College of Medicine and Health - Doctoral Theses
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Item To what extent are Child and Adolescent Mental Health Services engaged in Trauma Informed Practice: an Irish study(University College Cork, 2023) Heffernan, Sinead; Leahy-Warren, Patricia; Drennan, Jonathan; Dalton O'Connor, CarolineBackground: Children and adolescents attending the mental health services are likely to have experienced childhood or intergenerational trauma. International and national mental health policy recommends that services integrate TIP into mental healthcare provision. A lack of research studies exploring the integration of TIP, with this cohort were identified. Method: A descriptive correlational study design utilised a convenience approach to gain a sample from the target population: all CAMHS staff nationally. Data were collected using a psychometrically validated organisational assessment tool. Mostly descriptive, inferential, and some thematic analyses were deployed. Results: Respondents reported low levels of TIP, overall. The majority of respondents were female, community based, clinical staff. Levels of trauma informed therapeutic engagement with service users, and organisational supports for TIP were ascertained from a staff perspective. Results indicated a varied results with therapeutic engagement revealing higher scores than the organisational related areas in CAMHS. Areas that pertained to person centred approaches to consistent care delivery, safety and care planning, and de-escalation were to some extent developed. Gaps in care provision related to language, culturally sensitive care provision, and coproduction including eliciting feedback routinely, communication, flexibility, and staff supports to mitigate vicarious trauma were identified. Further gaps pertained to educating both service users and staff about trauma and its impact on mental health, as well as TIP delivery and evaluation. Overall organisational rather than individual staff factors represented require significant development to achieve TIP. The results of inferential analysis identified relationships between staffs’ levels of satisfaction in current role; which was found to be the strongest predictor of TIP (R2=14.7%, p<0.001), followed by location of role (R2=8.2%, p<0.001) and length of service (R2=3.3%, p<0.040). No relationships were found re: role in CAMH service (p=0.495) and attending TIP training (p=0.840). Thematic analysis found that training was not systematically provided or attended. Gaps in relation to TIP training content, frequency and duration were identified. Discussion: TIP has been described as a humanistic approach to care delivery that recommends approaches that can optimise therapeutic relationships and person-centred care characterised by flexibility, peer supports and collaboration and require further development. Organisational supports for training provision for all CAMHS staff, that is sustainable, evaluated, and accessible, is required. Staff supports that mitigate vicarious trauma for staff also requires further development. An organisational commitment underpinned by resources, strategies to deliver change, guided trauma-informed policy to support TIP, is recommended. Conclusion: CAMHS acute and even more so, community-based services are not currently engaged in TIP, as recommended by mental health policy. The multifaceted nature of TIP requires an organisational approach to guide implementation. The results from this study have identified gaps in relation to organisational support for TIP which can add to the growing knowledge base to support the integration TIP into CAMH Services.Item SErENdipITy - study of electrophysiological biomarkers (electroencephalogram and heart rate variability) in neonatal seIzures and encephalopathy(University College Cork, 2023) Pavel, Andreea; Boylan, Geraldine B.; Murray, Deirdre M.; Dempsey, Eugene M.; Health Research Board; Wellcome Trust; Science Foundation IrelandBackground In recent years, the use of conventional electroencephalographic (EEG) monitoring in newborns has increased and it is now recognised worldwide to be the gold standard monitoring for neonatal seizure detection, as well as a reliable biomarker for brain injury and long term prognosis in this population. Similarly, heart rate variability (HRV) is a non-invasive monitoring which provides information regarding the autonomic nervous system function, and has also been explored as a biomarker for brain function and prognosis in newborns. These physiological monitoring have been proven useful, especially in newborns with encephalopathy following hypoxic ischaemic injury. Despite the increased use of therapeutic hypothermia (TH) and the decrease in adverse outcomes following hypoxic ischaemic encephalopathy (HIE), the incidence of HIE is 1.6 per 1000 live births in high-income countries. Early identification of newborns with HIE which might benefit from TH is still challenging in clinical practice. HIE is also the main cause of seizures in newborns. Due to the