Endometriosis-related infertility describes a case of deteriorated fecundity when endometriosis is diagnosed. Numerous mechanisms have been proposed in an effort to delineate the multifaceted pathophysiology that induces impairment of reproductive dynamics in patients with endometriosis. In this critical analysis, authors present the plethora of molecular events that are entailed and elaborate on how they potentially impair the oocyte’s and embryo’s competence in patients with endometriosis. Reactive oxygen species, dysregulation of the immune system and cellular architectural disruption constitute the crucial mechanisms that detrimentally affect oocyte and embryo developmental potential. The molecular level impairment of the reproductive tissue is discussed, since differentiation, proliferation and apoptosis constitute focal regulatory cellular functions that appear severely compromised in cases of endometriosis. Mapping the precise molecular mechanisms entailed in endometriosis-related infertility may help delineate the complex nature of the disorder and bring us a step closer to a more personalized approach in understanding, diagnosing and managing endometriosis-related infertility. Endometriosis constitutes one of the numerous medical enigmas resulting in compromised fertility. It is a chronic benign disease characterized by chronic inflammation, principally affecting women of reproductive age. The vague clinical symptoms regularly accompanying endometriosis render a timely and precise diagnosis rather challenging. It is clear that where endometriosis-related infertility is concerned, the asymptomatic nature of the underlying disorder complicates things. This harbors the risk of a false unexplained infertility diagnosis and subsequent futile in vitro fertilization (IVF) attempts ,2. It isThe conundrum on how the reproductive potential of a patient with endometriosis is compromised has been thoroughly discussed in the literature. Several studies have suggested that fertilization rate, the number of competent embryos, blastocyst formation rate, implantation rate and pregnancy rate are impaired in cases of diagnosed endometriosis . ClinicaSince oocyte and embryo quality are the two pillars of a successful IVF outcome, patients undergoing assisted reproduction with severely impaired oocyte and embryo quality due to endometriosis may be predestined to fail. In light of the lack of thorough mapping of the underlying molecular mechanisms responsible for the pathophysiology of endometriosis-related infertility, our understanding is restricted. This fact instigates a domino effect revealing weaknesses and limitations regarding the diagnosis, and management of infertile women presenting with endometriosis. Where endometriosis-related infertility is concerned more information on the molecular footprint of the impacted oocyte and embryo could serve as a more individualized predictor and means of evaluation. In the present review of literature, we focus on presenting the molecular pathways involved in endometriosis which may activate mechanisms that impair oocyte’s fertilization capacity and as well as subsequent embryo’s developmental capacity under the influence of a chronic inflammation. Providing insight from the molecular front of the oocyte and embryo perspective, is of critical value in decision making. Such data is required to orientate future research, emphasize on promising theories and prioritize them accordingly. A comprehensive review of the literature was performed in PubMed/Medline, Embase, and Cochrane Central databases up to December 2020. The keywords employed and combined for the search strategy were: ‘’Endometriosis’’, ‘’Endometrioma’’, ‘’Ovarian Endometrioma’’, ‘’Endometriosis Related Infertility’’, ‘’Endometriosis Pathophysiology’’, ‘’Endometriosis Pathology’’, ‘’Embryo Quality’’, ‘’Embryo Developmental Arrest’’, ‘’Oocyte Quality’’, ‘’Oocyte Maturation’’, ‘’Laparoscopy’’, “In Vitro Fertilization”, “Assisted Reproduction”, “Assisted Reproduction Techniques”, “Medical Assisted Reproduction”. The search was limited to full-length manuscripts published in English in peer-reviewed journals. Original research articles describing studies performed in both humans and animal models as well as review papers concerning the impact of endometriosis on oocyte quality and embryo developmental capacity were sourced. Following literature review, authors identified three major aspects via which endometriosis compromises oocyte quality and embryo developmental potential namely, increased reactive oxygen species (ROS) and free radical production; immune system dysregulation; impaired extracellular matrix remodeling and meiotic spindle distribution. A critical analysis on these three aspects was performed highlighting the major pathophysiological mechanisms via which endometriosis affects oocyte quality and embryo developmental dynamic.A pivotal physiological process for embryos is the metabolism of molecular oxygen with a subsequent ROS production. ROS constitutes the side products of aerobic respiration and a natural part of cellular metabolism. Gametes, embryos, and their surroundings could constitute potential sources of ROS emissions. The categorization amongst endogenous and exogenous factors responsible for ROS generation allows for better understanding of the physiological processes involved in this event. Endogenous sources include numerous metabolic pathways and enzymatic activation on a cellular level, where the substantial contribution of several oxidases namely OXPHOS, xanthine oxidase and NADPH located in oocytes and embryos should be highlighted. Exogenous sources inducing ROS production include the oxygen concentration surrounding the developing embryo, metallic cations, visible light, and amine oxidase, as well as the ROS generated by spermatozoa which exert an equally detrimental effect on embryos . These nThe correlation between endometriosis and ROS has been thoroughly investigated in literature . The incS-transferase’s (GST) concentration and functionality are compromised, highlighting that their total antioxidant capacity is mitigated [Another interesting aspect worth reporting on regarding the theory of the retrograde menstruation into the peritoneal cavity is that the presence of numerous lysed erythrocytes of the refluxed menstrual blood results in elevated iron levels which are a source of free radicals production in vivo ,19. Due itigated ,22.The excessive production of ROS, also affects certain molecular components in the cells, namely adenosine triphosphate (ATP) synthesis or intracellular calcium ions’ concentration. This in turn prompts a series of events interfering with numerous cellular functions . InitialAs demonstrated, ROS exert a detrimental impact in several aspects of reproductive physiology namely oocyte maturation, ovarian steroidogenesis, ovulation process, implantation capacity, and blastocyst formation. The cytotoxic effects of ROS include peroxidation of membrane phospholipids, leading to increased permeability of the cell membrane, impaired cell membrane integrity, enzyme activation and dysfunction along with severe deterioration in DNA structure, and subsequently cell death ,28. Rega202 [Endometriosis is accompanied by elevated levels of ROS. Therefore, several considerations are raised as to the extent that these byproducts of metabolism complicate physiological processes leading to subfertility or even to infertility. Interestingly, it has been suggested that ROS effect on bovine’s embryo’s implantation dynamic depends on the developmental stage during which the embryos exposed to ROS. Zygotes and blastocysts are considered to be particularly sensitive and not resistant to the toxic effects of exogenous H202 . In vivo202 . Based o202  which is202 , therefo202 . Further202 , while c202 . OverallThe complexity of the immune system allows for its mechanisms to maintain homeostasis and restore balance in physiological processes when disrupted. In order for endometriosis to manifest, it has been documented that endometrial cells emerge in ectopic areas, in places where the immune system lacks the ability to detect and eliminate them, mistakenly allowing them to implant and grow . In a nuPeritoneal fluid constituents are cells participating in the immune response, controlling the environment gametes and embryos are exposed to . NormallInvestigation of the immune system sheds light on another perspective of endometriosis-related infertility. The severe established case of chronic inflammation in patients with endometriosis may affect fertility potential in numerous ways. The enhanced levels of several cytokines in the follicular fluid including interleukin-1β, IL-8, IL-10 and TNF-α may be linked to impaired ovarian response . ProstagIn an advanced stage, intensified apoptotic events are detected, compromising oocyte quality in patients presenting with endometriosis. Molecular mechanisms involving the immune response that may interfere with the ovulatory process promote dysregulated steroid ovarian secretion or poor luteal function . This dyIt becomes evident that this vicious cycle of inflammation releasing ROS and ROS contributing to the release of cytokines that in turn orchestrate inflammation should be further explored, and interpreted as the complex nature of these mechanisms and the interrelationships that bind them may hold the key in providing vital information on endometriosis related infertility and how to manage it. Several studies investigating the isolation of peritoneal fluid from patients with endometriosis and its implementation in culturing mouse embryos, have contributed contradicting data. On one hand it is indicated that the developmental capacity of these embryos may be impaired, while others report no adverse effects. This contradiction leaves room for variant interpretations and calls for further investigation. However, it appears that there is value in following on the hypothesis that the preimplantation embryo of patients with endometriosis is exposed to a toxic environment attributed to the intraperitoneal fluid. Considering the three pillars, namely that apoptosis in granulosa cells is a tool to assess the quality of oocytes, coupled by the fact that endometriosis patients present with the highest prevalence of apoptotic granulosa cells compared to fertile patients , and finAmongst the multiple pathways explored to define the culprits of endometriosis-related infertility, alterations in meiotic spindle that promote increased rates of aneuploidy have been proposed. Nuclear and cytoplasmic impairment, namely cytoplasmic fragmentation and uneven cleavage have been described as findings indicative of endometriosis. What is more, nuclear and cytoplasmic maturation are essential for a successful