Biomedicine and pain

The focus of my research is on contemporary biomedical construction of pain as an object, i.e. the different ways in which pain has been conceptualized and approached as a specific site of investigation in biomedicine. A significant shift in the scientific conception of pain occured in the second half of XXth century. In 1965, Ronald Melzack and Patrick D. Wall propose the Gate Control theory of pain mechanism. This theory denies a fixed and direct relationship between stimulus and pain perception, and emphazises the role played by psychological factors in pain. The IASP utilizes this perspective on the phenomenon, describing pain as “an unpleasant sensory and emotional experience associated to an actual or potential tissue damage or described in the terms of such a damage.” The relationship between pain and damage is pivotal in the definition of pain as a pathological entity. In particular, the biomedical approach to pain appears to be strongly characterized by a dualistic view of its aetiology. Disease conceptions such as “psychogenic pain” and chronic pain are deeply influenced by the ways in which psychological factors have been interpreted as components, or as causes of pain. In the second part of my dissertation, I focus on fibromyalgia, which is emblematic of the problematic acknowledgment of chronic pain as a disease. Even if fibromyalgia is actually treated in Rheumatology, its status as a disease is blurred, mainly because of its complex symptomatology including both physiological manifestations and psychological ones. In the conclusion, I present a scenario of the different ways in which this disease is dealt with in biomedical knowledge, through medical literature, clinical practice, and patients’ accounts. The findings of an ethnographic enquiry in the Rheumatology Division of a local clinic and a visual research on patients’ experiences are analyzed and discussed.

Global and regional sea level variations in the recent past and future: insight from observations and modeling

This work is focused on the analysis of sea–level change (last century), based mainly on instrumental observations. During this period, individual components of sea–level change are investigated, both at global and regional scales. Some of the geophysical processes responsible for current sea-level change such as glacial isostatic adjustments and current melting terrestrial ice sources, have been modeled and compared with observations. A new value of global mean sea level change based of tide gauges observations has been independently assessed in 1.5 mm/year, using corrections for glacial isostatic adjustment obtained with different models as a criterion for the tide gauge selection. The long wavelength spatial variability of the main components of sea–level change has been investigated by means of traditional and new spectral methods. Complex non–linear trends and abrupt sea–level variations shown by tide gauges records have been addressed applying different approaches to regional case studies. The Ensemble Empirical Mode Decomposition technique has been used to analyse tide gauges records from the Adriatic Sea to ascertain the existence of cyclic sea-level variations. An Early Warning approach have been adopted to detect tipping points in sea–level records of North East Pacific and their relationship with oceanic modes. Global sea–level projections to year 2100 have been obtained by a semi-empirical approach based on the artificial neural network method. In addition, a model-based approach has been applied to the case of the Mediterranean Sea, obtaining sea-level projection to year 2050.

Analysis of cerebral and autonomic response to respiratory events in patients with Sleep Apnea Syndrome

The arousal scoring in Obstructive Sleep Apnea Syndrome (OSAS) is important to clarify the impact of the disease on sleep but the currently applied American Academy of Sleep Medicine (AASM) definition may underestimate the subtle alterations of sleep. The aims of the present study were to evaluate the impact of respiratory events on cortical and autonomic arousal response and to quantify the additional value of cyclic alternating pattern (CAP) and pulse wave amplitude (PWA) for a more accurate detection of respiratory events and sleep alterations in OSAS patients. A retrospective revision of 19 polysomnographic recordings of OSAS patients was carried out. Analysis was focused on quantification of apneas (AP), hypopneas (H) and flow limitation (FL) events, and on investigation of cerebral and autonomic activity. Only 41.1% of FL events analyzed in non rapid eye movement met the AASM rules for the definition of respiratory event-related arousal (RERA), while 75.5% of FL events ended with a CAP A phase. The dual response (EEG-PWA) was the most frequent response for all subtypes of respiratory event with a progressive reduction from AP to H and FL. 87.7% of respiratory events with EEG activation showed also a PWA drop and 53,4% of the respiratory events without EEG activation presented a PWA drop. The relationship between the respiratory events and the arousal response is more complex than that suggested by the international classification. In the estimation of the response to respiratory events, the CAP scoring and PWA analysis can offer more extensive information compared to the AASM rules. Our data confirm also that the application of PWA scoring improves the detection of respiratory events and could reduce the underestimation of OSAS severity compared to AASM arousal.

