XXII International Conference on Mechanics in Medicine and Biology - Abstracts Book

This book contain the abstracts presented the XXII ICMMB, held in Bologna in September 2022. The abstracts are divided following the sessions scheduled during the conference

Reflex syncope : an integrative physiological approach

Síncope, a forma mais comum de perda temporária de consciência é responsável por até 5% das idas aos serviços de emergência e até 3% dos internamentos hospitalares. É um problema médico frequente, com múltiplos gatilhos, incapacitante, potencialmente perigoso e desafiante em termos diagnósticos e terapêuticos. Assim, é necessária uma anamnese detalhada para primeiro estabelecer a natureza da perda de consciência, mas, após o diagnóstico, as medidas terapêuticas existentes são pouco eficazes. Embora a fisiopatologia da síncope vasovagal ainda não tenha sido completamente esclarecida, alguns mecanismos subjacentes foram já desvendados. Em última análise, a síncope depende de uma falha transitória na perfusão cerebral pelo que qualquer factor que afecte a circulação sanguínea cerebral pode determinar a ocorrência de síncope. Assim, o objectivo do presente estudo é caracterizar o impacto hemodinâmico e autonómico nos mecanismos subjacentes à síncope reflexa, para melhorar o diagnóstico, o prognóstico e a qualidade de vida dos doentes e dos seus cuidadores. Para isso, desenhámos e implementámos novas ferramentas matemáticas e computacionais que permitem uma avaliação autonómica e hemodinâmica integrada, de forma a aprofundar a compreensão do seu envolvimento nos mecanismos de síncope reflexa. Além disso, refinando a precisão do diagnóstico, a sensibilidade e a especificidade do teste de mesa de inclinação (“tilt test”), estabelecemos uma ferramenta preditiva do episódio iminente de síncope. Isso permitiu-nos estabelecer alternativas de tratamento eficazes e personalizadas para os doentes refractários às opções convencionais, sob a forma de um programa de treino de ortostatismo (“tilt training”), contribuindo para o aumento da sua qualidade de vida e para a redução dos custos directos e indirectos da sua assistência médica. Assim, num estudo verdadeiramente multidisciplinar envolvendo doentes com síncope reflexa refractária à terapêutica, conseguimos demonstrar uma assincronia funcional das respostas reflexas autonómicas e hemodinâmicas, expressas por um desajuste temporal entre o débito cardíaco e as adaptações de resistência total periférica, uma resposta baroreflexa atrasada e um desequilíbrio incremental do tónus autonómico que, em conjunto, poderão resultar de uma disfunção do sistema nervoso autónomo que se traduz por uma reserva simpática diminuída. Igualmente, desenhámos, testámos e implementámos uma plataforma computacional e respectivo software associado - a plataforma FisioSinal –incluindo novas formas, mais dinâmicas, de avaliação integrada autonómica e hemodinâmica, que levaram ao desenvolvimento de algoritmos preditivos para a estratificação de doentes com síncope. Além disso, na aplicação dessas ferramentas, comprovámos a eficácia de um tratamento não invasivo, não disruptivo e integrado, focado na neuromodulação das variáveis autonómicas e cardiovasculares envolvidas nos mecanismos de síncope. Esta terapêutica complementar levou a um aumento substancial da qualidade de vida dos doentes e à abolição dos eventos sincopais na grande maioria dos doentes envolvidos. Em conclusão, o nosso trabalho contribuiu para preencher a lacuna entre a melhor informação científica disponível e sua aplicação na prática clínica, sustentando-se nos três pilares da medicina translacional: investigação básica, clínica e comunidade.Syncope, the most common form of transient loss of consciousness, accounts for up to 5% of emergency room visits and up to 3% of hospital admissions. It is a frequent medical problem with multiple triggers, potentially dangerous, incapacitating, and challenging to diagnose. Therefore, a detailed clinical history is needed first to establish the nature of the loss of consciousness. However, after diagnosis, the therapeutic measures available are still very poor. Although the exact pathophysiology of vasovagal syncope remains to be clarified, some underlying mechanisms have been unveiled, dependent not only on the cause of syncope but also on age and various other factors that affect clinical presentation. Ultimately, syncope depends on a failure of the circulation to perfuse the brain, so any factor affecting blood circulation may determine syncope occurrence. Thus, the purpose of the present study is to understand the impact of the hemodynamic and autonomic functions on reflex syncope mechanisms to improve patients diagnose, prognosis and general quality of life. Bearing that in mind, we designed and implemented new mathematical and computational tools for autonomic and hemodynamic evaluation, in order to deepen the understanding of their involvement in reflex syncope mechanisms. Furthermore, by refining the diagnostic accuracy, sensitivity and specificity of the head-up tilt-table test, we established a predictive tool for the impending syncopal episode. This allowed us to establish effective and personalised treatment alternatives to patient’s refractory to conventional options, contributing to their increase in the quality of life and a reduction of health care and associated costs. In accordance, in a truly multidisciplinary study involving reflex syncope patients, we were able to show an elemental functional asynchrony of hemodynamic and autonomic reflex responses, expressed through a temporal mismatch between cardiac output and total peripheral resistance adaptations, a deferred baroreflex response and an unbalanced, but incremental, autonomic tone, all contributing to autonomic dysfunction, translated into a decreased sympathetic reserve. Through the design, testing and implementation of a computational platform and the associated software - FisioSinal platform -, we developed novel and dynamic ways of autonomic and hemodynamic evaluation, whose data lead to the development of predictive algorithms for syncope patients’risk stratification. Furthermore, through the application of these tools, we showed the effectiveness of a non-invasive, non-disruptive and integrated treatment, focusing on neuromodulation of the autonomic and cardiovascular variables involved in the syncope mechanisms, leading to a substantial increase of quality of life and the abolishment of syncopal events in a vast majority of the enrolled patients. In conclusion, our work contributed to fill the gap between the best available scientific information and its application in the clinical practice by tackling the three pillars of translational medicine: bench-side, bedside and community