fertilization. Any disturbances regarding these procedures could lead to morphologic and genetic abnormalities. Poor quality oocytes incurring such anomalies are accompanied by reduced fertilization and implantation rates . In turnThe spindle apparatus is a fundamental component for securing correct segregation of the genetic material performed during meiotic divisions, while it maintains chromosomal organization. Spindle’s integrity is also considered as a potential marker for oocyte quality and dynamic . SpindleChromosomal organization, along with the formation of the second polar body depend on the meiotic spindle . A meiotMatrix metalloproteinases (ΜMPs) are a family of proteins associated with structural cellular events, namely the degradation of extracellular matrix (ECM) and components of basement membrane . The extThe puzzling issue of connecting the dots between endometriosis and infertility extents into the perplexing contribution of cellular kinetics. Microtubule and chromosomal changes have been observed in patients with endometriosis, adding another level of complexity to the mechanisms entailed in the infertility manifested. Available evidence is sourced from bovine and mouse oocytes suggesting that chromosomal and spindle misalignments could occur in cases of endometriosis, however as aptly commented by Mate, the extrapolation to the human physiology requires more concrete data. Less recent studies demonstrating increased aneuploidy rates present with certain limitations that pose a great challenge when aiming to draw safe conclusions. On the other hand, recent studies proposing that there is no association between aneuploidy and endometriosis present with more robust data . It shouthe causal relationship between endometriosis and infertility has not been clearly established” [As the Practice Committee of ASRM aptly commented in 2012, “blished” . The inaOverall, literature findings suggest that one of the primary causative factors for infertility in endometriosis is the limited number of matured oocytes , accompaTo further complicate the underlying mechanisms participating in the onset of endometriosis-related infertility, epigenetic changes may play a significant role. In surgically induced endometriosis in rat animal models with subsequent compromised oocyte and embryo quality and development, an intriguing conclusion was drawn that further expands our current knowledge on endometriosis. It was indicated that oocytes and embryos originating from the first generation of the rats which did not undergo any surgical intervention exhibited anomalies in oocytes and preimplantation embryo development similarly to their mother with induced endometriosis. What is more, it was reported that the first generation presented with reduced fecundity. This constitutes the first report in literature showcasing that maternal exposure to endometriosis exerts a negative impact on the oocyte and embryo quality and impacts developmental capacity in subsequent generations. Therefore, the worrisome argument on the permanent epigenetic changes caused by endometriosis in subsequent generations appears to be valid and merits further investigation in humans . Several meta-analyses support the notion that reduction in fertilization and implantation rates are expected in women with endometriosis , and a mTo elaborate on the limitations observed in current literature, data and evidence on the mechanisms impairing oocyte and embryo quality principally originate from animal studies. This constitutes a considerable limitation in investigating endometriosis. Researchers highlight the bioethical dilemmas raised by manipulating human genetic material and note the ethical restrictions in manipulating human embryos . Thus, fIn light of the lack of concrete data optimal management of endometriosis still raises heated debate. Investigating strictly one parameter in a multifaceted pathology seems to serve as a fundamental and inevitable limitation in published studies. The role of the endometrium along with the molecular pathways involved in patients with endometriosis is a promising field of study. Weighing the role of either the endometrium, or the quality of oocytes and embryos individually when they all are equally deteriorated in these patients may prove to lead to futile conclusions. In theory, what is required-yet not feasible-is an all-inclusive approach taking into account all aspects in this complicated issue. Nonetheless, proper research methodology allows for examining one parameter at a time and this in itself is the major conundrum here, as it is impossible to study in an isolated methodologically sound manner one parameter. Following the chain of intertwined events from diagnosis to treatment, it is the lack of robust and minimally invasive tools in detecting endometriosis, which fails to enable a timely and precise diagnosis which could in turn set the tone for an optimal treatment strategy. Following diagnosis, clinicians face a dilemma when managing a case of endometriosis-related infertility, since the optimal approach is yet to be defined. The available strategies include either subjecting the patient to an IVF protocol or proceeding with attempting to surgically treat endometriosis. Following surgical intervention to restore pelvic anatomical structures and remove endometriotic lesions, patients are invited to either initiate assisted reproduction treatment or conceive naturally when there is no other underlying pathological etiology detected. As aptly indicated by Taylor, the micro metastasis and all systemic effects may not be eradicated by simply removing signs of the disease . SurgicaInterestingly, there are no published studies reporting on the efficiency of different management strategies on improving oocyte and embryo quality in patients presenting with endometriosis-related infertility. Only indirect conclusions can be drawn with regard to the impact of different treatment strategies on oocyte and embryo quality by studying the IVF outcomes in patients presenting with endometriosis-related infertility. Discrepancies are observed between the practices all over the word with regard to the most efficient management protocols that patients should be subjected to in order to improve IVF outcomes in the context of better managing endometriosis related infertility. According to the European Society of Human Reproduction and Embryology (ESHRE) guidelines, which depict evidence-based clinical practice in Europe, surgical removal of endometriotic lesions via laparoscopy could enhance IVF outcomes in patients presenting with minimal endometriosis . With reThe aforementioned indicate that the adopting of a specific line of approach for all patients as a panacea or what is described as “horizontal treatment application” may not be favored. As mentioned, a wide spectrum of parameters reflect the rich variation in pathophysiology, along with the heterogeneity manifested in the phenotypes of endometriosis-related infertility . As the Endometriosis has been in the spotlight of research for many decades; however, many of the fundamental questions raised are far from being resolved. Despite its high prevalence, researchers and clinicians are conflicted on optimal treatment and management for both endometriosis and endometriosis-related infertility. This study showcases the considerable gap in translating the results provided by the ongoing research on endometriosis-related infertility. The scientific community is invited to take a step back to basic research aiming to address the principles of the molecular events leading up to manifestation of endometriosis. The mechanisms discussed herein focusing on impairment of oocyte and embryo competence should be further researched. Certain molecular pathways affecting oocytes and embryos have been introduced and conceptualized as causative factors for endometriosis-related infertility. For instance, the low mitochondrial content accompanied by high prevalence of mitochondrial abnormalities that was reported in patients with endometriosis is an interesting observation that calls for further interpretation . This isDetangling current knowledge on the molecular mechanisms responsible for manifestation of endometriosis and impairment of fertility is imperative. Endometriosis is a complex systemic gynecological disorder and its true extent beyond the reproductive system should be considered. Τo add to that, we need to readdress and investigate treatment options while aiming to tackle the core of endometriosis rather than targeting symptomatology. For that to be pursued, molecular evidence and data on the onset of the disease is required. The option of addressing endometriosis related infertility by embarking on an IVF cycle, may be perceived as futile when considering the intense physiological events leading to deteriorated oocyte and embryo quality. To resolve this conundrum, it becomes clear that research should focus on an in-depth analysis on the molecular backbone of how endometriosis compromises oocyte and embryo competence. Taking into account the embryologist’s perspective, an endometriosis patient does not always present with a distinctive pattern of impaired quality of oocytes and embryos. Especially as we principally rely on morphological data to evaluate an oocyte’s and embryo’s quality, competence and implantation potential. This emphasizes the need for discovering biomarkers capable of profiling endometriosis patients, and the requirement to detect the underlying molecular mechanism, and assess its effect on oocyte and embryo quality. This review highlights that oxidative stress as well as the immune system dysregulation constitute the two major pathophysiological mechanisms affecting oocyte and embryo competence in patients presenting with endometriosis. Interestingly, published data suggest that their detrimental effect does not always correlate with severity of endometriosis. Considering the aforementioned, and in the era of precision and personalized medicine, it appears that future studies should be focused on discovering sensitive-novel tools reporting on both oxidative stress status as well as on the immune dysregulation system status. Additionally, these biomarkers may prove an essential tool for identifying patients who may benefit from receiving adjuvant treatments prior to addressing endometriosis related infertility, including antioxidant treatment and/or suggested pharmaceutical agents for controlling immune system dysregulation ,105. To conclude, effectively profiling endometriosis patients may potentially be the missing link in the equation of managing these perplexing cases. The future in the era of precision medicine should encompass individualized treatment plans and avoidance of futile IVF attempts.


