Qigong is the meditative movement and therapeutic exercise of Eastern medicine. A growing body of evidence is validating its health benefits leading to mechanistic questions of how it works. The purpose of this article is to explore mechanisms of action related to Qigong, with the intent of unifying Eastern and Western exercise theory and to present a model for Qigong exercise analysis. Three exercises from a standardized Qigong form: ‘Plucking the Stars’, ‘Lotus Leaves Rustle in the Wind’, and ‘Pacing Forwards and Backwards’ were selected for meditative, energetic, and physical analyses. Meditative aspects include relaxation response, interoception and exteroception. Energetic aspects include stimulation of meridians through mental intent, acupressure, and self-massage. Physical aspects include flexibility, strength, articular stimulation, neuro-integration, respiratory effect, fascial stretch, visceral massage, balance challenge CranioSacral pump, lymphatic and venous return and glandular stimulation, and physiologic response to relaxation. Knowledge of mechanisms of action for specific Qigong exercises can guide operational definition of Qigong, selection of outcomes assessment in future research, inform prescriptive practice addressing clinical health issues, and advance adoption of Qigong practice within integrative health care. The model of analysis demonstrated in this discussion may assist in these endeavors. Qigong is a broad discipline within Chinese philosophy. Academic study is composed of essential theories, practical skills, and clinical applications . Areas oA consensus working paper (2005) on Qigong and Tai Chi, generated by clinical researchers and experts in the field, identified the essential elements of Qigong practice to be either static or dynamic exercise combined with breath regulation, mental intent, and self-massage . Self-maIn 2016, a collaborative bibliometric review identified over 500 studies investigating therapeutic benefits of Tai Chi [A recently published map of 107 systematic reviews assessing benefits of Qigong exercise identified a wide range of outcome measures studied . Two thiThe following addresses the theoretical and conceptual framework of the current discussion. It is organized into three major foci: (a) meditative movement as a collective construct, (b) application of TCM Energy Theory, and (c) physical aspects of Qigong practice consistent with a Western medicine approach. Similar to conclusions of the 2005 Expert Panel on Qigong and Tai Chi, Larkey and colleagues propose that essential characteristics of MM consist of: first, a meditative state of mind, usually involving a focus of awareness on the body; second, some form of prescribed (or sometimes spontaneous) movement; third, explicit attention to the breathing; and fourth, a state of deep relaxation . PracticRelaxation responses are integral to MM practice. Payne et al., addressed the concept that relaxation responses maintain a state of completely balanced tone, eutonis, in which every muscle is doing exactly what it should . This stThis relaxation response leads to decreases in heart rate and blood pressure, release of muscle tension, improved digestion, improved sleep cycles, enhanced anti-inflammatory effects, decreases in stress and anxiety, decreased pain, enhanced mood, and helps to regulate the autonomic nervous system . HoweverFoundational within Energy Theory are at least two contributory theories. Yin/Yang Theory and 5 Element Theory. Yin/Yang Theory predicates on an understanding that optimal function  results from a balancing of opposite natural forces and their respective interplay  . SimilarQi circulation occurs through pathways of flow including 12 major meridians and 8 curious meridians . ThroughIn TCM, clinical treatment is approached with consideration that one has both a physical body and an energetic body or biofield that is both internal and external to the physical body. In addition to stimulation of acupuncture points within the physical body, adjustments to the energetic biofield can also influence ones health. While there has been little study of Qigong in terms of self-biofield adjustment and its effect on organ function, there is subjective evidence that external (applied by another) biofield massage such as Reiki or Therapeutic Touch can among other things, lessen fatigue, restore vitality, manage pain, and raise sense of well-being . Functional, pain-free joint mobility requires skeletal stability, healthy articular cartilage, and appropriate extensibility of peri-articular dense connective tissues . ArticulBasic human functional activities often require movement and coordination of multiple body parts and systems in multiple planes simultaneously. This is a common theme throughout Qigong and Tai Chi movements—the body moves as an integrated unit, through continuous, curved and spiral body movement patterns (multi-planar movements). Through these whole-body, continuous, circular movements, the fascial system of the body is engaged. According to the Fascia Research Congress, fascia is the soft tissue component of the connective tissue system that permeates the human body forming a whole-body continuous three-dimensional matrix of structural support . It intePhysical activity improves cognitive function and brain plasticity . Many acy is the study of interactions among behavioral, neural, endocrine, and immunologic processes of adaptation [The movements and practice of Qigong have characteristics that are beneficial throughout multiple systems of the body. Coordinated, spiral movements, often crossing midline are similar to complex movement patterns found in proprioceptive neuromuscular facilitation patterns used in neurological rehab. Neuroimmunologaptation . Recent aptation . Furtheraptation .The purpose of the current analysis is to explore mechanisms of action related to Qigong by unifying applied Eastern and Western exercise theory with the intention that it may serve as a model for future Qigong exercise analyses.The research is designed as an applied theoretical discussion of mechanisms of action for three selected Qigong exercises.Four experts in the field participated in this research. They include two physical therapists, a medical doctor with certification in Medical Acupuncture, and a Qigong Master of international reputation. All are certified Qigong instructors within the Wu Yi Jie He family system of Tai Chi and Qigong. All are experienced researchers in the field. Three have academic teaching affiliations. Together, they have over 56 years of cumulative Qigong practice. Criteria for selection of dynamic postures included: (a) application for three major body areas ; (b) application for common clinical problems ; (c) applications of neuro-motor integration; (d) a range of proposed mechanisms of therapeutic effect; and (e) referent for traditional postures that appear as derivative within multiple Qigong forms.Three dynamic postures meeting selection criteria were identified from the modern 24-Movement Qigong Form  and are Discrete analyses of mechanisms of action are based on consensus expert opinion of the researcher team. Sources include integration of available research, applied theory, and connoiseurial interpretation of Qigong as experienced by the researcher experts. By consensus thematic analysis, researchers identified major categories of action and subsections within those major categories. Twenty Exercises for Treating Diseases and Prolonging Life, was codified in the 1950’s by Grand Master Wang Ziping, a doctor of TCM and esteemed martial arts master [The three exercises selected for analyses were ‘Plucking the Stars’, ‘Lotus Leaves Rustle in the Wind’, and ‘Pacing Forwards and Backwards’ from the Wu Yi Jie He family system, 24-Posture Qigong form. This form, initially named s master . Partials master . Figure The following discusses mechanisms of action related to meditative intent, energetic aspects, and physical aspects for each of the three selected exercises. Note that in the energetic body (biofield), all meridians are stimulated to one degree or another with any gross movement, however, depending on the specific exercise some meridians have more direct stimulation based on muscle contraction and fascial stretch generating mechanical forces acting on viscera and soft tissue including lymphatics. . The reference source used in the linking of meridians to organs and organ function is a primary text on clinical acupuncture . In ‘PluThe following energetic analysis is based on application of energy theory. In the first part of the exercise as the active hand rises through midline, intent is simultaneously focused on both hands to stimulate micro-cosmic orbit or small heavenly circulation (xiao zhou tian) consisting of the Conception (du mai-yin highway) and Governing (chong mai-yang highway) vessels. The placement of the tip of the tongue on the hard palate connects the two vessels or pathways. The front hand slowly rises in midline in the path of the Conception vessel until the arm reaches full extension above the head. The upper bio-field  is combed at arm’s length throughout the return to resting position. Mental intent is maintained. This intent directs the path of the Qi flow. Through the lifting, spiraling, stretching, contracting and relaxing of soft tissue, any impedance to upper body energy flow is minimized. In returning the outstretched arm to the side, the bioelectric field is stroked with the hands and activated by mental intention assisted by eye focus. Simultaneously, the hand maintained at the back stimulates the Ming Men Gate of Vitality and the Governing vessel. The Governing vessel is one of the eight curious meridians and unites the Yang (Fu-hollow organs). Qi flows up the spine internally to the midline of the hard palate where it meets the Conception vessel. The Conception vessel is also categorized as a curious meridian and controls the Yin (Zang-solid organs) organs. It flows up the anterior midline to the center to the hard palate. Mediastinal structures and organs are stimulated by both movement and intention. The heart and its associated blood vessels are considered the root of life . The altAnalyzed from a biomechanical model, the movement through elongation or extension of the thoracic and cervical spines, with the arm progressively extending overhead, wrist extended. The thoracic and cervical spines are subject to losing mobility as we age, adapting more of a curved or rounded forward posture. This may also be exacerbated by various medical conditions  and postures adapted during various activities (extended periods of sitting at a desk or driving). This lack of mobility may contribute to faulty or inefficient apical breathing patterns, loss of balance skill, and pain. This lack of mobility can also lead to dysfunction in the mechanoreceptors in your neck and back. Koskimies et al., (1997) reported that individuals with “tension neck”, had greater postural deviations induced by vibration of their neck than persons without a stiff neck. In other words, a tight neck might increase input from muscle proprioceptors, and dizziness due to too much proprioception . MagnussAnother important feature of this complex posture is the extension of the arm over the head with the palm facing upwards, the wrist extended, and fingers pointing inward. Glenohumeral rhythm is maintained by keeping the hand close to midline and the shoulder joint in a loose-packed position minimizing the possibility of shoulder structure impingement as it rises. The act of assuming this position provides a gentle stretch of the nerves and surrounding fascia in the shoulder, arm, wrist, and hand, stimulating meridians of the arm and aiding in upper arm lymphatic drainage. This posture, along with extension of the spine, is beneficial for several reasons including breath adjustment and facilitation of CranioSacral pump. Training isolated to individual muscle groups may exercise that muscle, but can leave out integrated fascial tissues necessary to the body’s health in functional movement. Basic human functional activities often require complex, whole task movement with coordination of multiple body parts and systems in multiple planes . This is‘Lotus Leaves Rustle in the Wind’In the first part of ‘Lotus Leaves Rustle in the Wind’, hand are placed over the kidney area as ribs expand with