unique physiological properties of the neonatal brain, this is the age period with the highest risk of seizures, with an incidence of 1-5/1000 live births. Recent evidence showed that seizures themselves might add to the degree of brain injury regardless of the background pathology, and a high seizure burden was associated with worse long-term neurodevelopmental outcome. The majority of neonatal seizures are subclinical (electrographic only) or have very subtle clinical manifestations, thus the importance of early biomarkers to identify newborns which will develop seizures, as well as the importance of prolonged EEG monitoring for seizure detection. Aims The aims of this thesis were to explore the value of physiological biomarkers, such as early clinical parameters, EEG and HRV features for early prediction of neonatal HIE severity and seizures, as well as neonatal seizure detection and evolution. Using early EEG and HRV analysis I aim to develop prediction models for seizure occurrence and HIE severity. In addition, I plan to assess the clinical value of a neonatal seizure detection algorithm (ANSeR algorithm). By analysing newborns with HIE and electrographic seizures, I aim to describe the temporal evolution of seizures during TH and to evaluate if seizure burden and intensity (power) correlates with HIE severity and long-term outcome. Furthermore, I aim to assess if the time to treatment of the first electrographic seizure in newborns with HIE had an impact on subsequent seizure burden and outcome. Methods To achieve my goals, I have analysed infants recruited from two European multicentre cohort studies, across eight European tertiary neonatal intensive care units, between January 2011 and February 2017 (ClinicalTrials.gov Identifier: NCT02160171 and NCT02431780). The studies included infants born at 36 to 44 weeks corrected gestational age, requiring prolonged EEG monitoring for being at high risk of developing seizures or being suspected of having seizures. All infants had continuous EEG monitoring using disposable electrodes according to the 10:20 electrode placement system for neonates (F3, F4, C3, C4, Cz, T3, T4, O1/P3 and O2/P4), with simultaneous electrocardiography (ECG) monitoring. The clinical diagnosis of HIE was established by the teams at each recruiting site based on signs of perinatal asphyxia and encephalopathy on neurological examination (modified Sarnat score within 24 hours of age) and retrospectively corroborated with abnormalities suggestive of HIE on EEG and brain MRI. The clinical grade of HIE was based on the most severe score of modified Sarnat score. The encephalographic grade of HIE was established by visually analysing the EEG background using a system described previously by our group: 0-normal EEG background, 1-mild abnormalities, 2-moderate abnormalities, 3-major abnormalities and 4-inactive EEG background. The quantitative EEG analysis was performed using the NEURAL software package, extracting a set of features for power, discontinuity, spectral distribution and inter-hemispheric connectivity. The HRV analysis was performed using an in-house software (HRV Analysis, Beta Version 1.12, ©University College Cork 2008-2012) which automatically identified R-peaks on ECG recording. The RR interval was generated as the time difference between each R peak. HRV was expressed in time, frequency and complexity features. Electrographic seizures were defined as at least one EEG channel with sudden, repetitive and evolving waveforms for minimum 10 seconds. For all infants, electrographic seizures were identified by two neurophysiology experts in neonatal EEG. Seizure characteristics and seizure quantification were calculated based on these expert annotations. Results The two studies included 504 newborns, out of which 266 newborns had a diagnosis of HIE (3 newborns with HIE following postnatal collapse). Machine learning models were developed for early prediction of newborns with seizures in HIE, by analysing a cohort of 164 newborns with EEG monitoring before 12 hours of age. The best predictive models included both clinical parameters and EEG features: clinical and qualitative-EEG model (MCC (95% CI) 0.470 (0.336 to 0.602), AUC (95% CI) 0.721 (0.681 to 0.813)) and clinical and quantitative-EEG model (MCC (95% CI) 0.513 (0.376 to 0.645), AUC (95% CI) 0.746 (0.700 to 0.833)). A randomised controlled trial evaluating the real-time performance of a seizure detection algorithm (ANSeR algorithm) showed a higher detection of seizure hours in the algorithm group compared to the non-algorithm group (absolute difference (95% CI): 20.8% (3.6% to 37.1%)). Seizure hours detection between the two groups was even greater at weekends (Saturday-Sunday vs Monday-Friday), difference (95% CI): 16.6% (0.1% to 32.3%). Another study assessed the impact of the time to treatment of the first electrographic seizure on subsequent seizure burden showed significantly lower seizure burden and less seizures were noted in infants treated with anti-seizure medication (ASM) within 1 hour from seizure