Since then, an overwhelming number of studies in human cohorts and animal models have provided support for that hypothesis. It is becoming clear, however, that exposure in the parent generation can lead to multigenerational and transgenerational inheritance of breast cancer. Importantly, recent data from our lab and others show that pre-conception paternal diets reprogram the male germline and modulate breast cancer development in offspring. This review explores the emerging evidence for transgenerational epigenetic inheritance of breast cancer focusing on studies associated with ancestral nutritional factors or related markers such as birth weight. We also explore paternal factors and the epigenetic mechanisms of inheritance through the male germline while also reviewing the existing literature on maternal exposures in pregnancy and its effects on subsequent generations. Finally, we discuss the importance of this mode of inheritance in the context of breast cancer prevention, the challenges, and outstanding research questions in the field.The past decade has made evident that in addition to passing their genetic material at conception, parents also transmit a molecular memory of past environmental experiences, including nutritional status, to their progeny through epigenetic mechanisms. In the 1990s, it was proposed that breast cancer originates  The genome is relatively stable throughout an organism's life span; however, the epigenome is malleable to ensure short-term adaptation to the environment . BecauseBRCA1 and BRCA2 explain only a small proportion of breast cancers. Despite intense search, no major genetic mutations have emerged  which will help it to survive after birth  induces epigenetic changes that can increase the risk of chronic diseases such as cancer. However, the disease phenotype might only manifest itself when an individual is exposed to certain environmental signals after birth  during pregnancy increased estradiol levels and subsequent risk of mammary cancer in the female offspring . Anotherin utero exposures can lead to breast cancer reduction in animal models. For instance, prenatal exposure to a lard-based high-fat diet during pregnancy or pregnancy and lactation significantly reduced the offspring susceptibility to mammary cancer  is likely due to fetal programming of the mammary tissue as many studies show morphological and molecular changes in that tissue induced by a number of prenatal exposures . Howeverneration , which cneration , 45]. Seneration . Whetherneration –49.in utero exposure to a N-6 PUFA diet. We also showed that maternal exposure to an ethinyl-estradiol (EE2)-supplemented diet  led to an increase in breast cancer predisposition not only in daughters (F1) and granddaughters (F2) but also in great-granddaughters (F3)  . DNA meters (F3) , 53. Durers (F3) , 54. To ers (F3) . The traers (F3) ]. A receers (F3) .Because of the intimate relationship between mother and the developing fetus during pregnancy, the evidence for developmental programming and epigenetic inheritance of disease comes overwhelmingly from studies investigating maternal environmental exposure during gestation and outcomes in the offspring and subsequent generations as described earlier in this review. However, a variety of pre-conception paternal experiences ranging from nutritional status, alcohol consumption, and stress to exposure to pollutants have been shown to alter the male germline epigenome and impact their children's and, sometimes, grandchildren's health [Using a carcinogen-induced mouse model of breast cancer, we showed that both paternal obesity and malnutrition programs development of breast cancer in offspring , 7, 40. While population studies investigating paternally induced programming of breast cancer are still scarce, a few reports can be found in the literature. For instance, both paternal age and ethnicity have been associated to the risk of breast cancer in daughters , 57. UsiThe role of environmentally induced epigenetic reprogramming of the germline has been actively investigated in recent years , 9, 68. The proposed mechanism by which paternal environmental exposures are linked to disease phenotypes in offspring is sperm epigenetic reprogramming . While DMore recent studies show that small non-coding RNAs, which are abundant in sperm , 76, plaThe sperm non-coding RNA load and the abundance of specific RNA subtypes changes as the sperm travels through the male reproductive tract . It is wA variety of nutritional and environmental exposures can program the sperm epigenome, particularly sperm non-coding RNAs , 59, 70.While it is increasingly evident that environmental and nutritional insults modulate the sperm epigenome in animal models and humans , 84, howIn eutherian mammals, such as human and rodents, the placenta connects the fetus to the mother and provides the nutrient and gas exchanges necessary for the proper fetal development . The plaPpara and Casp12 while female placentas did not show this difference in gene expression. However, paternal obesity significantly increased global DNA methylation levels in female placentas, which could explain differences in phenotypic changes faced by male and female offspring. Thus, the placenta effects could hold a potential answer into how poor paternal nutrition can modulate breast cancer risk and other diseases in offspring. We are currently exploring whether sperm non-coding RNAs play a role in placenta development and ultimately modulate disease phenotypes such as breast cancer in offspring.Paternal effects on the placenta are potentially important as its development is driven mostly by the paternal genome and epigenome , 89. In It has long been known that maternal experiences in pregnancy can modulate offspring's breast cancer risk in human populations and animal models. This is not surprising given that maternal environmental insults could directly affect the developing fetus' mammary gland. However, the past decade showed that history of exposure in the parental generation could lead to multigenerational and transgenerational predisposition for breast cancer. The evidence stems primarily from animal models and replication of those findings in human cohorts is urgently needed to determine whether transgenerational inheritance of breast cancer also occurs in humans.In recent years, animal models have also provided important experimental support for epigenetic inheritance and showed that pre-conception paternal factors can modulate breast cancer development in daughters through the germline. In humans, epidemiological studies have linked food supply in the grandparental generation to health outcomes in the grandchildren  and pateWhile a growing number of studies have shown that ancestral dietary and environmental factors can lead to intergenerational and transgenerational epigenetic predisposition to breast cancer, there is still a lot that we need to learn for how this happens mechanistically. Questions that still require answers in this emerging field include: How does paternal germline epigenetic programming alter embryonic mammary tissue development? How is epigenetically induced information transmitted between generations? Do the same mechanisms uncovered in animal models apply to humans? Can germline alterations be reversed in order to manipulate disease phenotypes in offspring? In addition to local mammary tissue alterations, do systemic metabolic changes in offspring play a role in environmentally induced breast cancer risk? These and other questions have important implications and need to be addressed with a multidisciplinary effort that will require knowledge from fields such as developmental and mammary gland biology, cancer biology, and epidemiology.It is also important to note that we have observed a striking overlap between phenotypes induced by paternal and maternal dietary exposures on both mammary gland morphology and breast cancer development, suggesting that a common mechanism may exist. We have also observed consistent systemic metabolic changes and mammary tissue-specific alterations in energy-sensing pathways in offspring induced by paternal diet paradigms. The consequences of those alterations for mammary cancer development also need to be further explored.The research summarized in this review challenges the current view of how breast cancer predisposition is transmitted between generations. If confirmed in humans, this research field could lead to a better understanding of non-genetic transmission of breast and other cancers and what drives tumor growth in a subset of women and how we can stop it. It could also lead to the development of population-based preventive strategies to reduce breast cancer incidence, including epigenetic markers to identify women at risk. This will be a daunting task though, as population studies to identify epigenetic markers of ancestral exposure will likely take decades, given the temporal distance between the parental exposure and breast cancer onset in daughters. Another challenge to overcome and confirm findings from animal models in humans is the difficulty in ascertaining exposures in parents retrospectively, although data from our lab and others , 61, 72 Another possible strategy to reduce epigenetically induced predisposition to breast and other cancers in offspring would require interventions in the pre-conception window. Preliminary data from our lab and others suggest that environmentally induced effects on the male germline are transitory and can be reversed if the environmental insult is removed , 84. ImpSA conceived and wrote the review. RC oversaw the literature research, and wrote and edited the manuscript. EC, MS, and JB contributed to the literature research, helped to write, and edit the review. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Abnormalities and irregularities in walking (gait) are predictors and indicators of both disease and injury. Gait has traditionally been monitored and analyzed in clinical settings using complex video (camera-based) systems, pressure mats, or a combination thereof. Wearable gait sensors offer the opportunity to collect data in natural settings and to complement data collected in clinical settings, thereby offering the potential to improve quality of care and diagnosis for those whose gait varies from healthy patterns of movement. This paper presents a gait monitoring system designed to be worn on the inner knee or upper thigh. It consists of low-power Hall-effect sensors positioned on one leg and a compact magnet positioned on the opposite leg. Wireless data collected from the sensor system were used to analyze stride width, stride width variability, cadence, and cadence variability for four different individuals engaged in normal gait, two types of abnormal gait, and two types of irregular gait. Using leg gap variability as a proxy for stride width variability, 81% of abnormal or irregular strides were accurately identified as different from normal stride. Cadence was surprisingly 100% accurate in identifying strides which strayed from normal, but variability in cadence provided no useful information. This highly sensitive, non-contact Hall-effect sensing method for gait monitoring offers the possibility for detecting visually imperceptible gait variability in natural settings. These nuanced changes in gait are valuable for predicting early stages of disease and also for indicating progress in recovering from injury. How individuals walk  can vary as a result of walking surface, individual body type, injury, disease, fatigue, and a variety of other factors. Abnormalities or irregularities in gait can both predict and indicate health problems. For instance, disturbances in gait have been found to be early predictors of fall risk in the elderly and of physical disability ,2. FurthA wide range of parameters are used to characterize gait, but stride width and stride width variability seem especially important for the diagnosis and monitoring of injury and disease. A stride is simply a sequence of two steps. Stride width is the distance between two imaginary parallel lines, passing through the heel of the foot  during aBecause the normalness of gait is affected by a wide range of factors, not all of which involve disease or injury, a vast majority of gait irregularity studies have been restricted to clinical settings. In clinical settings, extraneous factors can be controlled in order to focus on detecting and assessing gait disturbances that stem from physical injury, psychological origins, or central nervous system disease. In the clinical setting, gait analysis is typically conducted with camera monitoring systems that visually capture gait and are often combined with force platforms which capture ground reaction forces on the feet as an individual walks. These multi-sensor, three-dimensional systems capture an immense amount of data that are typically evaluated off-site by a qualified physician . ClinicaNevertheless, wearable sensor systems support a more practical health care paradigm that expands and equalizes access to quality health care across different populations. Systems that are capable of delivering health care services at any time and location have significant global implications for supporting personalized health care, disease prevention, point-of-care diagnosis, and treatment of chronic disease conditions ,17. WearExisting wearables have demonstrated their value to health care through their use as a safe, cost-effective health care device in tracking physical activity . There aGait monitoring technologies in clinical settings are typically not worn on the body and are dominated by camera-based systems and force-sensitive platforms. Cameras capture human movement and then utilize video and image processing to extract gait parameters . These sA number of wearable sensors for gait monitoring have been developed over the past two decades. A representative subset of these wearables is summarized in A vast majority of these wearables make use of a gyroscope (for measuring angular velocity and orientation), accelerometer, or inertial measurement unit  and are worn on the foot (shoe). For example, the GaitShoe uses an extensive suite of sensors including three accelerometers, three gyroscopes, four force sensors, and electric field sensors integrated into a sandal-like shoe that enables gait data to be collected unobtrusively over long periods of time and with minimal interference to normal gait . Data reAccelerometers and gyroscopes are not the only sensors integrated into these wearable sensors. For example, researchers have developed a wearable gait tracking device for gait characteristics by implementing a set of force-sensitive resistors (FSR) to detect foot pressure at various locations on the underside of the foot and use that information to categorize six different stride positions during human gait known as heel strike, foot flat, heel off, terminal stance, and toe off . UltrasoWhile the research and development space for wearable gait monitoring sensors may seem crowded, human gait is complex and multi-faceted, which leaves ample opportunity for other wearables to address gaps that remain in the literature. This study seeks to fill the “Fitbit” gap for wearable gait monitors by targeting an unobtrusive, low-power, and durable wearable based on a Hall-effect sensor that can act not only as a monitor of healthy gait but also as an early indicator of gait disturbances, irregularities, or abnormalities. To reach these goals, the wearable presented herein focuses specifically on measuring cadence and stride width variability which can serve as an important monitor of Parkinson’s disease progression  and recoHall-effect sensors have been demonstrated in past research efforts for wearable systems. For example, four magnets embedded in silicon rubber were mounted in shoes above four Hall-effect sensors to measure the loading on the feet in normal and shear directions, which is often critical for properly treating diabetic foot ulcers . Hall-efGiven these advantages of the Hall-effect approach, this study seeks to explore the suitability of the Hall-effect sensor for capturing cadence and leg gap as a proxy for stride width and stride width variability. The feasibility of using this system for detecting gait disturbances is evaluated using a prototype wearable sensor system that is mounted on the upper leg  just above the knee. Upper leg wear is less vulnerable to abuse and premature wear and tear compared to sensors that are mounted on the bottom or side of shoes or the feet due to fewer mechanical stresses experienced along the upper leg. This combined with the fact that Hall-effect sensors have no moving parts offers the possibility for a much longer lifetime in a corresponding wearable than classical alternatives that use accelerometers or gyros.A block diagram of the wearable sensor system used to monitor gait at the knee and upper leg is shown in The sensor was mounted on the outside of a lightweight knee brace  such thaRQ1: Does leg gap width captured using the wearable system make a sufficient proxy for stride width in terms of differentiating abnormal and irregular strides from normal strides?RQ2: Can the wearable system capture cadence with sufficient accuracy to differentiate abnormal and irregular strides from normal strides?The goal of testing and data collection at this phase in the research was proof of concept, leading to two research questions:To evaluate these two research questions, the gait monitoring system prototype was tested on four individuals walking with five different types of gait. Each individual walked six different segments consisting of approximately 10 m each on smooth concrete in an indoor environment, for a total of 60 m walked for each of the five types of gait per individual . AbnormaVdd/2  at zero magnetic field where Vdd is the power supply (5 V) supplied to the sensor. The raw digital data were preprocessed to generate an analog voltage corresponding to the sensor output:Among the five groups of strides and four subjects evaluated, the number of strides recorded for each segment varied with the type of gait, individual, speed of gait (cadence), and stride length. Raw data collected over the wireless Xbee connection were in the form of 10 bit digital signals representing sensor signals between 0 and 5 V. The ratiometric nature of the Hall-effect sensor forced the sensor output to x from the center of the magnet along an axis perpendicular to the flat disk surface  was estimated using known properties of the magnet and of the Hall-effect sensor. The magnetic field is related to the distance  surface  as folloxB is known, the output of the Hall-effect sensor can be estimated as:S is the sensitivity of the Hall-effect sensor. The distance x can be calculated numerically based on the sensor output using these relationships.Once the magnetic field Finally, the leg gap width  is then estimated as:In order to eliminate the impact of variations in swing between the two legs, leg gap width  was calculated at the peak sensor output associated with each step involving only the swing of the left leg . In order to determine these mid-stance peaks, noise in the raw sensor data was first reduced by identifying local maxima in the sensor output that were at least 0.8 s apart. This minimum stride time corresponds to a maximum detectable cadence of 150 steps/min, well above the 115–120 steps/min at which a typical adult walks. Once these local maxima were identified, the sensor output was filtered by replacing all data that did not correspond to one of these local maxima with the value of the sensor baseline, essentially zeroing the non-maxima values out. Then, the local maxima were filtered by their prominence in order to eliminate spurious, low-signal maxima that did not represent mid-stance peaks. While this approach eliminated some valid mid-stance peaks, it ensured that very few false peaks remained in the data. The timestamps of the remaining peaks in the preprocessed data were then retained to calculate cadence and the raw sensor output voltage corresponding to the mid-stance peak locations retained to calculate leg gap width using Equations (1)–(4).tn is the time at which a mid-stance peak occurs for stride n while tn−1 is the time at which a mid-stance peak occurs for the stride immediately before stride n. Since a stride consists of two steps, the cadence was then calculated as twice the strides per minute:Strides per minute were calculated simply as the reciprocal of adjacent mid-stance peaks (in sec) and scaled to minutes:Once calculated and checked for normality, cadence and stride width were used to evaluate differences among stride types among all four individuals tested. The goal of data analysis was to understand whether the data collected by the wearable sensor system was capable of distinguishing abnormal gait  and irregular gait  from normal gait via differences in cadence, differences in stride width, differences in stride width variability, differences in cadence variability, or some combination thereof.Appropriate statistical tests were then used to assess whether the null hypothesis that an abnormal or irregular gait for a given subject was the same as a normal gait could be rejected. For cadence, a Kruskal–Wallis test was used to assess whether cadence associated