deep breathing there is an interoceptive awareness of the breath adjustment. In the second half of the exercise, hands are place on the Ming Men energy gate. Interoceptive and exterocepting (throught touch) awareness are focused on the mobility of the pelvic bones. In ‘Lotus Leaves Rustle in the Wind’, intitially the hands are placed over the kidney area. Practitioners are instructed to imagine that each clearing breath energizes and clears the kidneys of any toxins. In the second part of the exercise. In the second part of the exercise, intention focused on opening of the Ming Men gate and visceral stimulation with intent to store (accumulate) renewable energy generated from the exercise into the lower Dan Tien vessel. Assuming a wider stance stabilizes the lower extremities and upper spine. Rotations occurring at the pelvis create a mechanical force on the Yin organs of the spleen, kidney and liver and the Yang organs of the urinary bladder, gall bladder and stomach. The spleen controls movement of the fluids in the stomach. Gall bladder is appended to the liver, and they mutually assist one another. The kidneys control water and filter toxins. The liver stores and transforms the blood and among its many functions has a role in regulation of blood pressure. The urinary bladder flushes fluids for elimination. The stomach assists in digestion. All Yin (Zang) and Yang (Fu) organs are replenished with Qi from the stomach. The rhythmic contraction and relaxation of trunk core, the gluteals, the muscles of the inner thigh, and internal pelvis stimulate several acupuncture points on the meridians flowing to and through the legs and hip areas.This movement starts with the feet slightly wider apart than shoulder width, hands on the low back. Keeping the head and lower body relatively static, the pelvis is then rotated in a circular direction in one direction for 4-8 times, followed by the opposite direction with slight over pressure from the hands to assist in lateral shift. This rotation of the pelvis on the femur coupled with the contractions and relaxation of muscles of the trunk core and in and around the pelvis and thighs provide slow cyclical compression and decompression achieved by joint movement, muscle contraction, and intermittent weight bearing required to nourish cartilage in the joint. The slow, rhythmic rotation of the pelvis on the femur also helps in relaxation of the spinal and pelvic muscles . ‘Pacing Forwards and Backwards’In ‘Pacing Forwards and Backwards’, mental intent focuses on bodily sensations created by the slow, progressive transition of weight bearing from one foot to the other and the intention that the abdominal core (coinciding with the location of the lower Dan Tien) leads the slow, alternating, heel-to-toe, forwards and backwards walking progression. Pacing Forwards and Backwards, all lower leg meridians are activated. The weight-shift progresses laterally and from posterior to anterior and then reversing resulting in stimulation of Liver L1 point, Kidney K1 point and acupuncture points along the spleen meridian. Stabilizing of lateral-weight shift stimulates the gall bladder meridian and in particular: GB31 point located mid lateral thigh. Among other things, the slow reversing cycle of contracting and stretching the calf muscles acts on urinary bladder UB57 point. In the mobility exercise: This movement starts with the feet together and the knees bent slightly. A majority of the movement is performed with both knees bent slightly elevating and lowering slightly in rhythm with weight shifting, producing an eccentric and concentric contractions through the quadriceps and gluteal muscles and CranioSacral pump. One of the legs is then advanced forward, contacting the ground with the heel first as weight is slowly transferred from one leg, to both, and then the alternate leg in a cyclic pattern. In this gait, walking is centered and controlled throughout, in contrast to a modern Western descriptions of gait as controlled falling. There is also a balance challenge resultant for the slow fluid pacing and increased proprioceptive and kinesthetic awareness associated with correct foot placement, while the body or center of mass (COM) remains unchanged. Next, the weight is slowly transferred forward and the person begins to shift weight onto the lead foot. This transition from double limb to single limb stance has been identified as the most hazardous phase for a slip during level walking . As the The following discusses analyses by major category as well as challenges in application, suggestions for future research and limitations of the work.For millennia, it was the convention to explain Qigong exercise in terms of TCM and energy theory. More recently modern research has explored the benefits of this ancient exercise within Western exercise physiology and integrative health care. A challenge of informing practice from a Western medicine perspective has been the lack of operational definition of Qigong exercise. The movement analysis conducted herein has identified several mechanisms of action suggesting that Qigong exercise is more than just slow, gentile, repetitive exercise. These mechanisms have been organized into three major categories: meditative, energetic, and physical aspects with subsections within each. Meditative aspects include relaxation response, interoception and exteroception. Energetic aspects include stimulation of meridians through acupressure, mental intent, and self-massage. Physical aspects include flexibility, strength, articular stimulation, neuro-integration, respiratory effect, fascial stretch, visceral massage, balance challenge CranioSacral pump, lymphatic and venous return and glandular stimulation, and physiologic response to relaxation. These major aspects and subcategories of action may serve to organize analysis of other dynamic Qigong exercises .As a mindfulness exercise, meditation is an essential element of Qigong. There is a strong body of evidence defining effects and mechanisms of action for meditation that generalizes to the meditative and mindful practices of Qigong. While related research is extensive and a full discussion of this topic is beyond the scope of this article, a brief discussion is warranted. Recent meta-analyses and individual studies demonstrated common brain effects for attention-based meditative practices and active-based meditations in the brain areas involved in reward processing and emotional control . Hölzel Unique to Qigong exercise among MM modalities is the intention to affect energy flow or clear Qi stagnation regionally and to mechanically stimulate acupuncture points. An example of this intentional aspect occurs in ‘Lotus Leaves Rustle in the Wind’, where hands are placed over the kidneys and there is instruction to practitioners to imagine that each breath clears the kidney to optimize organ function. Beyond articular stimulation, improved flexibility, and muscular coordination within the physical domain, the relaxation effect of slow deep breathing is evident in Qigong practice. In addition to this relaxation response and optimalization of respiratory function, the dynamic exercise within each of the three exercises discussed also includes facilitation of the CranioSacral Pump. The concept of CranioSacral Pump is the basis for Cranio/Sacral Therapy (CST). Cranio/Sacral Therapy is a gentle, hands-on method of evaluating and enhancing the functioning of a physiological body system called the craniosacral system—comprised of the membranes and cerebrospinal fluid that surround and protect the brain and spinal cord . Self-reThe third dynamic Qigong posture: ‘Pacing Forwards and Backwards’, is a dynamic balance training exercise. The evidence that dynamic Qigong and Tai Chi can improve balance and aid in fall prevention has been addressed in previous research. In the Central Sidney Tai Chi Trial (N = 702), relatively healthy older adults underwent a 16-wk program of community Tai Chi training . This waThe vast majority of research on therapeutic value of Qigong exercise in integrative health care addresses assessment of effect. It is only very recently that research agenda have begun to address mechanisms of action. Research on meditation is strong and infers benefit of MM where intent and learned relaxation combined with dynamic exercise are considered essential elements of the exercise phenomenon. Further research exploring similarities and differences between static and moving meditation may provide added insights for practice. Knowledge of physiologic and biomechanical actions occurring within Qigong practice is sufficiently documented to, at least, partially validate the proposition that slow, gentle, spiral movements result in mechanical stimulation of articular surfaces, soft tissues, and organs. While mapping of acupuncture points and meridians provide some evidence of the existence of an energy system within the body, and clinical research has also provided evidence of effect of acupuncture point stimulation, it is a jump to infer that Qigong exercise self-stimulates this energetic system. While the notion that muscle action and fascial stretch can result in electrical differential and chemical changes at acupuncture points similar to acupuncture therapy can be assessed, direct evidence of changes in Qi flow is not so easily measured. This may be due, in part, to limitations in instrumentation. Advances in micro-electric, infrared, magnetic, and vibrational bio measurement hold promise to expand our knowledge of mechanisms of action . Until tAnother future research approach is to operationally define a set or individual Qigong exercise patterns and propose a theoretical model of mechanism of action on organs and structures. Predictions of how given Qigong exercises or forms might normalize organ function might then be used to assess validity of proposed theoretical models. Likewise, if it is purported that mental intent such as demonstrated in the second exercise: ‘Lotus Leaves Rustle in the Wind’, can improve kidney organ function, this could be assessed in individuals with abnormal function tests to determine if there is any normalization of kidney function with targeted Qigong practice.In addition to quantitative theory validation, Dr. C. Kerr, a specialist in the field of brain and brain-body mechanisms underlying mindfulness and mind-body therapies including Tai Chi and Qigong, has suggested that understanding how one perceives Qigong exercise through ethnographic study may provide additional valuable information . As sentAn a priori limitation of this discussion is the limited availability of mechanistic research into how Qigong works. Therefore, much of the analysis is inferred application of theory rather than validated proof. As we learn more about mechanisms of action, this limitation will diminish. A potential limitation may be that a relatively small team of investigators conducted the dynamic posture analyses. However, the team does represent requisite expertise in both Eastern and Western medicine and therapeutic exercise, so any deficit in this area is considered minimal. There is also a potential bias in selection of the exercises chosen for analyses. Again, this bias is considered minimal as variations and derivations of these traditional Qigong exercises appear in numerous Qigong forms. Energetic, meditative, biomechanical, and physiologic analyses of three Qigong exercises demonstrate a theoretical model of how Qigong practice can selectively and holistically contribute to optimal function for health maintenance, healing and longevity. Meditative aspects include relaxation response, interoception and exteroception. Energetic aspects include stimulation of meridians through mental intent, acupressure and self-massage. Physical aspects include flexibility, strength, articular stimulation, neuro-integration, respiratory effect, fascial stretch, visceral massage, balance challenge CranioSacral pump, lymphatic and venous return and glandular stimulation, and physiologic response to relaxation. Knowledge of mechanisms of action for specific Qigong exercises can guide practice instruction, prescriptive practice addressing clinical health issues, future research agenda toward adoption of Qigong practice within integrative health care. The model of analysis demonstrated in this discussion is offered to assist in these endeavors.