Augmentation of Brain Function: Facts, Fiction and Controversy. Volume III: From Clinical Applications to Ethical Issues and Futuristic Ideas

The final volume in this tripartite series on Brain Augmentation is entitled “From Clinical Applications to Ethical Issues and Futuristic Ideas”. Many of the articles within this volume deal with translational efforts taking the results of experiments on laboratory animals and applying them to humans. In many cases, these interventions are intended to help people with disabilities in such a way so as to either restore or extend brain function. Traditionally, therapies in brain augmentation have included electrical and pharmacological techniques. In contrast, some of the techniques discussed in this volume add specificity by targeting select neural populations. This approach opens the door to where and how to promote the best interventions. Along the way, results have empowered the medical profession by expanding their understanding of brain function. Articles in this volume relate novel clinical solutions for a host of neurological and psychiatric conditions such as stroke, Parkinson’s disease, Huntington’s disease, epilepsy, dementia, Alzheimer’s disease, autism spectrum disorders (ASD), traumatic brain injury, and disorders of consciousness. In disease, symptoms and signs denote a departure from normal function. Brain augmentation has now been used to target both the core symptoms that provide specificity in the diagnosis of a disease, as well as other constitutional symptoms that may greatly handicap the individual. The volume provides a report on the use of repetitive transcranial magnetic stimulation (rTMS) in ASD with reported improvements of core deficits (i.e., executive functions). TMS in this regard departs from the present-day trend towards symptomatic treatment that leaves unaltered the root cause of the condition. In diseases, such as schizophrenia, brain augmentation approaches hold promise to avoid lengthy pharmacological interventions that are usually riddled with side effects or those with limiting returns as in the case of Parkinson’s disease. Brain stimulation can also be used to treat auditory verbal hallucination, visuospatial (hemispatial) neglect, and pain in patients suffering from multiple sclerosis. The brain acts as a telecommunication transceiver wherein different bandwidth of frequencies (brainwave oscillations) transmit information. Their baseline levels correlate with certain behavioral states. The proper integration of brain oscillations provides for the phenomenon of binding and central coherence. Brain augmentation may foster the normalization of brain oscillations in nervous system disorders. These techniques hold the promise of being applied remotely (under the supervision of medical personnel), thus overcoming the obstacle of travel in order to obtain healthcare. At present, traditional thinking would argue the possibility of synergism among different modalities of brain augmentation as a way of increasing their overall effectiveness and improving therapeutic selectivity. Thinking outside of the box would also provide for the implementation of brain-to-brain interfaces where techniques, proper to artificial intelligence, could allow us to surpass the limits of natural selection or enable communications between several individual brains sharing memories, or even a global brain capable of self-organization. Not all brains are created equal. Brain stimulation studies suggest large individual variability in response that may affect overall recovery/treatment, or modify desired effects of a given intervention. The subject’s age, gender, hormonal levels may affect an individual’s cortical excitability. In addition, this volume discusses the role of social interactions in the operations of augmenting technologies. Finally, augmenting methods could be applied to modulate consciousness, even though its neural mechanisms are poorly understood. Finally, this volume should be taken as a debate on social, moral and ethical issues on neurotechnologies. Brain enhancement may transform the individual into someone or something else. These techniques bypass the usual routes of accommodation to environmental exigencies that exalted our personal fortitude: learning, exercising, and diet. This will allow humans to preselect desired characteristics and realize consequent rewards without having to overcome adversity through more laborious means. The concern is that humans may be playing God, and the possibility of an expanding gap in social equity where brain enhancements may be selectively available to the wealthier individuals. These issues are discussed by a number of articles in this volume. Also discussed are the relationship between the diminishment and enhancement following the application of brain-augmenting technologies, the problem of “mind control” with BMI technologies, free will the duty to use cognitive enhancers in high-responsibility professions, determining the population of people in need of brain enhancement, informed public policy, cognitive biases, and the hype caused by the development of brain- augmenting approaches

