercise in this evolution. Through a longitudinal study using actimeters and thermistors with memory we identified precociously a circadian rhythm in wrist temperature, while in motor activity we found a dominant ultradian rhythm, as well as, in sleep/wake cycle and feeding behavior, with changes in this pattern just after hospital discharge. In rats reared under constant light, we offered melatonin and a wheel during lactation and after weaning, finding differences in the emergency of the circadian rhythm for both groups.

Fatores ambientais podem modificar o desenvolvimento dos ritmos biológicos em neonatos, como já demonstrado em ratos. Neste contexto insere-se o estudo de recém-nascidos pré-termo mantidos em unidades de cuidado neonatal. Descrevemos neste trabalho a evolução da ritmicidade no ciclo vigília/sono, atividade/repouso, temperatura do punho e alimentação na fase neonatal. Paralelamente, caracterizamos o desenvolvimento dos ritmos biológicos em ratos mantidos sob luz constante durante a lactação e a atuação da melatonina e do exercício físico nessa evolução. Em um estudo longitudinal utilizando actímetros e termistores com memória, identificamos precocemente ritmo circadiano na temperatura do punho, enquanto na atividade motora há predomínio de ritmos ultradianos, bem como no ciclo vigília/sono e no comportamento alimentar, padrão este que se modifica logo após a alta hospitalar. Em ratos sob o paradigma de luz constante, oferecemos melatonina e uma roda durante a lactação e após o desmame, encontrando modificações na emergência do ritmo circadiano em ambos os grupos. / Environmental factors can change the development of biological rhythms in neonates, as has already been demonstrated in rats. In this context is the study of preterm newborns maintained in neonatal care units. We describe in the present work the evolution of rhythmicity in sleep/wake cycle, activity/rest, wrist temperature and feeding behavior along the neonatal phase. Simultaneously, we characterize the development of biological rhythms in rats maintained under constant light during lactation and the action of melatonin and physical exercise in this evolution. Through a longitudinal study using actimeters and thermistors with memory we identified precociously a circadian rhythm in wrist temperature, while in motor activity we found a dominant ultradian rhythm, as well as, in sleep/wake cycle and feeding behavior, with changes in this pattern just after hospital discharge. In rats reared under constant light, we offered melatonin and a wheel during lactation and after weaning, finding differences in the emergency of the circadian rhythm for both groups.

A dissertation submitted to the Faculty of Engineering and the Built Environment, University of Witwatersrand in fulfilment of the requirements for the degree of Master of Science in Engineering. 2017 / The baroreceptor is a stretch receptor which detects changes in pressure in arterial blood vessels. Baroreceptor nerves inform the brainstem of changes in blood pressure, which then influences sympathetic and parasympathetic nervous activity to counteract that change. Due to the relationship between essential hypertension, sympathetic nervous activity and the baroreflex, there is some debate in the literature about whether the baroreflex can act as a long-term controller of blood pressure. This debate has increased in recent years, due to the high prevalence of essential hypertension in all societies and the introduction of new technologies to counteract drug-resistance hypertension. The baroreflex has become a source of debate due to the complex physiological feedback control that regulates blood pressure and due to new stimulating electrical devices, which have shown promising results in reducing drug-resistant essential hypertension. system. This is done through a literature survey extending through experimental and modelling research, where selected mathematical models of the baroreceptor are then analysed and simulated to find the best performing model, so that they may be simulated for an extended frequency response than what would be experimentally possible. The purpose of this investigation is to determine, through simulation, what the sensor static and dynamic characteristics are. Through this characterisation of the sensor behaviour of the baroreceptor in the baroreflex control loop, it is then possible to infer whether the baroreflex can act as a long-term controller of blood pressure. An overview of experimental and analytical investigations on the baroreceptor over the last 70 years is summarised. This overview includes mathematical models, which predict experimental results. A subset of four models from Srinivasen et al., Bugenhagen et al., Beard et al. and Mahdi et al. are selected. These models are implemented in MATLAB and Simulink. The parameters and experimental conditions are integrated into the Simulink models, and the simulated results are compared to the reported experimental data. In this way, each mathematical model is evaluated using secondary data for its ability to simulate the expected behaviour. Thereafter, all simulated models are compared under the same input conditions (a 0-230 mmHg step input over 12 s). These results are used to select the best performing models, based on how well they were parameterised and validated for experimental tests. The best performing models are those of Beard et al. and Bugenhagen et al. They are tested for a wide range of artificial inputs at different frequencies, with sinusoidal inputs which have periods that range from 0.1 s to 10 days and have a 100 mmHg operating point with a 1 mmHg peak amplitude. All modelling techniques studied show that the baroreceptor firing response resets due to the rate of change in strain in the visco-elastic arterial wall. Both tested model frequency responses, although parameterised for different species and for different major vessels, show high sensitivity to inputs in range from 1 s to 1 min 36 s (0.01 Hz 1Hz), and very low sensitivity for changes that are longer than 16 min 36s (0.001 Hz). This extrapolated simulation suggests a zero gain near DC. The simulated frequency response of the best performing baroreceptor models, which were validated against short-term experimental data, indicate that the baroreceptor is only able to sense changes that happen in less than 1 min 16s. The critical analysis of all the simulated baroreceptor models show that this characteristic of the baroreceptor is caused by the visco-elastic layers of the arterial wall, and is likely in all baroreceptors regardless of type or species. It also indicates that under electrical stimulation of the baroreceptor, the input signal from the electrical device bypasses the baroreceptor nerve ending (which is embedded in the arterial wall) and that the electrical signal of the baroreceptor is bypassed by the new stimulated electrical signal of the device. Furthermore, if the sensor can only detect short-term changes, then it is unlikely that the baroreceptor can inform the brainstem on longterm changes to mean arterial blood pressure. Therefore, based on the models examined in this study, this suggests that the baroreceptor is unlikely to be involved in long-term blood pressure control. This analysis of the best performing model is presented to show the limitations of the baroreflex in long term control of blood pressure. It serves as a simulated experiment to rationalise the contentious debate around the role of the baroreflex in long term blood pressure control, and to allow for future improvements that can be made on the baroreceptor model to allow for more extended modelling on sor characteristics. An improvement that could be applied to the best performing baroreceptor models, implemented in this study, is to examine the effects of ageing and inter-species variability on carotid sinus dimensions and visco-elastic wall properties. / CK2018