The continuous technological advances in favor of mHealth represent a key factor in the improvement of medical emergency services. This systematic review presents the identification, study, and classification of the most up-to-date approaches surrounding the deployment of architectures for mHealth. Our review includes 25 articles obtained from databases such as IEEE Xplore, Scopus, SpringerLink, ScienceDirect, and SAGE. This review focused on studies addressing mHealth systems for outdoor emergency situations. In 60% of the articles, the deployment architecture relied in the connective infrastructure associated with emergent technologies such as cloud services, distributed services, Internet-of-things, machine-to-machine, vehicular ad hoc network, and service-oriented architecture. In 40% of the literature review, the deployment architecture for mHealth considered traditional connective infrastructure. Only 20% of the studies implemented an energy consumption protocol to extend system lifetime. We concluded that there is a need for more integrated solutions specifically for outdoor scenarios. Energy consumption protocols are needed to be implemented and evaluated. Emergent connective technologies are redefining the information management and overcome traditional technologies. Efforts and developments for pervasive healthcare are growing swiftly worldwide; this fact reveals that universities, researchers, and enterprises are aware of the need for functional and accurate systems that are able to satisfy the increasing demand for a better medical attention infrastructure . AlthougHealth monitoring is one of the ways to improve the emergency and healthcare services. Heath monitoring enables the early detection of diseases and the prompt medical care under emergencies resulting in the reduction of suffering and medical costs. The use of sensors for monitoring and transmitting the patient's vital signs is useful for identification of patients under risk. The medical personnel can determine the actions to safeguard the patient's health using the sensor information. The delivery of opportune medical care could be the difference between life and death.Advances in mHealth services incorporate platforms based on wireless body sensor networks (WBSN) as a central aid for remote reporting of data to a medical center under medical emergencies. The WBSN collects data from biomedical sensors and cameras using a user-friendly interface. The WBSN is also able to transmit images, physiological signals, and video . In 6],,6], the An emergency condition can be caused by multiple and different factors, such as natural disasters, human carelessness, explosions, traffic accidents, and degenerative diseases. On these events, early attention is very important, also to have a plan of action, and, of course, the caregiver capabilities. Once the caregivers are notified about the emergency situation, the prehospital assistance starts with the intention to control the emergency by stabilizing the patient for further transportation to a medical center.Events resulting in an emergency condition are natural disasters, human carelessness, explosion, traffic accidents, degenerative diseases, and so forth. These events may be may be multiple and different. Addressing these events also require (1) early attention, (2) a plan of action, and (3) a capable caregiver.After notifying the caregiver about the emergency, the prehospital assistance starts with the intention of stabilizing the patient for further transportation to a medical center.Providing first aid and requesting the assistance of a specialist physician at the same time increases the chances of a better outcome for patients in critical conditions. To do this, the assistance request to the specialist physician must include an accurate overview of the patient. This overview should be prepared by collecting and sending patient's information in real time.Under this emergency scenario, the incorporation of a wireless body sensor network (WBSN) enables real-time monitoring and results in delivering better and opportunistic medical services. Nevertheless, developing this integrated system for emergency care becomes a challenging task. Many factors play important roles and the accurate design of the system could become the key to obtain the desired outcomes. This integrated system should be capable of handling the large amounts of data obtained in a very short time from different vital sign sensors. Common sensors collect vital sign information such as heart rate, blood pressure, or electrocardiography (ECG). Also, the accurate design of this integrated mHealth system should address energy consumption issues in the network, the mobile computer, and the medical sensors . Other iThe aim of this paper is to systematically review the architectures, connective technologies, and energy optimization protocols implemented in the mHealth systems for emergency scenarios in outdoors in the last five years. There are several surveys and taxonomies about the deployed mHealth architectures for healthcare domain, and also, some studies are targeted for emergency scenarios. However, to the best of our knowledge, no systematic review has been conducted to overview the different types of mHealth architectures currently being implemented for emergency scenarios in outdoors. Moreover, our systematic review seeks for the efforts surrounding the mHealth systems to attend the patient in emergency situations in terms of architecture integration, communication, and energy optimization proposals. In that manner, this review collects valuable information about the following: (1) mHealth third-tier architecture for emergency scenarios in outdoors, (2) the traditional and emergent infrastructure connectivity technology between the three tiers, and (3) energy optimization protocols employed to increase the lifetime of the mHealth systems. The study concludes by discussing the future directions in the field.This examination was conducted in September 2016–April 2017. The main goal was to find, study, and evaluate the recent efforts related to the infrastructure and architecture in favor of mHealth systems. This objective was fulfilled via the Internet by selecting the following databases: IEEE Xplore, Scopus, SpringerLink, ScienceDirect, and SAGE. The keywords used (employing Boolean phrases) in the searching were as follows: mobile health, m-health, mHealth, remote health, ubiquitous health, mobile healthcare, pervasive health, architecture, infrastructure, and emergency. Considering our interest to provide an analysis of novel productions, articles published after 2012 were considered. We included exclusively productions published in English and research from peer-reviewed journals. During the first stage, duplications were excluded and papers were analyzed by their title and abstract seeking for a match with our scope of interest. On a second stage, the remaining productions were subjected to a full-text review.The initial query displayed 5801 results. After the first stage , the number was reduced to 366. Once initiated the full-text review, we aimed our analysis in publications addressing the remote tracking of medical emergencies in outdoor scenarios, considering the importance previously described about traffic accidents or sudden-onset emergencies as a consequence of chronic degenerative assistance. The inclusion criteria were performed as follows: (i) articles including emergency events handling ; (ii) the study includes system and prototype developments, evaluation or validation of algorithms, protocols, models, and systems; (iii) the study was a peer-reviewed article published in journals; (iv) articles where approaches considered collecting data for at least one wireless sensor; (v) studies displaying evidence in the use of wireless technologies, that means, their infrastructure and architecture included two or more tiers; and (vi) articles were written in English language. In the course of full-text review exclusion criteria was determined by (i) articles derived from posters, glossaries, conferences, congresses, meeting, front covers, and book chapters; (ii) articles not written in English language; (iii) articles not supporting emergency situations; (iv) articles considering emergency management for hospital scenario; and (v) studies where the architecture for mHealth services included just organizational and conceptual models (lack of infrastructure in the deployment). All articles were evaluated looking for real evidence in the outcomes presented. After two stages of evaluation process, 25 articles were selected for the present analysis.In our review, we detected only 5 (20%) articles that are specific for outdoor environments. The other reviewed architectures 20 (80%) were targeted for indoors and outdoors. After the analysis of the selected articles, we extracted the main information of the recent architectures used for mHealth monitoring in emergency situations. This section reports demographic data extracted from the 27 selected articles. The articles were from 20 different journals; the most common journal was International Journal of Distributed Sensor Networks 4 (16%).The taxonomy of mHealth system architecture for emergency scenarios in outdoors is focused on the three tier structure: intra-WBSN communication for the first tier, inter-WBSN communication for the second tier, and beyond-WBSN communication for third tier.The first tier considers the implementation of a body sensor network (BSN). The sensors have a direct communication with the personal server (PS) implemented in the second tier. The main sensor units for mHealth systems in emergency scenarios in outdoors correspond to physiological and environmental sensors. The selected studies used a diverse type of physiological data to monitor the internal condition of the person; however, authors in  did not The second tier considers the implementation of a PS (mobile unit). The PS has a direct communication with the database servers implemented in the third tier. Smartphones and tablets are the most common units used for mHealth systems. The main built-in technologies used by the smartphone users are the video and the global positioning system (GPS) technologies. The use of GPS technology is fundamental to locate the person with