Online detection of tonic-clonic seizures in pediatric patients using ECG and low-complexity incremental novelty detection

Home monitoring of refractory epilepsy patients has become of more interest the last couple of decades. A biomedical signal that can be used for online seizure detection at home is the electrocardiogram. Previous studies have shown that tonic-clonic seizures are most often accompanied with a strong heart rate increase. The main issue however is the strong patient-specific behavior of the ictal heart rate features, which makes it hard to make a patient-independent seizure detection algorithm. A patient-specific algorithm might be a solution, but existing methods require the availability of data of several seizures, which would make them inefficient in case the first seizure only occurs after a couple of days. Therefore an online method is described here that automatically converts from a patient-independent towards a patient-specific algorithm as more patient-specific data become available. This is done by using online feedback from the users to previously given alarms. By using a simplified one-class classifier, no seizure training data needs to be available for a good performance. The method is already able to adapt to the patient-specific characteristics after a couple of hours, and is able to detect 23 of 24 seizures longer than 10s, with an average of 0.38 false alarms per hour. Due to its low-complexity, it can be easily used for wearable seizure detection at home.status: publishe

Novel Diagnostic and Therapeutic Approaches for Mitochondrial Disorders

Mitochondrial disorders are among the most common inherited genetic disorders, with a combined prevalence of 1:5,000. These are genetically, biochemically, and clinically heterogeneous disorders affecting any organ or tissue in the body. A poor understanding of gene-to-phenotype relationships and pathophysiological mechanisms has resulted in sometimes years-long diagnostic odysseys and a lack of curative therapies. Consequently, outcomes are often poor with most patients dying in early childhood. The aim of this project is to improve patient outlooks by using novel tools to address both the diagnostic and therapeutic challenges associated with mitochondrial disease. The diagnostic aspect of the study involved the creation of four interactive diagnostic resources which can complement next generation sequencing (NGS) technologies to achieve more rapid diagnoses for patients. MitoEpilepsy Map, MitoCardio Map, MitoLiver Map, and MitoMedicine Map were created to aid in the diagnosis of mitochondrial epilepsy, cardiomyopathy, liver disease, and the entirety of mitochondrial disease, respectively. These, maps were accurate in identifying candidate genes from clinical vignettes of genetically confirmed cases of mitochondrial disease in 69-100% of cases. These maps will be valuable resources for interpreting NGS results, hopefully facilitating quicker and more accurate genetic diagnoses for affected patients. The therapeutic aspect of the project aimed to develop a new treatment strategy for mitochondrial disease caused by nonsense mutations. Translational read-through therapy involves pharmacological incorporation of a near-cognate amino acid in place of a premature stop codon during translation. A systematic in vitro proof-of-principle study was performed in patient fibroblasts harbouring bi-allelic nonsense mutations in ten different mitochondrial disease genes. In five patient cell cultures, translational read-through therapy was able to restore transcript, protein, and mitochondrial function, thus demonstrating in vitro efficacy and paving the way for future clinical development. Together, these approaches help improve outcomes for patients suffering from mitochondrial disease

Frameshift mutations at the C-terminus of HIST1H1E result in a specific DNA hypomethylation signature

BACKGROUND: We previously associated HIST1H1E mutations causing Rahman syndrome with a specific genome-wide methylation pattern. RESULTS: Methylome analysis from peripheral blood samples of six affected subjects led us to identify a specific hypomethylated profile. This "episignature" was enriched for genes involved in neuronal system development and function. A computational classifier yielded full sensitivity and specificity in detecting subjects with Rahman syndrome. Applying this model to a cohort of undiagnosed probands allowed us to reach diagnosis in one subject. CONCLUSIONS: We demonstrate an epigenetic signature in subjects with Rahman syndrome that can be used to reach molecular diagnosis