onset (p value=0.029 and 0.035, respectively). A similar trend was noted in the subgroup of infants who had a diagnosis of HIE (n=42). Analysis of newborns with HIE requiring TH with EEG monitoring throughout the rewarming phase, showed that newborns with seizures during active cooling and rewarming had a significantly higher seizure burden compared with newborns with seizures during active cooling exclusively (median (IQR) 167(54-275) vs 69(22-104) minutes, p=0.003). Seizure burden peaked at approximately 24 hours in both study groups and had a secondary seizure peak at 85 hours of age for the group of newborns with seizures during active cooling and rewarming. Newborns with seizures during active cooling and rewarming had a significantly higher risk of abnormal outcome compared to infants without seizures (OR(95% CI):4.62(1.40 to 15.24), p=0.012). In another study all electrographic seizures from 64 newborns with HIE and 2-year neurodevelopmental outcome were analysed. Infants in the severe HIE group had a higher seizure period, with more frequent seizures but less intense (lower mean seizure power), compared to infants in the moderate HIE group. Similar characteristics were associated with abnormal outcome at two years. Early HRV analysis was assessed to predict the EEG grade in neonatal HIE within the first 12 hours of life in 120 newborns. Performance of the HRV model was AUROC 0.837 (95% CI: 0.759-0.914), however performance of the HRV and clinical model combined had an AUROC of 0.895 (95% CI: 0.832-0.958). Conclusion Early qualitative and quantitative-EEG features alone and in combination with early clinical information can reliably predict infants that will later develop seizures in HIE, hours before seizure onset. The quantitative-EEG model proved as reliable as the analysis of a neonatal neurophysiologist expert (qualitative-EEG analysis) in predicting the likelihood of seizures, which could be also used to individualise the neurophysiology review frequency of the continuous EEG monitoring. The findings of the neonatal seizure detection algorithm trial validated in real time the performance of the ANSeR seizure detection algorithm by demonstrating its’ usefulness as a support tool for clinicians, especially during weekends when a limited number of health care professionals are available on site. The study of ASM timing for the first electrographic seizure showed that inappropriate treatment remains a concern in clinical practice, and that early anti-seizure treatment was associate with lower total seizure burden. Current findings suggest that treatment of neonatal seizures might be time-critical. The study of seizure evolution in HIE showed that one third of infants with HIE undergoing TH continued to have seizures after the completion of active cooling, increasing the overall seizure burden which might have an impact on long-term outcomes. Supporting the current guidelines recommendations, there is a clear need for continuous EEG monitoring during active cooling, rewarming and beyond when seizures persist. The seizure analysis in HIE showed that seizures were more frequent and were less intense in severe HIE compared to moderate HIE, and in newborns with adverse outcome compared to newborns with normal outcome at two years. This may have implications for seizure identification as low power seizures are usually harder to detect, especially using aEEG monitoring, which might have an impact on anti-seizure treatment and subsequently on long-term outcome. The study of early HRV analysis showed that HRV and clinical model had a good prediction of encephalopathy HIE severity in the early newborn period and may be a very useful additional tool for neonatologists who are often faced with challenging decisions about TH, especially where EEG monitoring is not available or feasible.Item The design of cyclodextrins for delivery of siRNA - a structure-activity relationship(University College Cork, 2024) Kont, Ayse; O'Driscoll, Caitriona M.; Griffin, Brendan T.; Science Foundation Ireland; Jazz Pharmaceuticals; Advanced Materials and Bioengineering ResearchPreviously non-viral delivery of therapeutic nucleic acids (NAs) has been achieved for the treatment of liver disease and in the case of the COVID-19 vaccine. The delivery vector in both applications was a lipid-base nanoparticle (LNP). To expand the therapeutic application of NAs to treat more complex chronic diseases, such as cancer, delivery systems with wider biodistribution capable of going beyond the vaccine and the liver are required. This thesis aims to investigate the potential of modified cyclodextrins (CDs) as alternative biomaterials for siRNA delivery and to identify the optimum functional groups to maximise safety and efficacy. To help reduce the overall cationic charge and the potential for in vivo toxicity a co-formulation approach using a blend of an anionic and cationic amphiphilic CDs was investigated. The co-formulation was characterised and a reduction in the positive charge was achieved. The NPs were evaluated in vitro in