the emergency situation in outdoors. In , a smartThe use of video technology is valuable for visual monitoring the scenario of the emergency in real time. In , video sThe third tier considers the implementation of database servers in order to store, manage, and visualize the patient data. The main units used are local and remote servers. The most common deployments for mHealth systems for emergency scenarios in outdoors include the communication with the local server and the communication with the remote servers via the Internet. In , 17, 24,Infrastructure connectivity refers to the communication technology implemented between each tier of the mHealth system. The taxonomy proposed for this category includes the traditional connective technology and the emergent connective technology.The traditional connective technology considers the available communication services to manage and transmit the information. Either wired or wireless sensors transmit the physiological information to a mobile device via Bluetooth or Zigbee, the mobile device sends the data through a cellular network or a local area network services, and finally, the data is managed, visualized, and stored into a local or a remote server.Nowadays, the information is being managed in different manners, not only via one-way traditional services. The emergent Internet connective technologies consider other types of manners to transmit, process, and manage the data, such as cloud services, Internet-of-things (IoT), distributed services, machine-to-machine (M2M), vehicular ad hoc network (VANET), and service-oriented architectures (SOA).The most common implemented connective technology for mHealth systems in emergency scenarios in outdoors is the cloud services. In , a namedThe combination of cloud services and IoT connective technologies is another alternative for mHealth systems. In –31, the It is important to take into account the lifetime of the mHealth systems especially when these systems are intended for emergency scenarios, in which the data transmission is demanding, in real time and critical. Moreover, for outdoor environments, the mobility of the platforms prevents the components of the system  to be energized at any time, so the lifetime of the system must be sustainable.Although energy optimization procedures were proposed for increasing the lifetime of the mHealth systems in emergency scenarios in outdoors, few studies implemented an energy consumption protocol. In , a lifetThe other studies only suggested that some actions could be taken to improve battery lifetime. In terms of minor data transmission, , 25, 31 Architecture and infrastructure for mHealth services vary depending on the different ways to deploy a wireless sensor network for emergency scenarios in outdoors. After analyzing 25 articles, our review process pointed out that the majority of the reviewed mHealth systems were intended for patients suffering from either cardiac, epilepsy, dementia, or paralysis disease. Also, the elderly was the predominant population, and the athletes and disabled people represented the secondary population.In the majority of the revised articles, 80%, the mHealth systems were intended for indoors and outdoors; however, the deployment and evaluation of these systems were only for indoor scenarios. This finding highlights the need to show real evidence of mHealth systems supporting emergencies in outdoors scenarios. The need of mhealth systems deployed for outdoors along with two key factors makes evident our decision to highlight how wireless body sensor networks (WBSN) are handling emergency events. The key factors are the need for emergency care for patients within the golden hour and the previously stated increment in the rate of traffic accidents . Our revA final WBSN-based design and implementation has to consider energy efficiency. The whole WBSN-based system can fail if one or more nodes run out of battery. The WBSN-based design has to take into account consumption-aware policies and adaptive behaviors regarding network and patient conditions , 36.Our systematic review presented a comprehensive overview of the integrated mHealth architectures for outdoor emergencies. Our systematic review also highlighted the emergent connectivity technologies and the energy optimization protocols implemented in mHealth systems for outdoor emergencies.Despite the growing presence of remote health monitoring in home, hospital, and emergency scenarios, the development based on wireless body sensor networks (WBSN) is still at a redefinition stage especially for outdoor emergencies.Our review also highlighted the need for more integrated mHealth solutions specifically for outdoor scenarios. Only one of our surveyed studies presented an integrated solution based on the need of mHealth systems capable of switching among requirements depending on an outdoor or indoor context. Also, the integration of emergent connective technologies into mHealth architectures are redefining the way information is being managed. Emergent technologies such as cloud services and Internet-of-things (IoT) represent new paradigms for the communication among specific layers found in mHealth systems. The sensor nodes demanded by these technologies must satisfy several requirements: (1) high degree of integration with a small size, (2) local processing of multiple signals, (3) reduction in power consumption of the microprocessor, (4) reduction in wireless data transmission, (5) data intensive collection, and (6) reduced duration of the processor's active mode. Finally, our review highlighted the need for implementing and evaluating energy consumption protocols.


Of the studies surveyed, five studies dealt with epidemiological anddemographic issues, 12 were clinical trials i.e. were based on testing andimplementation of instruments in human subjects, 33 studies were basic researchinvolving studies of mice, rats and non-human primates, and biochemical andThe work sought to highlight which neural networks are most involved inprocessing information, as well as their location within brain regions andthe way in which neurotransmitters interact with each other for theformation of these memories. Moreover, it was shown how memory changesduring the normal human aging process, both positively and negatively, byanalyzing the morphological alterations that occur in the brain of agingindividuals. Memoryalso plays a key role from an evolutionary standpoint because it is essential forreproduction and survival, for example in remembering food foraging sites or theimminent decision for fight or flight.13The events outlined above are generally emotionally loaded, both positively andnegatively, and are the product of neurochemical changes and interactions withearlier memories, consequently increasing the likelihood of storage of thisinformation.14 can be classified in terms of retention time andtheir nature, with respective types and subtypes. Regarding retention time, memoriescan be defined as: very short term (lasting only a fewseconds); short term (up to three hours); and longterm (lasting days or years). Concerning the nature of memory, this canbe classified as: explicit (or declarative);episodic ; semantic; implicit (ornon-declarative); perceptual representation (represents images withunknown meaning); procedural (habits and rules);associative (classic and operative conditioning);non-associative (habituation or sensitisation of the stimulus);and operational (or working memory)."Memories" in the plural sense as defined by Lent,11 and subsequentlyretrieved.9 Thus, learningby information acquisition constitutes the first step toward the formation ofmemory.Although retrieval of memories requires, obligatorily, that the information has beenacquired at some point, its mere acquisition does not make this information a memoryper se. The information only becomes a memory when information is learned,stored11Information acquisition can occur in a variety of ways, albeit through empiricalexperiences, stimuli captured by our sensory and somesthetic systems, or eventhrough situations created in our own thoughts.15Indeed, any stimuli that pass through the memory-related neural systems may beselected for subsequent consolidation. The process of information selection isimportant to enable systems involved in memory to refine, amongst all the complexityof information it receives, which items are most relevant based on the focus givento the information, emotions involved with it, among other as yet unknown systems ofrefinement.13Defining specific brain regions or circuits dedicated to memory is hard given theseprocesses are distributed throughout the brain, but some circuits have more affinityfor certain stages of the memory formation process.16 there is evidence that with time, hippocampal activitydecreases in response to the retrieval of distant memories. On the other hand, anincrease in cortical activity takes place. This suggests that memory progressively,dynamically and in a plastic manner, becomes independent of the hippocampus and moredependent on cortical regions, a process called Systemic Consolidation orReorganization of Memory.17The hippocampus, a structure located bilaterally within the medial temporal lobe, hasthe function of consolidating information it receives, transferring this to theappropriate cortical regions or for temporary storage of copies of cortical enagramsvia interaction with other regions of the hippocampal formation, particularly theentorhinal cortex, through its connections with Ammon's horns and the dentate gyrusof the hippocampus. According to Cassini,18 The dentate gyrus appears to be involved in theseparation between similar spatial memories. The CA3 region seems to be important inthe processes of storage and retrieval of associative memories, while the CA1regions appears to be related to recognizing new items in context and to informationretrieval processes, contributing to the temporal aspects of memory.20The dentate gyrus region of the hippocampus, as well as CA1 and CA3 regions, performan important role in contextualizing aversive memories.11In addition, regions such as the medial and inferior temporal gyrus play a key rolein memory, housing the language lexicons which allow use to describe everydayobjects and situations. The posterior region of the parietal cortex