A computational framework for similarity estimation and stimulus reconstruction of Hodgkin-Huxley neural responses

Periodic stimuli are known to induce chaotic oscillations in the squid giant axon for a certain range of frequencies, a behaviour modelled by the Hodgkin-Huxley equations. Inthe presence of chaotic oscillations, similarity between neural responses depends on their temporal nature as firing times and amplitudes together reflect the true dynamics of theneuron. This thesis presents a method to estimate similarity between neural responses exhibiting chaotic oscillations by using both amplitude fluctuations and firing times. It isobserved that identical stimuli have similar effect on the neural dynamics and therefore, as the temporal inputs to the neuron are identical, the occurrence of similar dynamicalpatterns result in a high estimate of similarity, which correlates with the observed temporal similarity.The information about a neural activity is encoded in a neural response and usually the underlying stimulus that triggers the activity is unknown. Thus, this thesis also presents anumerical solution to reconstruct stimuli from Hodgkin-Huxley neural responses while retrieving the neural dynamics. The stimulus is reconstructed by first retrieving themaximal conductances of the ion channels and then solving the Hodgkin-Huxley equations for the stimulus. The results show that the reconstructed stimulus is a good approximationof the original stimulus, while the retrieved the neural dynamics, which represent the voltage-dependent changes in the ion channels, help to understand the changes in neuralbiochemistry. As high non-linearity of neural dynamics renders analytical inversion of a neuron an arduous task, a numerical approach provides a local solution to the problem ofstimulus reconstruction and neural dynamics retrieval

Disproportional signal of pericarditis with biological diseasemodifying antirheumatic drugs (bDMARDs) in patients with ankylosing spondylitis: a disproportionality analysis in the FAERS database

Objective: This study aimed to investigate the potential association between biological disease-modifying antirheumatic drugs (bDMARDs) and pericarditis and uncover relevant clinical characteristics in ankylosing spondylitis (AS).Methods: Reports of pericarditis recorded in the FDA Adverse Event Reporting System (FAERS) (January 2004–December 2022) were identified through the preferred term “pericarditis.” Demographic and clinical characteristics were described, and disproportionality signals were assessed through the reporting odds ratio (ROR) and information component (IC). A significant signal was detected if the lower bound of IC (IC025) was more than zero.Results: We found 1,874 reports of pericarditis with bDMARDs (11.3% of cases with fatal outcomes). Adalimumab (IC025 3.24), infliximab (IC025 4.90), golimumab (IC025 5.40), certolizumab (IC025 5.43), etanercept (IC025 3.24), secukinumab (IC025 3.97), and ustekinumab (IC025 7.61) exhibit significant disproportionality signals compared to other medications in the FAERS database. After excluding pre-existing diseases and co-treated drugs that may increase the susceptibility of pericarditis, the disproportionality signal associated with infliximab, certolizumab, etanercept, secukinumab, and ustekinumab remained strong. Pericarditis cases associated with all bDMARDs were predominantly recorded in women aged 25–65 years.Conclusion: More reports of pericarditis were detected with AS patients on bDMARDs than with other drugs in the overall database. Further studies are warranted to investigate the underlying mechanisms and identify patient-related susceptibility factors, thus supporting timely diagnosis and safe(r) prescribing of bDMARDs

A computational framework for similarity estimation and stimulus reconstruction of Hodgkin-Huxley neural responses

Periodic stimuli are known to induce chaotic oscillations in the squid giant axon for a certain range of frequencies, a behaviour modelled by the Hodgkin-Huxley equations. Inthe presence of chaotic oscillations, similarity between neural responses depends on their temporal nature as firing times and amplitudes together reflect the true dynamics of theneuron. This thesis presents a method to estimate similarity between neural responses exhibiting chaotic oscillations by using both amplitude fluctuations and firing times. It isobserved that identical stimuli have similar effect on the neural dynamics and therefore, as the temporal inputs to the neuron are identical, the occurrence of similar dynamicalpatterns result in a high estimate of similarity, which correlates with the observed temporal similarity.The information about a neural activity is encoded in a neural response and usually the underlying stimulus that triggers the activity is unknown. Thus, this thesis also presents anumerical solution to reconstruct stimuli from Hodgkin-Huxley neural responses while retrieving the neural dynamics. The stimulus is reconstructed by first retrieving themaximal conductances of the ion channels and then solving the Hodgkin-Huxley equations for the stimulus. The results show that the reconstructed stimulus is a good approximationof the original stimulus, while the retrieved the neural dynamics, which represent the voltage-dependent changes in the ion channels, help to understand the changes in neuralbiochemistry. As high non-linearity of neural dynamics renders analytical inversion of a neuron an arduous task, a numerical approach provides a local solution to the problem ofstimulus reconstruction and neural dynamics retrieval

Dysphonia measures in parkinson's disease and their use in prediction of its progression

Parkinson's Disease (PD) is a neurodegenerative disorder that impairs the motor skills, speech and general muscle coordination. The progression of PD is assessed using a clinically defined rating scale known as Unified Parkinson's Disease Rating Scale (UPDRS). Recent studies have shown the use of telemonitoring of PD using simple speech tests which replicate the UPDRS to clinician's accuracy. Regression analysis is performed on a database of speech recordings of 42 PD patients to analyse the relation between dysphonia measures and the UPDRS with the progression of PD. It is observed that there is a strong correlation between the dysphonia measures and the UPDRS and it is possible to predict the UPDRS scores weekly using linear regression techniques. The results also suggest that certain dysphonia measures evolve more significantly with the progression in PD. This is supported by Principle Component Analysis (PCA) which identifies the dysphonia measures that are strongly correlated during the course of PD progression. The data is classed by trials undertaken by the patients and each patient had at least 20 valid trials