HL-60, a leukaemia cell line, and results indicate that endosomal escape was a limiting factor to gene silencing with the siRNA. Structural modification of amphiphilic cationic CDs was investigated as a second approach to enhance the efficacy of CD NPs. The structural changes included varying the terminal amine, the linker, and the CD type, β versus γ. Primary amine proved to be more successful compared to tertiary amine in β- and γ-CDs. However, neither CD type was superior to the other, containing the primary amines. The exhaustive derivatisation of the secondary side of γ-CDs increased charge density and led to better transfection efficiency compared to O2-modified γ-CDs. Finally, the exchange of the linker group from triazole to thiopropyl increased the efficiency further in primary amine O2- and O3-substituted γ-CD. The optimum cellular uptake and gene silencing, in a lung cancer cell line (A549), was achieved with an O2- and O3-substituted γ-CD with a thiopropyl-linked primary amine. Finally, the potential ability of CD polymers to deliver siRNA was studied. Two cationic β-CD-polymers one functionalised with a primary amine and the other with a quaternary ammonium were used to formulate NPs containing siRNA. Both polymers formed NPs with sizes in the range of 150 to 200 nm. The primary amine functionalised polymer was taken up into the cells (A549) and produced 40% gene silencing. In contrast, the quaternary ammonium polymer failed to show any cellular uptake. The superior delivery effect achieved with the primary amine functional group agreed with the previous results from the monomer CD. In conclusion, modulation of the physicochemical characteristics of siRNA-NPs was achieved by changing the chemistry of the incorporated CD. The chemical structure significantly influenced the degree of gene knockdown. The primary amine showed superior efficiency in both monomeric amphiphilic cationic CDs and polymeric cationic CDs. Results indicate that further functionalisation of the CD is possible, and the potential exists to fine-tune the structure to achieve more specific biodistribution.Item Peripheral alterations underlying the negative effects of a cafeteria diet on brain and behaviour: exercise as a mitigating strategy(University College Cork, 2024) Nota, Minke H. C.; Nolan, Yvonne M.; O'Leary, Olivia; Irish Research Council; Science Foundation IrelandA Western lifestyle, characterised by inactivity and overconsumption of saturated fats and sugar, increases risk of depression, anxiety, and cognitive impairment. Obesity, metabolic dysfunction, (neuro)inflammation, and gut microbiota alterations, which can result from a Western lifestyle, are associated with mood disorders and cognitive impairment, thus constituting potential mechanisms by which Western lifestyle impacts the brain. Adult hippocampal neurogenesis (AHN), i.e., the birth of new neurons in the dentate gyrus of the hippocampus, is involved in certain forms of memory, including spatial memory and pattern separation, and in regulating emotion through anxiety behaviours and antidepressant action. A cafeteria (CAF) diet, mimicking human Western-style diets, has been shown to decrease AHN, impair memory, and increase anxiety-like behaviour in rodents, whereas exercise has antidepressant effects and has been shown to improve AHN and cognition. However, interactions between these lifestyle factors remain unclear. Furthermore, effects of Western-style diets and exercise on AHN and associated behaviours have primarily been researched in males, whereas depression, certain anxiety disorders, and dementia disproportionally affect women. The aims of this thesis were to investigate whether voluntary running exercise could alter the effects of a CAF diet on AHN and hippocampus-associated behaviour, and the intake of and preference for a CAF diet in adult male and female rats, and to determine if a CAF diet and exercise could impact metabolic markers, inflammation, and gut-derived metabolites in males. Exercise had anxiolytic effects in males and females, induced modest improvements in spatial learning in males, and decreased spatial memory in females. Additionally, exercise mitigated a CAF diet-induced increase in depression-like behaviour, and a CAF diet blunted an exercise-induced increase in AHN, in males but not females. In exercising males and females with access to CAF diet, intake of energy from CAF foods and saturated fat was decreased, and fibre and protein intake was increased compared to sedentary rats with access to a CAF diet. Moreover, compared to sedentary rats, exercising rats had reduced preference for CAF foods over standard chow, which was maintained for 2 and 5 weeks in females and males, respectively. Increased hypothalamic Drd1 gene expression, which has been shown to promote overeating, in exercising males with access to a CAF diet possibly explained reduced preference for CAF foods in exercising rats not being maintained past 5 weeks. Alterations in metabolic hormones and caecal metabolites offer potential explanations for behavioural