storesinformation on the place information, working in conjunction with the medialpre-frontal cortex which orients us on distance between locations.21 However, the intimate relationship that these nuclei have withthe hippocampus, whether through the connections via fibers of the fornix orcholinergic projections, indicates participation of these structures in memoryconsolidation, or as a co-adjuvant in this process.11The involvement of subcortical nuclei such as the diencephalic nuclei, septal nucleiof the prosencephalic base and mammillary bodies of the hypothalamus, in memoryprocesses remains unclear, although damage in these latter bodies can result inepisodic memory impairment in rats.22While the predominant role of the brain structures outlined is the storage ofinformation, other structures are pivotal for this process to take place, namely,the structures making up the so-called to limbic system.22 consists of aseries of structures located mainly in the temporal lobes, and includes structuressuch as the hypothalamus, amygdala, basal ganglia, pre-frontal area of the cortex,cerebellum, septum and nucleus accumbens. Nevertheless, this is only one definitionof "limbic system", since there is no consensus in the literature regarding theregions involved in the emotional circuitry modulating memory.24The limbic system, originally referred to as "Broca's lobe" or "Papez'sCircuit",25 The importance of emotions inmemory processes arises since events intertwined to strong emotional reactions havea greater likelihood of being stored with a single exposure to events.29These structures are intimately related with emotions to be aggregated to informationreceived in so-called "reward pathways" and "fear circuit".31 According to the authors,information derived from the cerebral cortex and hypothalamus enters the amygdaloidcomplex via the basolateral nucleus and is transmitted to the central nucleus of theamygdala and subsequently distributed to regions of the brain trunk and hypothalamuswhich orchestrate defense behavior.33A number of studies have shown that the amygdala , also lo35 LTP can bedefined as the increase in post-synaptic responses over a long period, after briefrepetitive stimulation of pre-synaptic afferents, in which the resulting synapticmodifications are retained for a long period after the transcription of genes andsynthesis of proteins, resulting in greater efficacy of synaptictransmission.38Since activation of the fear pathway plays a relevant role for the survival of theorganism, the formation and storage of this information can lead to long termpotentiation (LTP) in the amygdala.41 otherstudies propose a modulating role played by the amygdala on the acquisition andstorage of information in other structures depending on the integrity of theconnections between it and the hypocampus.44While some authors hold that the amygdala has a role in forming the associationbetween stimulus and response to fear conditioning,44 The processes of memory consolidation can be regulated bycirculating adrenalin, noradrenalin, ACTH, among others, acting on the basolateralcomplex of the amydala.45The basolateral amygdala nucleus can influence hippocampal activity by means ofdirect projections to this structure, or via the entorhinal cortex, with involvementnot only in the processes mediating long-term consolidation, but also in theacquisition and codifying of information.45 reported that inanimal studies, the amygdala was found to regulate the processes of synapticplasticity important for the formation of memory in other regions of the brain suchas the hippocampus.Quevedo et al.46 Another region of the limbic system which formsthe neural substrate for emotional experience is the Nucleus Accumbens.10 This region comprises theprosencephalic base together with ventral portions of the caudate and putamen,constituting the ventral striatum.48Despite the amygdala and hippocampus complex being independent memory systems, theyinteract when the information has aggregated emotion.50 Moreover, this nucleus is known tobe involved in the so-called reward pathway, being associated to pleasurablestimulus. This structure of the prosencephalic base receives dopaminergic afferentsfrom the VTA and glutamatergic afferents from regions including the pre-frontalcortex, amygdala and hippocampus.51Despite the fact that the influence of the nucleus accumbens on the formation ofmemory has been little explored, some studies have implicated participation of thisarea both in spatial memory and associative memory by aversivestimulation.52Further, the increase in noradrenalin levels can lead to enhanced memoryperformance, whereas the blocking of noradrenergic receptors has the oppositeeffect, indicating an important role of noradrenalin in the processes of emotionalmemory.53The nucleus accumbens has a central region in its structure called the nucleus andanother denominated peripheral. The nuclear region receives noradrenergic afferentsoriginating from the Nucleus Tractus Solitarius (NTS) and also afferents from thehippocampus and amygdala, which process the newly acquired information. Theprojections from the basolateral nucleus of the amygdala provide affectivecomponents of experiences, and the projections from the region of the ventralsubiculum of the hippocampus supply information on the contextual characteristics ofthe environment. The noradrenalin released by the afferents of the Nucleus TractusSolitarius in the shell region of the nucleus accumbens exerts an importantmodulatory action on memory formation processes, regulating synaptic activity andfacilitating mnemonic processes.54 humans display greater activity incertain areas of the pre-frontal cortex depending on the type of reward. Sensoryrewards activate more posterior regions of the orbitofrontal cortex whilst abstractrewards tend to activate more anterior regions. Also, rewards tend to activatemedial regions of this cortex, proximal to the gyrus rectus, whereas aversivestimuli tend to activate more lateral regions of the orbitofrontal cortex. A studycarried out by Machizawa et al.55showed a strong relationship between the left inferior frontal gyrus and theformation of long-term memory, as well as the ventrolateral pre-frontal cortex andthe formation of these memories in humans.Both the amygdala and the nucleus accumbens are involved in the emotional processingwhich the information undergoes. The pre-frontal cortex belongs to this group,representing a region involved in the reward pathway which also receives afferentsfrom the nucleus accumbens. According to Haber & Knutson,53Besides the above-mentioned structures, the neurotransmission systems have direct orindirect action on memory processes. As cited earlier, noradrenalin has an importantrole in the formation of emotional memory in structures of the limbic system,interacting with cortisol during this process.56 Themajority of cholinergic efferents stem from the prosencephalic base by neurons ofthe medial septal nucleus, diagonal band, substantia innominata andbasal nucleus of Meynert.57 Theseneurons project to the hippocampus, neocortex, parts of the limbic system andamygdala to act in the modulation of processes involved in cognition, and theireffects are mediated by metabotropic muscarinic and nicotinic ionotropic receptors.A number of studies have shown the distribution of this receptor type in thehippocampus. its relationship with the formation of memories60 and induction of LTP.61 Acetylcholine also modulates glutamate release indopaminergic neurons in the VTA, which modulates the reward pathway.62Another neurotransmitter heavily involved in memory processes isacetylcholine.38 and in the Schaffer collateral and mossy fiberpathways.63LTP in the hippocampal is important for the formation of long-term memory andinvolves the activation of AMPA and NMDA receptors in synapses of pyramid cells inthe CA1 region of the hippocampus56 This processpromotes changes in synaptic transmission with long-term duration.During the initial process of LTP, phosphorylation of the AMPA receptors increasesits responsiveness for glutamate but during the maintenance phase of this process,new AMPA receptors are taken to the post-synaptic membrane and, later, due to theactivation of other mediators and signalling pathways, structural alterations andincreased synaptic contact occur.64 the duration of long-term memories differs among theperson's own memories and the mechanisms underlying this are not yet understood. Thecited author however, suggested that the effect of long-term aversive memory of ratsdisappeared after injection of a dopaminergic receptor antagonist (D1) into thedorsal hippocampus, some hours after the aversive stimuli. However,intra-hippocampal injection of a D1 antagonist under the same conditions as theprevious experiment resulted in the maintenance of the aversive memory. Theseeffects can be modulated by the brain-derived neurotrophic factor and regulated bythe ventral tegmental area (VTA), suggesting that the duration of these memoriesdepends on the dopaminergic connections between the VTA and hippocampus.The formation of memories is a slow and complex process for which any failure in anyof the mechanism results in non-continuity of the process and consequent loss ofinformation. According to Rossato et al.,56 In the mesolimbic and mesocortical pathways, cellularbodies are found in the mesencephalon and its fibers project into regions of thelimbic system, especially to the nucleus accumbens,65 amygdala and to pre-frontal cortex.56Dopamine is most abundant in the striated body, extrapyramidal motor system, someregions of the limbic system and hypothalamus.66dopamine plays a fundamental role in the modulation and performance of workingmemory, given the vast quantity of dopaminergic receptors found in the pre-frontalcortex. Behavioral studies have shown that blocking these receptors has adetrimental effect on working memory. Corroborating this notion, Cools etal.67 suggested thatsubjects with lower performance on a working memory task had less dopamine synthesisin the striatum, whereas individuals with high performance had greatersynthesis.According to Vijayraghavan,69found clinical evidence that patients with lesions in the hippocampus, or ablationof the structure, manifested serious problems consolidating declarative memory butnot