with each abnormal or irregular stride was significantly different from that associated with normal stride. The Kruskal–Wallis test is a non-parametric test that compares the medians rather than the means of different sample populations and does not rely on assumptions of normality for accuracy . This saThe four individuals from whom data were collected were all students or instructors in an independent study course focused on gait monitoring. As a result, the authors’ home institution determined that this study was not human subjects research and did not require institutional review board (IRB) approval.The leg-based gait monitoring system was used to measure distance between the legs slightly above the knees (leg gap) and cadence as well as variability in these two gait parameters. The wearable system was tested on four different individuals and five different types of gait: normal, abnormal , and irregular .The leg gap was measured in cm and calculated from the digital output obtained from the Arduino Uno during mid-stance . It servVariability in leg gap was measured using four variability parameters: maximum (max), minimum (min), interquartile range (IQR), and standard deviation (SD) of leg gap values captured in mid-stance . SkewnesNine of 20 groups failed the Lilliefors test. Therefore, subsequent statistical tests for the leg gap did not assume a normal distribution. Out of 20 groups of data, eight (40%) were highly skewed with absolute values greater than 1. Seven (35%) were moderately skewed with absolute values between 0.5 and 1, and the remaining five (25%) distributions were approximately symmetric with values ranging between −0.5 and 0.5 . Only onBecause almost half of the leg gap distributions failed the Lilliefors test for normality, a non-parametric Kruskal–Wallis test was used to compare the medians of leg width associated with abnormal strides  and irregular strides  to normal strides for each individual. The Kruskal–Wallis test does not require that data be normally distributed in order to evaluate the null hypothesis that two or more sets of data come from the same parent population  and is eTo assess the role of outliers in detecting differences between each abnormal  or irregular  stride and the normal stride for each individual, these tests were repeated after outliers were removed. Outliers were removed using the standard statistical technique of eliminating all samples in each population which were less than 1.5-fold the IQR less than the first quartile or 1.5-fold the IQR greater than the third quartile . After rTo evaluate leg gap variability, Levene’s test was used to evaluate the null hypothesis that two groups  have equal variances. While the performance of Levene’s test is not as good as the Bartlett test which is also used to compare variance, Levene’s test is less sensitive to departures from normality and therefore is better matched to the leg gap data collected in this study . ResultsWhen outliers were removed from the data using the 1.5 IQR rule, the accuracy of predicting abnormal or irregular strides based on variability in leg gap increased from 69% to 81% (13 of 16). These results are summarized in A second gait parameter, cadence (steps per minute), was also evaluated using similar tests to those used to evaluate leg gap. Descriptive statistics for the cadence associated with five types of stride among four subjects are summarized in Five of 20 sample distributions failed the Lilliefors test and subsequent statistical tests for cadence and cadence variability did not assume a normal distribution. Out of 20 groups of data , only 2 (10%) were highly skewed with an absolute value greater than 1. Five (25%) were moderately skewed with absolute values between 0.5 and 1, and the remaining 13 (65%) distributions were approximately symmetric with skewness values ranging between −0.5 and 0.5. Most data groups (12 of 20) were negatively skewed. Only five of the distributions indicated kurtosis (>4) that was much more peaked than a normal distribution.Results of non-parametric Kruskal–Wallis tests used to compare the cadence of abnormal  or irregular  strides to normal strides are summarized in Unlike leg gap variability, variability in cadence was not particularly useful in differentiating strides . Levene’The goal of this study was to evaluate the feasibility of using low-power, compact, high-resolution, analog (linear) Hall-effect sensors to differentiate normal gait from that which is abnormal in speed  or irregular in swing . To this end, two gait parameters (cadence and stride width) were evaluated using a self-contained, single-sensor system to answer two research questions.Does leg gap width captured using the wearable system make a sufficient proxy for stride width in terms of differentiating abnormal and irregular strides from normal?This question was evaluated based on the ability of the wearable sensor system to differentiate normal from abnormal or irregular strides. Leg gap (above the knee) is smaller than stride width and subject to smaller variations than stride width. However, it was anticipated that the high precision of the Hall-effect sensors (0.007 cm) in measuring leg gap width would compensate for the reduction in leg gap width and leg gap variability compared to corresponding stride width parameters (measured at the feet). When considering leg gap width alone, however, abnormal gait was significantly different from normal gait in only 69% of cases  but whenCan the wearable system capture cadence with sufficient accuracy to differentiate abnormal and irregular strides from normal strides?Previous research has indicated that cadence provides a necessary context for evaluating stride width variability. What constitutes extreme or concerning variability can change with cadence or gait speed of the individual . Thus, aAs with leg gap width, the precision of the Hall-effect wearable allowed for detecting small changes in both mean cadence times and nuances in the data distribution for different stride types. This raises the possibility that with high-resolution systems, cadence might also serve to support characterization of gait and detection of disturbances from normal gait. Given the evidence of how stable cadence is over an individual’s lifetime , howeverThe feasibility of the leg-mounted Hall-effect wearable has been demonstrated for differentiating two types of abnormal gait  and two types of irregular gait  from normal gait. Such functionality is similar to other efforts  which haPros: The Hall-effect wearable offers high precision (on the order of tenths of millimeters) in detecting leg gap width compared to existing systems which offer precisions on the order of cm in detecting stride width [de width ,38. Whilde width  which ofCons: Compared to the wealth of spatiotemporal information offered by accelerometers, gyros, and IMUs, the Hall-effect approach offers limited data. Its range is insufficient for monitoring stride length and other gait parameters that extend beyond 5 cm and temporal patterns of information are restricted to at or near mid-stance peaks. The leg wearable is also only suited to monitoring gait within an individual’s walking patterns and not across individuals. Comparing data between individuals is subject to too much variation in mounting location and other compliance related issues. These issues are minimized when sensors are integrated into the more rigid footprint provided by the shoe. However, one can easily imagine a highly inobtrusive Hall-effect sensor or sensors integrated into clothing which provide a low-overhead indicator of generalized gait disturbance and flag the potential need to monitor gait more comprehensively with the assistance of clinical or wearable systems that are designed to do so.The work presented here has focused on studying the feasibility of using Hall-effect sensors to identify gait disturbances. Statistical analyses suggest that leg gap, variability in leg gap, and cadence offer significant information for differentiating abnormal and irregular gait from normal gait. Future work should capitalize on the results of this work to explore efficient algorithms for recognizing gait disturbances based on cadence and leg gap data provided by these wearables. Time series analyses of the entire stride (rather than only the mid-stance peak) should also be considered in future efforts to explore the full functionality of the Hall-effect wearable in supporting everyday gait monitoring. Concurrently, we expect that future work will seek to miniaturize the wearable system such that it fully takes advantage of the small size and lower power sleep modes of the A139X series of Hall-effect sensors. Finally, the suitability of pairing a Hall-effect sensor wearable with a more comprehensive gait monitoring wearable will also be a topic of future research in this area.The feasibility of using linear analog Hall-effect sensors for monitoring spatiotemporal gait parameters has been evaluated. Results show that leg gap and leg gap variability (as a proxy for stride width) and cadence data collected from these sensors can successfully detect disturbances in gait within individuals. These findings provide 69% accuracy in identifying gait disturbance when using leg gap alone, 81% accuracy when using leg gap variability alone, and 94% accuracy when using both in combination. For the controlled experiments used in this feasibility study, the temporal parameter of cadence offered 100% accuracy in detecting abnormal or irregular strides. Based on these initial findings, we can conclude that the Hall-effect sensor offers a promising low-cost, low-power alternative to classical accelerometer, gyro, or IMU-based wearables for flagging gait disturbance. These Hall-effect systems may also act as a supplement to classical systems for continuous monitoring of gait for the purpose of triggering more comprehensive monitoring by more complex wearables or by traditional gait analysis systems used in clinical settings. Future work will investigate the design and fabrication of more compact, integrated Hall-effect wearables, appropriate algorithms for recognizing and flagging abnormal and irregular gait, and potential integration with other types of sensors that offer information about other gait parameters including step length, foot orientation, and gait speed. A more compact, next generation sensor system should also be tested on a broader range of individuals to gauge generalizability of the usefulness of this device. Further, the capacity of the sensor system can also be expanded in future efforts to include multiple Hall-effect sensors mounted at different locations along the leg.