and neurogenic effects observed in males. Exercise-induced increased PYY potentially contributed to anxiolytic effects of exercise, and a CAF diet attenuating exercise-induced increased GLP-1 possibly explained the blunting of neurogenic effects of exercise. Attenuation of CAF diet-induced increased leptin and insulin and decreased caecal indole-3-carboxylate and deoxyinosine by exercise potentially contributed to exercise mitigating CAF diet-induced increased depression-like behaviour. Furthermore, exercise attenuated a CAF diet-induced decrease in abundance of caecal anserine, a metabolite previously associated with improved cognitive function. No definitive pro- or anti-inflammatory pattern of a CAF diet and exercise emerged that might have contributed to changes observed in behaviour and AHN. However, ventral hippocampal Il-6r gene expression was decreased in exercising males with access to a CAF diet, possibly explaining the finding that in males, exercise attenuated a CAF diet-induced increase in depression-like behaviour, as reduced general IL-6 activity has been associated with antidepressant effects. Ultimately, these data highlight the importance of exercise combined with a healthy diet for hippocampal health, along with sex differences in lifestyle influences on brain and behaviour. Moreover, these data indicate potential mechanisms, including metabolic hormones and gut microbial metabolites, underlying interactions between a CAF diet and exercise on brain and behaviour, thereby aiding advancement of preventative measures for depression and cognitive impairment.Item Unravelling the role of circadian rhythmicity in microbiota-gut-brain axis signalling(University College Cork, 2023) Tofani Sousa e Silva, Gabriel; Cryan, John; Saks-Kavanaugh Foundation; Science Foundation IrelandModern habits are becoming more and more disruptive to health. Our days are often filled with circadian disruption and stress exposure. We need to understand how our responses to these external stimuli are shaped and how they can be targeted to promote health. A growing body of research demonstrates the role of the gut microbiota in influencing brain function and behavior. The stress and circadian systems, which are essential to maintaining appropriate responses to the environment, are known to be impacted by the gut microbiota. Although gut microbes have been shown to modulate circadian rhythms and stress response, such studies were conducted in an independent manner. Since these systems are interconnected through the hypothalamic-pituitary-adrenal (HPA) axis, there is a need to examine how the gut microbiota may play a role in regulating the integration of stress and circadian signals. In this thesis, I aimed to investigate the influence of circadian rhythmicity in the microbiota-gut-brain axis communication and the consequences of that to stress responsivity. To this end we developed a computational tool, Kronos, that allows us to determine rhythmicity of genes and metabolites in brain regions important to stress and circadian regulation under different microbial status. Moreover, we investigate the interplay of the circadian and stress systems in the absence of the microbiota to dissect its role in the modulation of these systems. Using transcriptomics, and applying Kronos, we demonstrate that microbial depletion by antibiotic administration or germ-free status disrupts the molecular clock in the superchiasmatic nucleus (SCN). Such alterations to the master clock were accompanied with disruptions in the rhythmicity of circulating corticosterone. Furthermore, multi-omics analysis in the hippocampus and amygdala, indicated that microbial status disrupted the diurnal oscillations in genes and metabolites that compose pathways important for the stress response. We then investigate the expression of genes related to circadian rhythms and HPA-axis in the paraventricular nucleus, pituitary, and adrenal glands across the day. This, together with alterations in corticosterone demonstrates a hyper-activation of the HPA-axis at the sleep/wake transition in microbial depleted animals. Such disruption to the rhythmic function of the HPA-axis resulted in a time-of-day specific impairment of the stress response and stress-sensitive behaviors. Lastly, we identify changes in the rhythmic profile of the gut microbiota following microbial depletion. This manifested as peak of bacterial load at the same time the impairments in HPA-axis function were observed. Furthermore, by conducting fecal microbiota transplantation we confirm that the diurnal oscillations in gut microbes after antibiotic treatment regulates glucocorticoids secretion and explore the microbial compositional changes underlying it. This work provides compelling evidence that the gut microbiota regulates stress responsivity via the circadian system. Moreover, we identify the gut microbiota as an important regulator of HPA-axis rhythmic function, demonstrating that the microbiota is essential to adaptively respond to psychological stressors throughout the day.