non-declarative memory. The nucleus accumbens, together with other regions ofthe cortex, is involved in the consolidation of episodic and recognition memories,while the ventral striatum is important for consolidating declarative memory.The consolidation of memory can occur in other brain structures besides thehippocampus. Bermudez-RattoniAll these memory processes described above remain relatively stable during certainperiods of our lives. However, during the course of the aging process, somecognitive changes can occur on a physiological level.71 Therefore, memory is one of theabilities which declines with ageing. Nevertheless, the different types of memorycan decline in different ways. According to Yassuda,5 working, episodic and explicit memories undergogreatest decline. Although the underlying reasons for these changes remain unclear,Bertolucci72 suggested aninfluence of perceptual deficits, difficulties concentrating and attention, besidessluggishness in processing information.Cognition in humans can be understood as abilities such as memory attention,learning, calculus, language, besides the perceptual modalities plus functional andmotor executives.73indicated that the pre-frontal cortex is subject to the greatest volume changesduring the process of normal aging, with a mean reduction of 5% per decade from 20years of age, whereas the hippocampal decline is more marked at around 60 years ofage. Cognitive aging can be influenced by genetic and biological aspects, as well asfactors of a social and cultural nature, thus constituting a multifactorialeffect.74 Brain weightalso changes with a gradual reduction of around 10% between 20 and 90 years ofage.75In addition, Mattay et al.Some abilities of executive functions and also episodic memory undergo linear declinefrom the age of 20 years. However, accumulated experience can result in animprovement in semantic memory up to the age of 60.76 Therefore, the process ofnormal aging can result in both declines in some memory types yet enhancedperformance in others.Against this background, both national and international studies will now bedescribed documenting the neurobiological process of memory in normal aging.The literature search was performed using the terms "biology of memory", "memory andaging", "memory impairment", "elderly and memory", and their equivalent terms inPortuguese. The abstracts from this search were analysed to check whether they metinclusion and exclusion criteria.The inclusion criteria adopted were articles in Portuguese or English publishedbetween 2000 and 2011 held on the databases PsycInfo, PubMed, LILACS, SciELO orScienceDirect as well as book chapters, dissertations and theses that dealt withissues concerning memory and aging.Exclusion criteria adopted were studies without information describing the analysesperformed, and work financed by private enterprises (to avoid conflict ofinterest).in vitro trials and finally, 52 studies wereliterature reviews or book chapters which in our view, fell into this category.In the literature search, a total of 128 studies were initially retrieved  related to the main theme "memoryand aging". After applying the above-described inclusion and exclusion criteria, 102studies were selected for inclusion in this review. Of the studies surveyed, fivedealt with epidemiological and demographic issues, 12 were clinical trials i.e. werebased on testing and the application of instruments in human subjects, 33 studieswere basic research involving studies of mice, rats and non-human primates, andbiochemical and The biological bases underpinning memory formation involve the recruitment ofproteins that are common in many living organisms, human or otherwise. Asignificant difference among individuals can be ascribed to the memories ofexperiences acquired. In this process, the same proteins are activated andmobilized, albeit in different ways, to create traits and memory circuits uniqueto the individual. According to the perspective of Ramon and Cajal described in1883,9 memories are structural alterations in synapses that are distinct foreach memory, or type of memory, and can be modulated by emotions, level ofawareness and states of excitation.As occurs in all biological systems, from the conception of the individualthrough until old age, the central nervous system develops in such a way that,up to a given point, the organism increases neuroplasticity at a rapid rate(referred to as maturation). After reaching a given point in development , thisdeclines along with the ability to learn new information. In addition, theability to retrieve consolidated memories also begins to diminish.77 Amid thecomplexity of structures and neuronal systems recruited together andunconsciously, the retrieval of implicit memory apparently enhances itsconsolidation, rendering this type of memory longer lasting.There are however, some types of memory that apparently do not decline duringnormal aging. Healthy elderly for instance, do not forget how to write, read ormake a cup of coffee. These abilities are associated to implicit or proceduralmemory and are related to regions of the brain that integrate sensoryperceptions, emotional information and motor coordination. These abilitiesrecruit areas such as the neocortex, neostriatum, cerebellum andamygdala.78Explicit or declarative memory is a type of associative, conscious and flexiblememory. More labile than implicit memory, it relies on the hippocampal system,the efficacy of neuronal transmission and sometimes on conscious reinforcementof learning. While episodic memory is more vulnerable to the typicalneurobiological changes seen in aging, semantic memory seems to be betterpreserved. For example, in the context of semantic memory, studies show thatvocabulary increases throughout the life course, provided the individual is notafflicted by hypertension or other chronic diseases impairingcognition.79 Thistheory could be related to the sustaining of implicit memory.Some theories attempt to explain the maintenance of some memories as well as theloss of others. These theories are based on biological concepts such as theformation and maintenance of long-term potentiation and long-term depression(LTD). LTD tends to occur among parallel fibers and Purkinje cells in thecerebellum. Apparently, this pairing reduces the stimulus of inhibitory neuronsin deep cerebellar nuclei, increasing the stimulation of excitatory neuronsrooted in the cerebellum that then lead to the execution of amovement.LTP on the other hand, takes place in many brain areas and is the only model ofelectrophysiological change induced by stimuli which can last for days to weeksafter a brief afferent stimulation. Since they were first proposed to thepresent day, this process is the best and most widely accepted description todemonstrate long-term memory.80 Otherbrain regions involved in memory formation where the LTP process wasdemonstrated included cortex and septohippocampal projections.LTP is a specific kind of neuroplasticity which normally persists for longperiods. The formation of LTP in areas such as the hippocampus and amygdala isimportant for the constitution and maintenance of memories. However, humanssuffering significant damage to the medial temporal lobe (including the twoareas cited above) present serious changes in the memorization process. A famouscase illustrating this effect was the patient H.M, who was submitted tobilateral removal of the temporal lobes in an attempt to treat persistentepilepsy.83 Therefore,the loss in neuroplasticity seems to be related not to neuronal cell loss but todecline in the efficacy of LTP. This reduced efficacy of LTP can occur in any ofthe three memory formation processes, namely, it can be related to difficultiesin the learning, consolidation and retrieval of information.The formation of LTP and maintenance of memory depends more on the integrity ofthe neurons of the cerebral temporal lobes than their quantity. A common notionholds that significant neuronal loss is associated to aging, and can contributeto memory loss in elderly. This notion arises from the observation that neurondemise takes place as a result of diseases such as encephalic vascular strokesand other types of neurodegenerative diseases. Nevertheless, rigorous anatomicstudies have shown no significant loss in neuronal cells occur in the regions ofAmmon's horns (particularly CA1 and CA3) or in the dentate gyrus in thehippocampi of humans, monkeys, rats or mice during aging. Moreover, recentstudies have shown neurogenesis in structures related to the limbic system suchas the hippocampus, amygdala, cortex and striatum in the adult phase, a processconfirmed in a number of species of mammal.27The consolidation of immediate memory into long-term memory actively engages thehippocampus and entorhinal cortex and this, as explained earlier, is related tothe formation of LTP. Some authors emphasize that the medial temporal lobes donot comprise the final repository of memories but rather, are responsible forcoordinating the strengthening of neural connections. In fact, storage isrelated to specific processing sites during the perception of novel informationand is therefore interlinked with sensory areas.84The formation and maintenance of LTP requires cellular and molecular events whichresult in the induction, expression and consolidation of neuronal plasticity.Induction is initiated with cellular depolarization which can be reproducedexperimentally using tetanic type electrical stimulation . The resulting depolarizations aretransmitted along the length of the whole axon to reach the axon terminal. Atthis juncture, neurotransmitters are released and the chemical synapse isestablished. These stimulations connect proteins of the cytoskeleton such as theintegrins-actin system and changes in this system modify the density ofpost-synaptic dendritic spines.The stimulations occurring in these axon terminals promote stable changes in thecytoskeleton, which constitute consolidation of LTP, visible microscopically ascross-linking of actin filaments. After these events, an increase in receptordensity takes place (particularly glutamatergic) or the mobilization ofextra-synaptic areas to the dendritic spicules. This leads to stability ofpost-synaptic excitatory currents.4receptors. For a comprehensive review on this aspect of LTP, see