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Unraveling the neurological basis of Tinnitus by studying its initial onset and subsequent chronification

Wed, 01 Jan 2025 00:00:00 GMT

Title: Unraveling the neurological basis of Tinnitus by studying its initial onset and subsequent chronification Authors: Umashankar, Abishek Abstract: Despite tinnitus being too common and present (prevalence: 13%, remission rate: 17.1%), it is still unclear as to why tinnitus is generated and why it persists, thus making it challenging to come up with definitive treatments. For better understanding of tinnitus mechanism, it is warranted to analyse, how the tinnitus transits from its initial onset or acute stages (duration of tinnitus less than 4 weeks) until its chronic stage (duration of tinnitus greater than 6 months). We were motivated to carry out a tinnitus study with an aim to unravel the neurobiological basis of tinnitus by studying its initial onset until its subsequent chronification. We hypothesized that the neural processes such as synchrony and gain (auditory hypersensitivity) linked to tinnitus will be maximal around the onset and reduces over time as a regression to the mean. The study involved individuals with Acute Tinnitus, who were monitored longitudinally for six months post-onset, alongside individuals with Chronic Tinnitus and a Control group matched to the Acute Tinnitus cohort. Our results culminating multiple measures (subjective and objective) of tinnitus reveal that the neural processes linked solely to the tinnitus activity were maximal around the time of onset and reduced over time which is in line with our hypothesis. We further established that measures of generalized auditory sensitivity (gain) do not significantly differ between the groups. Increased dynamic range adaptation, were observed in the Acute Tinnitus group, but not in the Chronic Tinnitus or Control groups thus indicating that tinnitus is an outcome of excess auditory hyperactivity as an invariance (mitigator) to central gain through properties of increased dynamic range adaptation that tends to persist through modes of sustained attentional networks. This would explain why tinnitus generates and persists as it seeks to modulate excessive hypersensitivity within the auditory system. Description: PhD Thesis

The impact of Vasopressin on coronary microcirculation in ST-elevation myocardial infarction

Wed, 01 Jan 2025 00:00:00 GMT

Title: The impact of Vasopressin on coronary microcirculation in ST-elevation myocardial infarction Authors: Mohammed, Ashfaq Abstract: Background: When treating patients with an acute myocardial infarction, the coronary microcirculation is an area that still eludes understanding. One suspected mechanism for microvascular dysfunction in this patient group is ongoing coronary vasoconstriction during reperfusion. Animal models suggest that Arginine Vasopressin (AVP) has a vasoactive effect on the coronary microcirculation. Aims: 1) To evaluate the blood levels of vasopressin in STEMI patients over the course of the myocardial infarction and during reperfusion. 2) To assess the impact of vasopressin on the coronary microcirculation in STEMI. Methods: Arterial blood samples were taken from patients admitted to the Freeman Hospital, Newcastle with an acute STEMI, who subsequently underwent PPCI, over the time course of reperfusion. Copeptin, a precursor of vasopressin was measured. Cardiac MRI was performed to evaluate microvascular obstruction, infarct size and ejection fraction. Index of Microvascular resistance (IMR) was performed to measure microvascular dysfunction. Results: In STEMI patients copeptin levels at baseline are markedly elevated (126.8 ± 13.94 pmol/l) with copeptin levels falling significantly by 90 minutes (86.15 ± 12.57 pmol/l) (p < 0.0001). Copeptin levels at 24 hours are significantly higher in patients where TIMI 3 flow was not achieved post PCI (<0.05). Copeptin levels were not related to the presence of microvascular obstruction or IMR, but higher copeptin levels resulted in significantly lower CFR (p <0.01). Higher copeptin levels at baseline and 30 mins post reperfusion were noted in patients with smaller infarctions (p <0.01). Conclusion: In STEMI patients, circulating copeptin is elevated over the course of reperfusion, with increased levels at 24 hours signifying poor reperfusion. Copeptin does not impact on the coronary microcirculation but does significantly affect the coronary flow after reperfusion. Higher copeptin levels at baseline suggest a cardioprotective element with smaller infarctions. Description: MD Thesis