Uma das características dos adolescentes é a fase atrasada dos ritmos biológicos circadianos. Esse atraso na expressão da ritmicidade circadiana pode gerar um atrito entre o tempo biológico e o tempo social (horário escolar). Assim, analisamos a expressão do atrito temporal entre o tempo biológico e o tempo social em adolescentes escolares. Todos os adolescentes atrasaram os horários do inicio e do final do sono na comparação entre os dias letivos e não letivos. Os adolescentes atrasam a acrofase da temperatura periférica, e a MFS na comparação entre os dias letivos e não letivos. Foi observada uma diminuição significativa para os vespertinos, na ritmicidade circadiana da temperatura na transição dos dias letivos para os dias não letivos. Dessa forma, o deslocamento da acrofase da temperatura e o deslocamento da MFS podem ser a expressão do atrito temporal. Esse cronicidade do atrito pode trazer conseqüências negativas para o bem estar dos adolescentes. / And one of the adolescents characteristics is the latest phase of circadian biological rhythms, compared with children and adults. This delay in the expression of circadian rhythmicity may generate friction between biological time and social time. Thus we analyzed the temporal friction between biological time and social time in scholar adolescents. All adolescents delay the time of beginning and the end of sleep in school days compared to non-school days. All adolescents had a delay in the peripheral temperature acrophase, and the MFS in the comparison between school days and non-school days. Therefore we understand the friction time between the biological and the social through changes in the CVS patterns, shift of peripheral temperature acrophase, and displacement of the MFS, in the transition from school days to non-school days. This chronicity of friction can have negative consequences for the well being of the adolescents.