Izquierdo etal.38The types of receptors recruited for the formation of LTP depend on the brainarea in which LTP is being formed. Thus, in the CA1 area of the hippocampus,NMDA type and metabotropic glutamatergic receptors are the target to commenceLTP. In the CA3 area, as well as in hippocampus and other areas, an NMDAindependent mechanism involving kainate receptors is used. In the amygdala, thelate phase of maintenance of LTP appears to depend on serotonin 5HT86The actin network is constantly modulated by endogenous factors that positivelyor negatively affect the production and maintenance of stable LTP. Positivemodulators include brain-derived neurotrophic factor (BDNF) and nerve growthfactor (NGF), besides some neurotransmitters such as serotonin, acetylcholine,cannabinoids and hormones e.g. corticosteroids and sexual hormones. Theneurotransmitter adenosine however, was described as a potent negative modulatorof LTP.In elderly individuals, the functionality of LPT can be affected by interferencein induction, expression or consolidation of the process, and also as a resultof a decline in positive modulators, or increase in negative modulators.However, no underlying mechanism has yet been defined for theseneuropharmacological alterations. For example, the reduction in renal depurationof extracellular adenosine was observed in elderly rats, which may contribute toa decline in LTP. Nonetheless, there is no consensus in the literatureconcerning the maintenance of the quantity of BDNF and NGF neurotrophins inelderly brain. Possible changes in the neurotransmitter systems andneuromodulators can influence the maintenance of LTP for new informationacquired at more advanced ages.Three basic characteristics have been postulated in a bid to better define thebasic mechanisms of short-term storage: it is transient; 2) it does not requireanatomic changes in order to be maintained; 3) it does not require new proteinsynthesis.Pharmacological trials using enzyme and genic transcription inhibitors revealedthat STM does not involve activation of transcription factors, gene expressionor protein synthesis, but does require activation of existing enzyme cascades.Therefore, evocation of this type of memory does not require complex changes inneural substrates of the pathways involved. These memories play an importantrole in keeping information present, when its definitive storage has yet to beprovided for (long-term memory).Briefly, the stages necessary for the formation of STM in the hippocampus,entorhinal cortex and posterior parietal cortex involve, besides mobilizingglutamatergic receptors, the positive modulation of cholinergic receptors(muscarinic and nicotinic), dopaminergic (D-1) and noradrenergic (β) andnegative modulation of GABAergic receptors.87In the hippocampus and entorhinal cortex, for the first 60 minutes afterlearning, the activation of calcium-dependent protein kinases (CDPKs) isnecessary, and in the ensuing 30 minutes, the hippocampus requires theparticipation of cAMP-dependent protein kinases (second intracellularmessenger). Despite CDPK involvement, no phosphorylation of cAMP responsiveelement binding protein 1 (CREB-1), a genic transcription factor, occurs i.e. noprotein transcription takes place.Given this mechanism relies on pre-existing intra-cellular pathways, STM is oftenspared in elderly. However, consolidation of new information in STM, a processwhich occurs between 6 and 8 hours after initial learning, is a processinvolving more stages, leading to LTP formation. In some elderly individualsthis process can be more compromised.An important component reinforcing consolidation of information is attention. Theamount of attention applied during the learning process leads not only toimproved codification of information but also positively influences itssubsequent retrieval. Neuroanatomical and electrophysiological studies show thatthe brain areas critically relating attention with memory consolidation are thepre-frontal and entorhinal cortex, which send out efferents to the hippocampus.Thus, the greater the stimulation and maintenance of attention, the greater thechances of a given item of information remaining permanently consolidated.For this description, it is assumed that attention depends on mental andemotional states. Some brain areas have been implicated in the modulation ofpleasurable or aversive emotions, which contribute greatly to the consolidationof information created during situations loaded with emotions. The amygdala forinstance, is a structure which encompasses more than ten nuclei forming theso-called amygdaloid complex.88Each nucleus receives projections from multiple brain regions such as cortex,thalamus, hypothalamus and encephalic trunk. The cortical and thalamic afferentsprovide information from sensory areas and memory-related structures. Since the amygdala hasaccess to all this newfound information and has projections extending tostructures of the limbic system, this creates the conditions conducive to makingassociations between current sensory afferents and past experiences.The basolateral complex of the amygdala is responsible for initiating associativelearning. Afferents which carry information regarding conditioned andnon-conditioned stimuli form the neocortex, thalamus and hippocampus converge inthis complex. Lesions to this structure hamper learning and the expression offear conditioning.30Fear conditioning occurs when a stimulus becomes associated with danger. In fearconditioning experiments, hitherto neutral conditioning stimuli (CS) becomeassociated with unconditioned aversive stimuli (US). CS can be a sound and/orlight whereas US a slight electrical stimulus to the paws. With time, CS aloneis able to create behavioral responses of defense or fear, such as freezing . Thus, this conditioning allows the animal to detect and avoidsituations that represent danger, an essential mechanism for survival. Thisbehavior is acquired quickly and is retained in memory for longperiods.In rats , the circuits mediating fear conditioning consist of afferents relatedto CS and US, which converge to the basolateral amygdala complex where theinformation is processed. The information is then carried to the central nucleusfrom which efferents protrude to the hypothalamus, resulting in the expressionof the fear response (such as freezing), autonomous response (such as rise inblood pressure and tachycardia), and endocrine response .50Recent studies have shown that LTP occurs within afferents transmitting CS to theamygdala, and that drugs interfering with this type of plasticity whenintroduced into the lateral amygdala, also affect fear conditioning. It hastherefore been suggested that LTP in this nucleus may represent a mechanism bywhich memories of CS-UC associations are stored. This hypothesis is alsosupported by the fact that, in the event of interruption in the synthesis ofproteins in the basolateral complex of the amygdala, no consolidation of fearconditioning memory takes place. This finding is consistent with the idea, nowwidely accepted, that the synthesis of proteins is essential for the conversionof short-term to long-term memory in neurons storing associativememories.89 described a case of declarative amnesia  after hemorrhage in the anterior portion of the basal ganglia region,more specifically the nucleus accumbens region. Other studies have reportedinvolvement in this area in spatial memory as well as associative memory,created by aversive stimuli.50 In fact, this nucleus receivesafferents from the pre-frontal cortex, hippocampus, amygdala, and thalamicnuclei. Together with the known involvement of the nucleus in the rewardpathway, it can be inferred that it has a role in the formation of memories,perhaps reinforced by pleasurable stimuli.In addition to memory enhancement through aversive stimuli, informationconsolidation can also be enhanced through pleasurable stimuli. The nucleusaccumbens plays a key role in this process. There is some evidence of theinfluence of the nucleus accumbens in the formation of memories in theliterature. In 1999, Goldenberg et al.91 This correlation was confirmed experimentally in youngand old animals submitted to enriched environments  that presentedbehavioral as well as morphological and functional changes in the centralnervous system.95 Hence, improved quality oflife with increased social interaction,98 physicalactivity,99 cognitivestimuli,100 sensorystimuli  and the adoption of a healthy balanceddiet can, even at older ages, lead to improvements in cognitive functions andmemory. Furthermore, these factors may also stimulate genic transcription orreduce their deactivation, which in turn can contribute to the maintenance ofLTP102 and declarativememories.The influence of emotions on the modulation of positive and negative factorstoward maintaining the efficacy of LTP, represent a broad field for research inneurosciences. The structural plasticity needed for the consolidation processand consequently, for memory retrieval (i.e. the formation of the cited LTPmechanism) is dependent on the development of the central nervous system, aprocess modulated throughout the life course by nutritional status, oxidativebalance, physical and cognitive activities, life style as well as mental states.The degree of LTP impairment during aging can also be influenced by the quantityand quality of stimuli which the brain is subjected to during the aging process.Indeed, individuals submitted to intellectual activities throughout the lifecourse have a lower probability of developing dementia.The present article sought to expound on the main biological aspects involved inthe processes of memory and aging. However, it should be noted this review wasunable to exhaustively cover all knowledge on the subject, since this themeinvolves a large array of different approaches. Pathological aspectscompromising memory were also not addressed since this was beyond the scope ofthe study. It should also be noted that some of the studies cited in thisarticle used animals and therefore generalization of findings to humans shouldbe done with caution. The aim of the study was to provide neurobiologicaldescriptions documented to date on the formation of memories. This field ofscience is still in its infancy, and the present study can serve to supportfuture investigations on the topic.