Multivalvular destruction may be a clinical manifestation of infective endocarditis (IE), which is a devastating infection of the heart either alone or superimposed with congenital subaortic membrane as in this case report. Here, we report a case of multivavular destruction with severe vegetation presented as a manifestation of infective endocarditis (IE) in a neglected case of 18-year-old male with previous rheumatic heart disease. Transesophageal echocardiography is an important imaging modality for diagnosis of superimposed aortic and heart lesions. Early necessary investigation and correct diagnosis is mandatory to prevent bad complications. Infective endocarditis (IE) is an infection of a heart valve that can affect a native or prosthetic valve. It is a devastating disease with a 30% mortality rate at one year.The case involves an 18-year-old male with known rheumatic heart disease (RHD) since 11 years of age who was on irregular treatment. The patient presented with shortness of breath (SOB) for two weeks. The patient was diagnosed, admitted, and treated as decompensated heart failure and improved. After one month, the patient returned with fever and SOB. On examination, he was conscious, oriented, and cooperative, but he was ill, pale, and toxic with third degree finger clubbing. Auscultation revealed decreased air entry in the chest bilateral basally, palpable hyperdynamic apex beat of the heart shifted to the sixth intercostal with palpable systolic thrill with diastolic murmur. Chest radiograph (CXR) revealed an enlarged left atrium of the heart. Transthoracic and transesophageal echocardiography (TTE and TEE) showed a dilated left atrium  and dest(TEE) confirmed the above, showing detracted aortic valve leaflets  and deteThe left ventricle was normal in dimension with good contractility and 63% ejection fraction (EF) apart from mild concentric hypertrophy. The right heart appeared normal in dimension apart from severe pulmonary hypertension causing moderate secondary TR (III/IV). Abdominal ultrasound imaging (US) revealed a congested and enlarged liver, inferior vena cava (IVC), and spleen. Blood culture revealed staphylococcus aureus. This was a case of aggressive IE severely destructing the aortic and mitral valves with vegetation-like masses and an incidentally discovered sub aortic valve membrane.The patient was admitted to the cardiology department and treated with excessive antibiotics according to the guidelines of European society of cardiology for one month.Post-operative TTE images show the prosthetic aortic and mitral valves  with gooIE is uncommon in developed countries but more prevalent in developing countries, including countries in the Middle East. It usually presents as an ambiguous disease with a wide variety of clinical manifestations, making diagnosis difficult or resulting in a misleading or false diagnosis.10Our case confirmed that TEE is useful as an imaging modality to diagnose papillary muscle abnormalities that may be difficult to discover by TTE even by experienced cardiologists as reported by Cahill et al., and Costa et al.Infective endocarditis is a devastating infection of the heart. Medical imaging plays an essential role in detecting cardiac lesions. Trans esophageal echocardiography is a highly valuable imaging modality for diagnosis of superimposed aortic valve and heart lesions in general and it is necessary to avoid a likely fatal events.SAA Prepared the initial and final draft of article and critically reviewed and approved the final draft and is responsible for the accuracy of the work.NNA collected and organized data.MBG analyzed and interpreted data.AMO revised the manuscript.


The submarine volcano Axial Seamount has exhibited an inflation predictable eruption cycle, which allowed for the successful forecast of its 2015 eruption. However, the exact triggering mechanism of its eruptions remains ambiguous. The inflation predictable eruption pattern suggests a magma reservoir pressure threshold at which eruptions occur, and as such, an overpressure eruption triggering mechanism. However, recent models of volcano unrest suggest that eruptions are triggered when conditions of critical stress are achieved in the host rock surrounding a magma reservoir. We test hypotheses of eruption triggering using 3-dimensional finite element models which track stress evolution and mechanical failure in the host rock surrounding the Axial magma reservoir. In addition, we provide an assessment of model sensitivity to various temperature and non-temperature-dependent rheologies and external tectonic stresses. In this way, we assess the contribution of these conditions to volcanic deformation, crustal stress evolution, and eruption forecasts. We conclude that model rheology significantly impacts the predicted timing of through-going failure and eruption. Models consistently predict eruption at a reservoir pressure threshold of 12–14 MPa regardless of assumed model rheology, lending support to the interpretation that eruptions at Axial Seamount are triggered by reservoir overpressurization. Volcanic deformation, commonly attributed to pressurization of a magma reservoir at depth, is often cited as a clear indicator of volcanic unrest and is frequently used to assess eruption potential in this way6. While this approach has been used to successfully forecast the 2015 eruption at Axial Seamount7, countless examples of unforecast eruptions illustrate the complex nature of the inflation-eruption relationship9.The ability to forecast volcanic unrest and evaluate precursory signals to assess whether a volcano is trending towards an eruption is a paramount goal in volcanology. The traditional approach for forecasting has been that of “pattern recognition,” in which known pre-eruptive conditions are assumed to manifest prior to the occurrence of an eruptive event10 or McTigue11 have been commonly used to model surface deformation. Such approaches have been used to calculate the expected surface deformation overlying an expanding magma reservoir and have frequently been used to assess pre-eruptive reservoir pressure conditions and eruption potential. However, such analytical approaches neglect critical crustal conditions such as temperature-dependence and inelastic behavior. Low-pressure, high-temperature deformation experiments reveal that Young’s modulus in particular is highly temperature dependent at brittle-ductile transition temperatures of 600–750 °C12. Furthermore, thermomechanical models of volcano deformation have shown that Young’s modulus greatly affects predicted surface deformation and strain accumulation15, and a recent investigation showed that rheology strongly impacts failure potential16.Despite this, geodesy remains one of the most widely used methods for monitoring active volcanic systems and deformation is a common constraint for models of unrest and eruption prediction. For example, analytical solutions such as those of Mogi17. Furthermore, the ductile nature of rock surrounding a hot magma reservoir is likely to buffer the system from mechanical failure. Some numerical findings suggest that eruptions are triggered when conditions of critical stress, induced by external phenomena such as tectonic stresses or large earthquakes, occur in the host rock supporting a magma reservoir19.A critical application of these considerations manifest in our understanding of volcanic eruption triggers and our approaches to address these phenomena numerically. The traditional paradigm in volcanology is that eruptions are triggered when the pressure within a magma reservoir exceeds the confining strength of the host rock surrounding it. However, recent investigations have challenged this paradigm citing the apparent open nature of many caldera systems as evidenced by observed degassing and lack of volatiles, and their inability to build such pressuresAxial Seamount is a rare example of a volcano that has had an accurate eruption forecast based on ground deformation alone. Given the (apparently) well-behaved nature of Axial Seamount’s eruption cycle, it provides an excellent case study to investigate the inflation-eruption relationship from a mechanical perspective and to test hypotheses of eruption triggering. Here we perform a series of numerical experiments to address the role of crustal rheology in models of volcano unrest. Specifically, we hindcast previous eruptions of Axial Seamount in 2011 and 2015 to investigate the role of crustal rheology on predictions of surface deformation, stress distribution, and mechanical failure of the host rock leading to eruption. These sensitivity tests strongly reinforce that rheology plays a critical role and should be considered in modeling surface deformation and forecasting eruptions.20. In the 1990s Axial became a site for intense scientific study of volcanic and hydrothermal processes and several key time-series studies addressing surface deformation, seismicity, vent chemistry, temperature, and biology began at this time24. Since the first measurements began, seafloor deformation coincident with three eruptions was recorded in 1998, 2011, and 20157  at Axial Seamount29. We implement an ellipsoidal reservoir measuring 6 