Comunidades que vivem em regiões sem energia elétrica apresentam suas atividades sincronizadas pelo ciclo dia/noite e por compromissos sociais podendo haver uma diferença sazonal no comportamento. No ambiente urbano a energia elétrica cria a possibilidade de nos organizarmos temporalmente de acordo com os nossos interesses. Este comportamento tem sido apontado como uma das causas para a ausência de sazonalidade nos ritmos biológicos humanos. Este estudo fenomenológico naturalístico em índios Guarani que viviam em casas sem energia elétrica nos permitiu refletir sobre a presença de sazonalidade nos ritmos biológicos. O ritmo de temperatura do punho em 21 índios e o ciclo de atividade/repouso em 16 índios foram comparados entre o inverno e verão. O perfil temporal da temperatura não se alterou nas duas épocas, mas houve diferença nos valores de amplitude e MESOR que pode ser explicada pela variação sazonal do padrão de dissipação de calor através da pele. Não houve diferença entre o inverno e verão para os valores de acrofase, e os índios mais novos apresentaram horários de acrofase da temperatura mais tardios que os índios mais velhos. Do inverno para o verão observamos um atraso nos horários de repouso sem alteração significativa na duração. Não verificamos diferença nos horários e na duração do repouso entre os dias de semana e fins de semana. O padrão de atividade/repouso não apresentou relação com a duração/alocação da noite no inverno e verão e houve uma correlação negativa com os valores de temperatura do punho. Os índios adultos da Aldeia Boa Vista apresentam ritmos biológicos com características típicas de uma comunidade de transição. As atividades na aldeia são sincronizadas pelas diferentes relações sociais que se estabelecem em cada época do ano. / Communities living in areas without electricity present biological rhythms synchronized by the day/night cycle and social schedules; it seems possible to detect seasonal differences in their behaviour. In urban areas electricity allow us to organize our activities according to our interests. This behaviour has been pointed as a cause for the absence of seasonality in human biological rhythms. The present naturalistic phenomenological study of Guarani indians that living in no electricity houses allowed us to think about the presence of seasonality in biological rhythms. Wrist temperature and activity/rest rhythms of 21 indians were compared between winter and summer. The temperature profile did not change, but a seasonal difference was found for amplitude and MESOR values which may be related to metabolic-behavioral processes involved in thermoregulation. In summer the vasodilation is intense and the heat dissipation is maximum (with low variability), the opposite tends to occur in winter. We did not find seasonality in acrophase values between subjects, and we also found the same correlation described for urban populations: a phase advance of body temperature in the elderly. From winter to summer the onsets/offset of rest were delayed, with no change in rest duration. For the indians there was no difference in the schedules of rest/activity during the week. The activity/rest cycle was not determined by the day/night cycle but showed a significant correlation with wrist temperature. The adult indians of Boa Vista settlement showed typical characteristics in their biological rhythms of a transition community. The activities in the settlement are synchronized by singular relationships that take place in each season.

Tanto as evidências experimentais que demonstraram a geração endógena de ritmos com períodos circadianos, quanto as investigações sobre os diferentes mecanismos de sincronização dos ritmos circadianos aos marcadores temporais externos de períodos fixos de 24h forneceram material para a elaboração de proposições importantes sobre as características do sistema de temporização biológica circadiana. Dentro desse cenário, foi de muita ajuda a aplicação da modelagem matemática. O desenvolvimento desses modelos permitiu a investigação de conjecturas que tentam explicar as características subjacentes aos mecanismos que coordenam esse sistema. Nosso objetivo, neste trabalho, foi de explorar a hipótese de que o mecanismo de controle da ritmicidade circadiana é exercido pela ação de laços de retroalimentação negativa acionados após tempos de retardo característicos do sistema. Para alcançarmos esse objetivo, elaboramos um modelo no qual o controle e a manutenção da expressão rítmica circadiana fossem conseqüentes da ação de dois laços de retroalimentação negativa com tempos de retardo distintos. Adicionalmente, avaliamos a resposta do modelo à ação de oscilações externas. Por meio da dinâmica não-linear resultante do modelo, nós observamos sugestiva similaridade entre as respostas obtidas nas simulações e as descrições experimentais da expressão do sistema de temporização circadiana citadas na literatura. Esses resultados deram suporte a hipótese inicial como explicação do funcionamento do sistema. / Both the experimental evidences of generation of biological circadian rhythms and the results of investigation about the mechanisms of synchronization between the circadian rhythms with the external cycles of 24-hour period provided material for the development of important assumptions about the characteristics of the circadian timing system. Inside this scenery, it was helpful the application of mathematical models. The development of these models permited the inquiry of some hypotheses which try to explain the underlying characteristics of this system. Our aim, in this work, was to investigate the hypothesis that explain the controlling mechanism of the circadian system as a result of the action of negative feedback loops triggered after charateristic time delays. For reaching this goal, our porpouse was to build a mathematical model which simulated circadian rhythmic expressions controlled by two feedback loops with different time delays. Additionaly, we also simulated the response of the model under external oscillations. Through the non-linear dynamic resulting from the model we observed suggestive similarity between the simulations and the experimental descriptions of the circadian system expressions present in many works. These results gave support to the validation of the initial hypothesis.