Here, we review the different methods that research groups have been investigating to create TEVGs in the last decades. We focus on the techniques employed in the manufacturing process of the grafts and categorize the approaches as scaffold-based  or self-assembled . Moreover, we highlight the attempts made so far to translate this new strategy from the bench to the bedside.Occlusive arterial disease, including coronary heart disease (CHD) and peripheral arterial disease (PAD), is the main cause of death, with an annual mortality incidence predicted to rise to 23.3 million worldwide by 2030. Current revascularization techniques consist of angioplasty, placement of a stent, or surgical bypass grafting. Autologous vessels, such as the saphenous vein and internal thoracic artery, represent the gold standard grafts for small-diameter vessels. However, they require invasive harvesting and are often unavailable. Synthetic vascular grafts represent an alternative to autologous vessels. These grafts have shown satisfactory long-term results for replacement of large- and medium-diameter arteries, such as the carotid or common femoral artery, but have poor patency rates when applied to small-diameter vessels, such as coronary arteries and arteries below the knee. Considering the limitations of current vascular bypass conduits, a tissue-engineered vascular graft (TEVG) with the ability to grow, remodel, and repair  Cardiovascular disease is the principal cause of death worldwide. Common manifestations are coronary heart disease (CHD) and peripheral arterial disease (PAD), which develop as a consequence of the critical atherosclerotic narrowing of supplying arteries. The worldwide annual incidence of deaths related to cardiovascular disease, is expected to rise to 23.3 million by 2030  interventions are recorded annually , Gore-Tex, and Dacron, prove to be effective when replacing large vessels. However, when used in the application of small-diameter vascular grafts, they were complicated by the occurrence of thrombotic occlusions  -based material and decellularized natural matrices.The scaffold-based approach represents the most diffuse strategy to build TEVGs. The popularity of this methodology is justified by the fact that the presence of physical support enables the cells to follow a pathway during their colonization and proliferation. As introduced previously, the study performed by Weinberg and Bell pioneered the development of the scaffold-based methodology which during the last 30 years, saw the introduction of many variables and the use of a great variety of manufacturing techniques and materials.Synthetic polymers have been widely used for the fabrication of TEVGs. The advantage is that the final properties of the graft can be tuned to meet the clinical needs, choosing the appropriate fabrication technique and specific material. However, the required higher level of technologies and the long period involved in the process of manufacturing constitute significant obstacles to clinical translation. Other prominant disadvantages shown by these materials are the lack of cell binding sites and the necessity to ensure an anti-thrombogenic property of the lumen, as required in the case of PLGA. A variety of polymers and copolymers have been tested. The most studied comprise degradable polyesters, like polyglycolic acid (PGA)   with a burst pressure of approximately 1313 mmHg, compliance of 1.7%/100 mmHg , but the strength of the anastomosis at the interface between the rat femoral artery and TEVG was still lower than the one between two portions of explanted rat femoral artery , the SG 100 SynerGraft® vascular graft,  and the already mentioned Artegraft . To improve the properties of these grafts, autologous ECs and VSMCs obtained from differentiation of bone marrow-derived cells were seeded in decellularized matrices and then tested in ovine  was the first to be assessed as a valid tissue source  approach. Self-assembled TEVGs are based on the concept that cells, placed in a 3D environment and with the right stimuli, would be able to organize themselves in a complex tissue. Currently, three main strategies have been investigated: cell-sheet assembly, micro-tissue aggregation, and cell printing Figure . DiffereIn the meantime, the scaffold-free engineered graft developed by L'Heureux et al., patented with the name of Cytograft , was used at the beginning of the 2000s in a clinical trial involving 10 patients that suffered from end-stage renal disease  is used as culturing surface, allowing the easy detachment of the cell aggregate when the culture is confluent  and to cellularize the scaffold in the pre-implantation stage. Autologous mature vascular cells, like VSMCs, ECs, and fibroblasts, have been used to cellularize TEVGs with success. Here, the main limitation is represented by the extraction from a patient biopsy, thereby leading to insufficient expansion (G et al., Owing to the growing target-population for tissue engineering technologies/products under development for cardiac and vascular indications, as well as the major healthcare costs associated with existing treatments, the potential financial figure for these products is in the range of multibillion-dollar volume. In the U.S. alone, the total potential market for tissue engineering and cell transplantation technologies is expected to exceed USD 22.8 billion in the year 2019. Furthermore, the global vascular graft market is expected to reach USD 3,626 million by 2022, according to a new study by Grand View Research, Inc. There is a positive prospect that rising healthcare expenditure, favorable reimbursement policies, and technological breakthroughs will boost growth in the vascular graft market over the next 10 years. At present, TEVGs contribute a minimal part of these financial figures, however, a number of positive factors indicate that this new technology will be successfully translated from research into medical practice.MC: searched the literature and drafted the manuscript; PM: critically revised the work.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.


Fibromyalgia is a complex chronic condition characterized by pain, physical fatigue, sleep disorder and cognitive impairment. Evidence-based guidelines recommend antidepressants as treatments of fibromyalgia where tricyclics are often considered to have the greatest efficacy, with amitriptyline often being a first-line treatment. Amitriptyline evokes a preferential reduction in pain and fatigue of fibromyalgia, and in the Fibromyalgia Impact Questionnaire (FIQ) score, which is a quality of life assessment. The multimodal profile of the mechanisms of action of amitriptyline include monoamine reuptake inhibition, receptor modulation and ion channel modulation. Several of the actions of amitriptyline on multiple nociceptive and sensory processes at central and peripheral locations have the potential to act cumulatively to suppress the characteristic symptoms of fibromyalgia. Greater understanding of the role of these mechanisms of action of amitriptyline could provide further clues to the pathophysiology of fibromyalgia and to a preferable pharmacological profile for future drug development. Fibromyalgia is a complex chronic condition characterized by widespread pain, physical fatigue, non-restorative sleep and cognitive impairment ,2. A higl-tryptophan and serotonin in blood are observed in patients with fibromyalgia compared to healthy controls [The evidence-based guidelines of the European League Against Rheumatism (EULAR) and the Association of Medical Scientific Societies in Germany (AWMF) recommend antidepressants, such as amitriptyline, duloxetine and milnacipran, as pharmacological therapies for fibromyalgia ,5,6. Altcontrols ,8.This review will focus on the pharmacology of amitriptyline that could be responsible for the benefits observed in the treatment of fibromyalgia.Serotonin reuptake transporters (SERT) and noradrenaline reuptake transporters (NET) are the main targets of antidepressants, such as tricyclic antidepressants , selective serotonin reuptake inhibitors , serotonin and noradrenaline reuptake inhibitors  and selective noradrenaline reuptake inhibitors . The affinities for monoamine reuptake transporters and selected neurotransmitter receptors of antidepressant drugs tested as treatments of fibromyalgia are summarized in The optimum analgesic action of antidepressants in the treatment of fibromyalgia, as with other chronic pain conditions, is usually achieved with a dose lower than that required to achieve mood enhancement indicative of intrinsic analgesic efficacy . AlthougOf the range of antidepressant classes , TCAs are often considered to have the greatest analgesic efficacy, with amitriptyline 10–50 mg/day) being recommended as a first-line treatment for fibromyalgia ,5,6. The0 mg/day A preferential outcome in the reduction of pain and fatigue associated with fibromyalgia and in the Fibromyalgia Impact Questionnaire (FIQ) score, which reflects a quality of life assessment, was observed with amitriptyline (10–100 mg/day) compared to the majority of other antidepressants ; Table 2N-methyl-d-aspartate (NMDA) and opioid receptors  which represent important intracellular effectors in the analgesic activity of TCAs [At therapeutic drug concentrations, amitriptyline also interacts with sodium, calcium and potassium channels. TCAs block open and inactivated states of sodium channels by binding to the local anaesthetic receptor, a property that may contribute to the analgesic efficacy in patients with fibromyalgia . Althoug of TCAs . Further of TCAs ,82.Dopamine deficiency in the CNS has also been implicated in the pathophysiology of fibromyalgia, with a decrease in dopamine concentration leading to central pain sensitization . There mA multimodal action of amitriptyline in fibromyalgia probably involves CNS and peripheral targets with contributory actions on receptors and ion channels in addition to monoamine reuptake inhibition.Treatment of fibromyalgia remains a major unmet medical need and optimal translation of current research to the clinic has been limited. Nociceptive signalling involves a range of receptors, mediators, cells, and physiological and genetic changes supporting the need to target multiple events to evoke effective control of the symptoms of diverse patients with fibromyalgia. Consequently, drugs that act through diverse mechanisms and that are given as combination therapy are often standard for the treatment of fibromyalgia ,5,6,87. The heterogeneity of fibromyalgia has led to the proposal of the existence of subgroups of patients ; however