km length by 3 km width and 1 km thick to simulate this high melt region. The simulated reservoir is consistent with the location of the imaged body in relation to the summit caldera .We utilize this twenty-two-year record of deformation to constrain 3D finite element models which hindcast the 2011 and 2015 eruptions of Axial Seamount. In particular, we expand upon the approach of Cabaniss We perform a series of numerical experiments to investigate the effect of rheology and assumed model boundary conditions on model-predicted surface deformation, stress, and mechanical failure of the host rock supporting the Axial magma reservoir. We investigate models under four different rheologic conditions: (1) a non-temperature dependent elastic rheology, (2) a non-temperature dependent viscoelastic rheology, 3) a temperature-dependent viscoelastic rheology, and (4) a temperature-dependent viscoelastic rheology that incorporates hydrothermal circulation . However, the models which incorporate hydrothermal circulation erupt in advance of those which do not— and far earlier than the observed eruption dates. Given the isolated nature of high temperature venting at Axial Seamount, we postulate that simulated hydrothermal circulation under the isotropic conditions assumed in the model space might not adequately represent the natural system. Instead, localized circulation may concentrate cooling and elastic behavior to focused regions in the model space, rather than impacting the entire region. However, we also acknowledge that poorly constrained factors such as the reservoir geometry (melt volume and dimensions), degree of convection, and/or the thermal regime may affect these model predictions. Results from additional numerical experiments addressing the impact of reservoir geometry on model predictions are presented in the supplementary materials. For further discussion of the impact of elastic and viscoelastic properties on results of unrest models we refer the reader to Zhan et al.16 and Head et al.31, respectively.Vigorous hydrothermal circulation is observed at three localized high-temperature vent fields in the summit caldera of Axial SeamountThe results presented here show that model rheology plays an important role in predictions of surface deformation, stress distribution, and failure. The numerical investigations also provide insight into possible mechanisms for triggering eruptions at Axial Seamount. In particular, we consider potential eruption triggers of tectonic stresses, seismicity, and critical overpressurization.et al.18 illustrated that for large, long-lived silicic caldera systems local tectonic stresses can destabilize the crust and promote eruption with relatively low magmatic flux rates over short timescales. While this effect appears to be enhanced at smaller caldera systems, the investigation did not include systems smaller than 100 km3 such as the Axial Seamount. Given Axial’s geologic location at the intersection of a mid-ocean ridge and a hot spot, tectonic effects may have an influence on the eruption cycle. We simulate the tectonic stress induced by plate divergence at the Juan de Fuca Ridge by imposing a spreading rate of 60 mm/year, full rate, orthogonally to the ridge axis on the surface of the model  Cabled Array implemented a network of seafloor sensors for real time monitoring, including a network of ocean bottom seismometers46. However, no record of seismicity yet spans the duration of an entire eruption cycle (e.g. eruption to eruption) with a consistent monitoring network. The most complete record is provided by the OOI data recorded before, during, and after the 2015 eruption47.Since the late 1990s, hydrophone arrays and campaign style ocean bottom seismometer (OBS) surveys have provided almost continuous earthquake event detection at Axial Seamount47.Seismicity provides a metric for assessing model-reliability in that predicted Mohr-Coulomb failure is anticipated in regions of observed seismicity at Axial Seamount. Our models predict top-down propagation of Mohr-Coulomb failure, whereby failure coincident with surface inflation manifests first in the near-surface regions of the model space Fig. . As the 46. The average moment magnitude (MW) for observed earthquakes in the months preceding Axial’s 2015 eruption is 0.1, with the highest magnitude earthquakes (MW > 2.0) occurring during syn-eruption diking46. Given the magnitude of precursory seismicity, it is unlikely that the culminating eruption is triggered by a large earthquake as has been observed several times in terrestrial systems48. However, the relationship between inflation and seismicity at Axial Seamount suggests an interplay between the magmatic system and the stress state in the surrounding host rock. It is likely that inflation of the magma reservoir causes host rock stresses to build along pre-existing caldera-related faults, which generates seismicity. At some point, the cumulative stress release from seismicity should damage the host rock such that strain occurs more readily, and surface inflation occurs with less pressurization of the magma reservoir. As such, we would expect high rates of seismicity accompanying high levels of reservoir inflation to be a precursor to eruption3. As noted earlier our model predicted eruption dates consistently precede the observed eruption dates, forecasting eruption well in advance of the actual timing. We postulate that incorporating faults in the model space to simulate this effect might result in more accurate forecast dates. Future work should therefore address this hypothesis to investigate interdependence of magmatic and seismic processes at Axial Seamount.The record of seismicity at Axial Seamount also suggests that earthquake frequency increases quasi-exponentially in the years preceding an eruptive event50. Under this paradigm, a stable magma reservoir is assumed to be in lithostatic equilibrium with the surrounding rock, such that the confining strength is equal to the pressure within the reservoir. As pressure builds due to injection of new melt or volatile exsolution, the system is no longer in equilibrium and the host rock responds by breaking (seismicity) and deforming. Eventually, pressure in excess of the host rock confining strength builds sufficiently to trigger eruption. As reservoir pressure is released, rapid underpressurization occurs, triggering the collapse of the overlying roof rock into resultant space in the reservoir50. Studies of dike propagation have revealed that pressures of 10–40 MPa are required to initiate diking, and as such, modeling studies have frequently cited 10–40 MPa of pressure as the amount required to trigger eruption in this way51.Critical overpressurization is a commonly described mechanism for triggering eruption17. This appears to be the case at Axial Seamount, where continuous CO2 flux from the hydrothermal system is observed, suggesting relatively steady-state volatile exsolution and release with no evidence for CO2 build up between eruptions and sudden loss during eruptions53. Therefore, volatile accumulation does not appear to be a major contributor to triggering eruptions. However, the nature of the inflation-eruption relationship observed at Axial Seamount suggests a critical deformation threshold after which eruptions are triggered, and if the surface deformation and reservoir inflation are linearly related, the observed deformation threshold may actually reflect a reservoir pressure threshold. Axial Seamount appears to have a near-continuous supply of melt as evidenced by stable inflation of the caldera floor with time. Therefore, as long as the melt supply is sufficiently high and consistent, overpressures should be able to build within the magma reservoir despite a steady loss of CO2. If eruptions of Axial Seamount are triggered via overpressurization, we would expect models to show a similar magnitude of reservoir pressure preceding predicted eruptions in 2011 and 2015. Conversely, dissimilar pressure conditions would suggest that eruptions are driven by external stress conditions. Nevertheless, the clear deformation threshold suggests similar pre-eruption conditions to trigger eruption. Gregg et al.13 found that flexure in the roof overlying a magma reservoir promoted top-down faulting which may ultimately trigger eruption of large basaltic caldera systems13. They postulated that the determining factor for this style of eruption was the roof aspect ratio (height of overlying roof rock/area of reservoir). Because rheology impacts a magma reservoir’s ability to expand and change its aspect ratio, the model sensitivity tests to rheology also provide the opportunity to assess whether eruptions of Axial Seamount may be triggered by flexure induced faulting.However, this paradigm has been widely debated in recent years as quantitative constraints on critical overpressure to drive eruption remain uncertain. Furthermore, vent degassing and the lack of volatile elements observed in many geochemical analyses suggest the open nature of some caldera systems and their inability to build large overpressures54.Rheology sensitivity tests reveal that modeled eruptions at Axial Seamount consistently occur when the