Understanding the biological basis of symptoms in primary biliary cholangitis

Wed, 01 Jan 2025 00:00:00 GMT

Title: Understanding the biological basis of symptoms in primary biliary cholangitis Authors: Wetten, Aaron Abstract: Background and Aims: Symptoms of pruritus, fatigue and cognitive impairment are common in Primary Biliary Cholangitis (PBC) with a significant impact on patients’ quality of life. The biological mechanisms underpinning these are poorly understood. Management of symptomatic PBC remains a significant unmet need, with no effective treatment for fatigue or cognition and only partially effective treatments for pruritus. This study explored markers associated with the pathogenesis of PBC and their relationship to symptoms. Method: Study 1 (exploratory) investigated 19 O-link serum proteomic markers in 289 fully characterised PBC patients from the UK-PBC cohort. Markers were compared to ‘clinically significant’ (c/s) symptoms, as assessed using the PBC-40. Study 2 (validation) compared a multiplex of 11 markers to a symptom-heavy cohort of 160 PBC patients and 40 healthy controls. Study 3 explored the neurosteroid allopregnanolone in 120 PBC patients and 40 healthy controls, comparing serum levels to c/s symptoms. Results: Interleukin-6 (IL-6) was positively associated with c/s fatigue, as compared with ‘not clinically significant’ (nc/s) fatigue (exploratory: median 2.63(IQR 0.80) pg/ml vs 2.42(0.89); p=0.047; validation: 1.62(0.89) vs 1.06(0.86); p=0.01), while Interluekin-4 Receptor Alpha (IL-4RA) was associated with c/s pruritus, as compared with nc/s pruritus (exploratory: 3.27(1.30) pg/ml vs 3.09(1.01); p=0.032; validation: 1081(173) vs 1000(200); p=0.022). Allopregnanolone was elevated in c/s cognitive (0.037 (0.04) vs 0.023(0.036); p=0.044) and emotional symptoms (0.039(0.056) vs (0.027(0.036); p=0.01). Conclusion: IL-6 was elevated in two distinct PBC groups with fatigue and has previously been implicated in skeletal muscle fatigability. IL-6 blockade therapies may present a new therapeutic strategy for fatigue. IL-4RA demonstrated positive associations for pruritus across both groups. An ongoing IL-4RA receptor antagonist trial may prove effective in treating cholestatic pruritus. Elevated serum allopregnanolone is associated with severe cognitive and emotional symptoms in PBC and may be amenable to novel compounds targeting GABA-A receptors Description: M. D. Thesis.

Discovering the genetic basis of epilepsies through computational analysis of clinical phenotype

Wed, 01 Jan 2025 00:00:00 GMT

Title: Discovering the genetic basis of epilepsies through computational analysis of clinical phenotype Authors: Lewis-Smith, David James Abstract: The epilepsies are complex, primarily because of their diverse seizure types, neurodevelopmental features, and comorbidities. High throughput sequencing and genotyping has accelerated the pace of discovery for new genetic causes and risk factors. The rate at which these biological discoveries have been translated into clinically actionable knowledge has been slower because of the burden of collecting, harmonizing, and analyzing precise clinical data manually, which prohibits detailed phenotypic analysis at scale. In this thesis, I report some of my contribution to the opening of this phenotyping bottleneck by modeling clinical neurological reasoning for computational scaling of phenotypic analysis to increase the clinical value of genetic discoveries. I present a conceptual model for harmonizing seizure descriptions based on contemporary classifications. I critically appraise methods of associating clinical and genetic features in epileptology and propose a new phenotypic similarity measure, SimMinTO, based on the communication of clinical features between experts that models the traditional notion of recognizing a genetically associated syndrome. Applying these tools in two studies of over 10,000 people, I characterize the clinical features of carriers of copy number variants and ultra-rare sequence variants with reference to other people with presumed genetic epilepsies, reflecting the situation in an epilepsy clinic. Finally, I present a detailed analysis of data from 67 adults with CDKL5 Deficiency Disorder, a developmental and epileptic encephalopathy in which prior knowledge has been limited to children. I show how harmonization of historical multisource data can enable retrospective natural history studies of rare disorders to inform prognostication and the design of expensive and lengthy prospective studies including precision medicine trials. I hope that this work will introduce new standards, promoting more formal clinical characterization of complex disorders that will facilitate the rapid discovery and validation of associations, improving classification for stratified care and research both within neurology and beyond. Description: PhD Thesis