Menopause, mood and memory : the effect of hormone replacement therapy on mood and everyday memory in mid-life women : a thesis presented in partial fulfilment of the requirements for the degree of Master of Arts in Psychology at Massey University

There is considerable neuro-scientific evidence that oestrogen influences memory and enhances mood because of its influence on brain mechanisms. Research on the effect of hormone replacement therapy (HRT) on both mood and memory is equivocal although findings indicate that oestrogen may enhance verbal memory. It has been suggested that this area of research should expand to include ecologically valid measures of everyday memory. This study examined the effect of HRT on mood and everyday memory in two separate samples of mid-life women. A cross-sectional comparison of HRT users and non-users among 124 women aged between 40 and 60 years showed that there were no significant differences in mood between HRT users and non-users. However, HRT users performed significantly better on tests of everyday memory and delayed verbal memory when the effects of age, IQ, and education were controlled for. A within-subjects comparison, using the same measures, with 17 women before, and 3 months after, HRT use, showed that negative mood states were reduced and positive mood states were enhanced by HRT, when change in stressful life events, self-rated health, sleep problems, vasomotor symptoms, and exercise were controlled for. The longitudinal sample also showed that everyday memory, working memory, and delayed verbal memory improved with HRT use. The improvement in memory was not mediated by mood. These results suggest that the effect of HRT on mood may only be short-term but that oestrogen does enhance everyday memory

Rheumatic and Musculoskeletal Adverse Events with Immune Checkpoint Inhibitors: Data from the United States Food and Drug Administration Adverse Event Reporting System

Background: Despite their efficacy, immune checkpoint inhibitors (ICIs) can cause significant immune-related adverse events (irAEs). Rheumatic and musculoskeletal irAEs can be serious and adversely affect the quality of life. The full spectrum of irAEs is still emerging, and to represent and better understand their scope, we evaluated the United States Food and Drug Administration Adverse Event Reporting System (FAERS) database. Methods: We used AERSMine, an open-access web application to mine FAERS data across 11,919,342 patients from 2011 (first quarter) to 2018 (fourth quarter). Measures of disproportionality were calculated using well-established pharmacovigilance metrics, proportional reporting ratios, and safety signals (information component), in patients receiving ICI. Results: We analyzed 63,979 cancer patients for reports of ICI-associated AEs. Eighty-two percent of these reports were in relation with anti-PD-1 inhibitors. Rates of rheumatic and musculoskeletal AEs were higher in men and in patients >65 years of age. Several statistically significant AEs were identified, most in relation with PD-1 inhibitors. AEs with the highest number of reports included arthralgia (n = 1062), followed by myalgia (n = 532), myositis (n = 438), arthritis (n = 403), and rhabdomyolysis (n = 230). Novel AEs affecting the skeleton included compression fractures, fractures at various skeletal sites (rib, thoracic vertebral, and humerus), osteonecrosis of the jaw, osteitis, and osteomyelitis. Conclusion: A wide spectrum of rheumatic and musculoskeletal AE signals were detected within the FAERS data which may signify the emerging trends of irAEs post approval of ICI. Additional research to explore mechanisms and identify optimal management strategies of these AEs is warranted

The Impact of Marijuana on Antidepressant Treatment in Adolescents: Clinical and Pharmacologic Considerations

The neuropharmacology of marijuana, including its effects on selective serotonin reuptake inhibitor (SSRI)/antidepressant metabolism and the subsequent response and tolerability in youth, has received limited attention. We sought to (1) review clinically relevant pharmacokinetic (PK) and pharmacodynamic (PD) interactions between cannabinoids and selected SSRIs, (2) use PK models to examine the impact of cannabinoids on SSRI exposure (area under curve (AUC)) and maximum concentration (CMAX) in adolescents, and (3) examine the frequency of adverse events reported when SSRIs and cannabinoids are used concomitantly. Cannabinoid metabolism, interactions with SSRIs, impact on relevant PK/PD pathways and known drug–drug interactions were reviewed. Then, the impact of tetrahydrocannabinol (THC) and cannabidiol (CBD) on exposure (AUC24) and CMAX for escitalopram and sertraline was modeled using pediatric PK data. Using data from the Food and Drug Administration Adverse Events Reporting System (FAERS), the relationship between CBD and CYP2C19-metabolized SSRIs and side effects was examined. Cannabis and CBD inhibit cytochrome activity, alter serotonergic transmission, and modulate SSRI response. In PK models, CBD and/or THC increases sertraline and es/citalopram concentrations in adolescents, and coadministration of CBD and CYP2C19-metabolized SSRIs increases the risk of cough, diarrhea, dizziness, and fatigue. Given the significant SSRI–cannabinoid interactions, clinicians should discuss THC and CBD use in youth prescribed SSRIs and be aware of the impact of initiating, stopping, or decreasing cannabinoid use as this may significantly affect es/citalopram and sertraline exposure