pressure boundary condition exceeds 12–14 MPa Fig.  regardleThe timing of our model predicted eruptions consistently occurs in advance of observed eruptions regardless of chosen rheology. However, the models do not simulate or take into account stress release via seismicity. Therefore, it is possible that the FEMs used in this study pre-predict eruption because they achieve the critical reservoir pressure threshold in advance of when it would occur if a condition to relieve stress through faulting were implemented. As such, future efforts should consider stress release to test the hypothesis that seismicity serves as both an eruption precursor and a buffer at the Axial Seamount.In recent years greater complexities have been revealed in the processes responsible for triggering volcanic eruptions. Increasingly, phenomena which operate externally to a volcanic system  are being attributed to triggering their eruptions. However, at the Axial Seamount numerical experiments indicate that eruptions are likely triggered by critical overpressurization of the magma reservoir and have little reliance on external fault or earthquake triggering.A series of numerical experiments were performed to assess the impact of rheology on predictions of volcanic deformation, stress state, and mechanical failure of the host rock surrounding the Axial Seamount magma reservoir. These model sensitivity tests reveal that rheology strongly impacts predictions of volcanic unrest. In particular, we show that non-temperature-dependent models require an unrealistically high pressure condition to reproduce the observed deformation at Axial Seamount. Similarly, we show that eruption onset is predicted years in advance of that observed for models which do not incorporate temperature dependence. Therefore, temperature-dependence is critical to include for such modeling efforts.Numerical results suggest that internal, magmatic processes likely drive external processes (seismicity), which in turn accommodate inflation of the magma reservoir precursory to eruption. We postulate that seismicity and fault slip on caldera-related faults work to relieve some of the host rock stresses induced by the expansion of the magma reservoir and serve as an eruption buffer rather than a catalyst (delaying the eruption onset). Ultimately, eruptions appear to be triggered by overpressurization of the magma reservoir when a critical threshold of ~12–14 MPa is exceeded.Given the inflation-predictable eruption cycle observed at Axial Seamount, it has frequently been described as a “well-behaved” volcano, particularly when compared to terrestrial systems, which often exhibit less repeatable pre-eruption trends. Why is it that eruptions at Axial Seamount are predictable and related to magma overpressures while others are more difficult to predict? The physical setting at Axial Seamount appears to be simpler system as compared to terrestrial volcanoes, and we hypothesize that it is “well-behaved” for a number of reasons. In particular, the crustal thickness at Axial Seamount is far thinner than that of continental crust and is therefore likely to be more chemically and structurally homogeneous than continental crust. Under these conditions, melt migration to the surface should be less complicated and therefore more rapid, reducing time for interaction and melt evolution in the crust. Furthermore, Axial’s unique location at a hotspot and mid-ocean ridge spreading center supplies the shallow magma reservoir with a nearly-continuous supply of melt as opposed to the terrestrial systems which are rejuvenated rather infrequently. In addition, the system is in a tensional tectonic regime due to continuous plate spreading. These factors likely lend themselves to an inflation-predictable eruption cycle, in which reservoir pressure, surface deformation, and the timing of eruptions at Axial Seamount can be anticipated because they are closely linked.Supplementary information.


In the neocortex, neuronal processing of sensory events is significantly influenced by context. For instance, responses in sensory cortices are suppressed to repetitive or redundant stimuli, a phenomenon termed “stimulus-specific adaptation” (SSA). However, in a context in which that same stimulus is novel, or deviates from expectations, neuronal responses are augmented. This augmentation is termed “deviance detection” (DD). This contextual modulation of neural responses is fundamental for how the brain efficiently processes the sensory world to guide immediate and future behaviors. Notably, context modulation is deficient in some neuropsychiatric disorders such as schizophrenia (SZ), as quantified by reduced “mismatch negativity” (MMN), an electroencephalography waveform reflecting a combination of SSA and DD in sensory cortex. Although the role of NMDA-receptor function and other neuromodulatory systems on MMN is established, the precise microcircuit mechanisms of MMN and its underlying components, SSA and DD, remain unknown. When coupled with animal models, the development of powerful precision neurotechnologies over the past decade carries significant promise for making new progress into understanding the neurobiology of MMN with previously unreachable spatial resolution. Currently, rodent models represent the best tool for mechanistic study due to the vast genetic tools available. While quantifying human-like MMN waveforms in rodents is not straightforward, the “oddball” paradigms used to study it in humans and its underlying subcomponents (SSA/DD) are highly translatable across species. Here we summarize efforts published so far, with a focus on cortically measured SSA and DD in animals to maintain relevance to the classically measured MMN, which has cortical origins. While mechanistic studies that measure and contrast both components are sparse, we synthesize a potential set of microcircuit mechanisms from the existing rodent, primate, and human literature. While MMN and its subcomponents likely reflect several mechanisms across multiple brain regions, understanding fundamental microcircuit mechanisms is an important step to understand MMN as a whole. We hypothesize that SSA reflects adaptations occurring at synapses along the sensory-thalamocortical pathways, while DD depends on both SSA inherited from afferent inputs and resulting disinhibition of non-adapted neurons arising from the distinct physiology and wiring properties of local interneuronal subpopulations and NMDA-receptor function. Organisms are continuously inundated with sensory information. Given that the majority of incoming information is redundant or behaviorally unimportant, organisms need to be able to suppress the neural processing of irrelevant stimuli to conserve resources. Such adjustments are made possible by a process referred to as stimulus-specific adaptation  while maintaining the ability to detect when a change occurs (DD) that might signal relevant, important information. Notably, most of the research regarding these phenomena has been carried out in the auditory and visual systems, and thoughtful experimental design efforts to differentiate SSA and DD  are an eWhile SSA and DD are typically measured at the neuronal level, they likely reflect circuit-level computations  merits consideration  to open-state NDMA receptors, as pharmacological blockade of NMDA receptors diminishes MMN and oddball-drive responses/DD  could effectively give rise to DD and send it back up-stream . Such an experiment constitutes an important test for our model.Notably, a number of the premises in Further, much of the SSA and DD work on which it is based, for instance, come from different sensory modalities , which may  while stimulating/inhibiting another  and measuring gross LFP output would be a suitable test of these aspects of the model, and such an experiment is possible through the use of double transgenic strategies involving both Cre-and Flp- dependent gene expression in a complementary fashion (He et al., Fourth, whether upstream inputs onto SSTs vs. PYRs are facilitated during this paradigm should be directly explored. This is a challenging experiment, but it is theoretically possible using 2P calcium imaging of axon boutons (Hamm et al., In vivo recordings in the sensory cortex during an oddball paradigm followed by precise subsequent ex vivo recordings of the same neuronal populations in slices (Karnani et al., Finally, a strong test of this model would be a demonstration that DD-like computations can be generated in isolated cortical circuits. Recent results obtained from animals using the oddball and various control sequences demonstrates SSA and DD are not only separable, but likely arise due to different mechanisms. Our synthesis of this data and hypothesized model  suggestsBoth SSA and DD are co-represented in the human neurophysiological MMN response. While MMN is known to be altered relative to neurotypical controls in several neuropsychiatric diseases, such as SZ, autism spectrum disorders, and major depressive disorder among several others, many of these exhibit shared and distinct genetic risk (Brainstorm et al., JR and JH discussed and contributed to the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.