Unraveling the pathophysiological mechanisms of visceral pain in the murine model of Fabry disease

Fabry disease (FD) is an X‐linked inherited, lysosomal storage disorder characterized by a deficient activity of the enzyme α-Galactosidase A (α-Gal A). This deficiency causes an accumulation of globotriaosylceramide 3 (Gb3), in nearly all organs. Gastrointestinal (GI) symptoms are among the earliest and most frequent symptoms of FD. It has been hypothesized that Gb3 accumulation is the leading cause of these, but their pathophysiology is complex and still poorly understood. Here, we aim at understanding the molecular mechanisms underpinning the GI symptoms of FD. For this purpose, we used the α‐Gal A (-/0) male mouse, a murine model of FD, to characterize morphological and molecular features of the colon tract. Our results show that α‐Gal A (-/0) mice display a thickening of the muscular layer due to a hypertrophic state of myenteric plexus ganglia, caused by an accumulation of Gb3 in neurons. Also, α-Gal A (-/0) mice present a decreased density of mucosal nerve fibres. Furthermore, α-Gal A (-/0) mice presented visceral hyperalgesia, by showing greater visceromotor response (VMR) values and obtaining higher abdominal withdrawal reflex (AWR) scores, following colorectal distension (CRD). Subsequently, the immunoreactivity of the pain-related ion channels TRPV1, TRPV4, TRPA1 and TRPM8 was detected at level of myenteric and submucosal plexus ganglia of both the genotypes. Further studies are required to assess differences of expression between α-Gal A (-/0) and control mice. Finally, we optimized the protocols to obtain three types of primary cultures from mouse intestine to be tested electrophysiologically: a mixed culture containing neurons and glia, an enriched culture of neurons, and one of glia. In summary, we revealed alterations that are likely to be part of the pathophysiological causes of FD GI symptoms. Therefore, together with further studies, this work could help identify new therapeutic targets for the treatment of visceral pain in FD.

Economic preferences in the health setting. Three case studies concerning the needs of breast cancer patients, pain management in oncology and extreme end-of-life decisions

The thesis describes three studies concerning the role of the Economic Preference set investigated in the Global Preference Survey (GPS) in the following cases: 1) the needs of women with breast cancer; 2) pain undertreament in oncology; 3) legal status of euthanasia and assisted suicide. The analyses, based on regression techniques, were always conducted on the basis of aggregate data and revealed in all cases a possible role of the Economic Preferences studied, also resisting the concomitant effect of the other covariates that were considered from time to time. Regarding individual studies, the related conclusion are: 1) Economic Preferences appear to play a role in influencing the needs of women with breast cancer, albeit of non-trivial interpretation, statistically "resisting" the concomitant effect of the other independent variables considered. However, these results should be considered preliminary and need further confirmation, possibly with prospective studies conducted at the level of the individual; 2) the results show a good degree of internal consistency with regard to pro-social GPS scores, since they are all found to be non-statistically significant and united, albeit only weakly in trend, by a negative correlation with the % of pain undertreated patients. Sharper, at least statistically, is the role of Patience and Willingness to Take Risk, although of more complex empirical interpretation. 3) the results seem to indicate an obvious role of Economic Preferences, however difficult to interpret empirically. Less evidence, at least on the inferential level, emerged, however, regarding variables that, based on common sense, should play an even more obvious role than Economic Preferences in orienting attitudes toward euthanasia and assisted suicide, namely Healthcare System, Legal Origin, and Kinship Tightness; striking, in particular, is the inability to prove a role for the dominant religious orientation even with a simple bivariate analysis.

[In search of] Digital biomarkers for objective pain assessment

Pain is a highly complex phenomenon involving intricate neural systems, whose interactions with other physiological mechanisms are not fully understood. Standard pain assessment methods, relying on verbal communication, often fail to provide reliable and accurate information, which poses a critical challenge in the clinical context. In the era of ubiquitous and inexpensive physiological monitoring, coupled with the advancement of artificial intelligence, these new tools appear as the natural candidates to be tested to address such a challenge. This thesis aims to conduct experimental research to develop digital biomarkers for pain assessment. After providing an overview of the state-of-the-art regarding pain neurophysiology and assessment tools, methods for appropriately conditioning physiological signals and controlling confounding factors are presented. The thesis focuses on three different pain conditions: cancer pain, chronic low back pain, and pain experienced by patients undergoing neurorehabilitation. The approach presented in this thesis has shown promise, but further studies are needed to confirm and strengthen these results. Prior to developing any models, a preliminary signal quality check is essential, along with the inclusion of personal and health information in the models to limit their confounding effects. A multimodal approach is preferred for better performance, although unimodal analysis has revealed interesting aspects of the pain experience. This approach can enrich the routine clinical pain assessment procedure by enabling pain to be monitored when and where it is actually experienced, and without the involvement of explicit communication,. This would improve the characterization of the pain experience, aid in antalgic therapy personalization, and bring timely relief, with the ultimate goal of improving the quality of life of patients suffering from pain.