Comparison of the Effects of Sensorimotor Rhythm and Slow Cortical Potential Neurofeedback in Epilepsy

Current conventional epilepsy treatments do not always aim to improve epilepsy comorbidities. For a treatment to be effective, is not necessary for it to keep the patient seizure-free; it is sufficient to show improvement in functions to help people who suffer from epilepsy to become more independent and productive in life. There is an urgent need to explore non- pharmaceutical/non-invasive interventions that can help in that regard. The earlier patients are treated with this condition, the more likely it is to prevent severe disabilities over time. Neurofeedback is a self-modulatory brain activity oscillatory intervention that previous researchers have found to reduce seizure frequency in patients with epilepsy. The aim of this work was to compare two Neurofeedback techniques that have shown some efficacy in improving symptoms in epilepsy. The novelty of this study is to explore further and included clinical, neurophysiological and cognitive outcomes in order to assess in more detail the effectiveness of epilepsy comorbidities. Forty-four patients, between the ages of 12 and 18 years, and diagnosed with focal epilepsy, divided randomly into three groups: sensorimotor rhythm (SMR) training, slow cortical potential (SCP) training, and control. The patients completed 25 sessions of intervention. The results showed that the SMR group training had an advantage in improving reaction time compared with SCP and control. Regression analysis revealed a significant correlation between the patients who learned to modify their brain activity in the SMR group and improving reaction time in two different tasks. In addition, the quality of life scale significantly improved in all three groups. The study supplies preliminary data to support that SMR neurofeedback training as an intervention should further be explored as a therapeutic option for children who suffer from focal epilepsy.CONACYT (Mexican Council of science and technology

Contributions to the Development of Objective Techniques for Presence Measurement in Virtual Environments by means of Brain Activity Analysis

En esta tesis, se propone el uso de la técnica de Doppler transcraneal (DTC) para monitorizar la actividad cerebral durante la exposición a entornos virtuales (EV) y así poder analizar los correlatos cerebrales del sentido de presencia. Las hipótesis de partida son las siguientes: 1) DTC se podrá utilizar fácilmente en combinación con sistemas de realidad virtual. 2) Los datos de velocidad de flujo sanguíneo medidos por DTC se podrán utilizar para analizar cambios de actividad cerebral durante la exposición a EV. 3) Habrá diferencias en la velocidad del flujo sanguíneo asociadas a distintos niveles de presencia. 4) Habrá correlación entre el grado de presencia medido por cuestionarios y parámetros de la velocidad de flujo sanguíneo. 5) Cada componente de la experiencia virtual tendrá una influencia en las variaciones de velocidad observadas. Para analizar las hipótesis planteadas, se realizaron cuatro experimentos distintos, en los que se analizó la velocidad del flujo sanguíneo durante: 1) distintas condiciones de navegación, 2) distintas condiciones de inmersión, 3) una tarea de percepción visual y 4) tareas motoras para manejo de un joystick. Durante la tesis, se han propuesto distintas técnicas de procesado de señal basadas en análisis espectral y en la obtención parámetros no lineales de la señal, que no habían sido utilizadas previamente en experimentos psicofisiológicos con DTC. Se ha observado que existe un incremento en la velocidad del flujo sanguíneo durante la exposición a un EV, el cual puede deberse a distintos factores que intervienen en la experiencia: tareas de interacción visuoespacial, tareas de atención, la creación y ejecución de un plan motor, cambios emocionales Los análisis han mostrado que existen correlaciones significativas entre la velocidad media de flujo sanguíneo en las arterias cerebrales medias durante la exposición al EV y respuestas a los cuestionarios de presencia utilizados.Rey Solaz, B. (2010). Contributions to the Development of Objective Techniques for Presence Measurement in Virtual Environments by means of Brain Activity Analysis [Tesis doctoral no publicada]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/8505Palanci

Effectiveness of intensive physiotherapy for gait improvement in stroke: systematic review

Introduction: Stroke is one of the leading causes of functional disability worldwide. Approximately 80% of post-stroke subjects have motor changes. Improvement of gait pattern is one of the main objectives of physiotherapists intervention in these cases. The real challenge in the recovery of gait after stroke is to understand how the remaining neural networks can be modified, to be able to provide response strategies that compensate for the function of the affected structures. There is evidence that intensive training, including physiotherapy, positively influences neuroplasticity, improving mobility, pattern and gait velocity in post-stroke recovery. Objectives: Review and analyze in a systematic way the experimental studies (RCT) that evaluate the effects of Intensive Physiotherapy on gait improvement in poststroke subjects. Methodology: Were only included all RCT performed in humans, without any specific age, that had a clinical diagnosis of stroke at any stage of evolution, with sensorimotor deficits and functional gait changes. The databases used were: Pubmed, PEDro (Physiotherapy Evidence Database) and CENTRAL (Cochrane Center Register of Controlled Trials). Results: After the application of the criteria, there were 4 final studies that were included in the systematic review. 3 of the studies obtained a score of 8 on the PEDro scale and 1 obtained a score of 4. The fact that there is clinical and methodological heterogeneity in the studies evaluated, supports the realization of the current systematic narrative review, without meta-analysis. Discussion: Although the results obtained in the 4 studies are promising, it is important to note that the significant improvements that have been found, should be carefully considered since pilot studies with small samples, such as these, are not designed to test differences between groups, in terms of the effectiveness of the intervention applied. Conclusion: Intensive Physiotherapy seems to be safe and applicable in post-stroke subjects and there are indications that it is effective in improving gait, namely speed, travelled distance and spatiotemporal parameters. However, there is a need to develop more RCTs with larger samples and that evaluate the longterm resultsN/

End points for sickle cell disease clinical trials: patient-reported outcomes, pain, and the brain

To address the global burden of sickle cell disease (SCD) and the need for novel therapies, the American Society of Hematology partnered with the US Food and Drug Administration to engage the work of 7 panels of clinicians, investigators, and patients to develop consensus recommendations for clinical trial end points. The panels conducted their work through literature reviews, assessment of available evidence, and expert judgment focusing on end points related to: patient-reported outcomes (PROs), pain (non-PROs), the brain, end-organ considerations, biomarkers, measurement of cure, and low-resource settings. This article presents the findings and recommendations of the PROs, pain, and brain panels, as well as relevant findings and recommendations from the biomarkers panel. The panels identify end points, where there were supporting data, to use in clinical trials of SCD. In addition, the panels discuss where further research is needed to support the development and validation of additional clinical trial end points

Changes in Cortical Activity in Stroke Survivors Undergoing Botulinum Toxin Therapy for Treatment of Focal Spasticity

Functional magnetic resonance imaging (fMRI) has provided evidence of neuroplastic changes following rehabilitation in stroke survivors. Botulinum toxin (BoNT) injection therapy has become a common approach to combating spasticity—a motor disorder characterized by a velocity dependent increase in muscle tone. The neurotoxin acts to inhibit muscle contraction, relieving spasticity symptoms with peak effects occurring between 4 and 6 weeks. With decreases in muscle tone, BoNT injections could free arm movement for rehabilitation, creating the opportunity for enhanced control of the upper limb, which would have underpinnings in altered brain activity. Given evidence of cortical activation changes following other stroke rehabilitative methods, it is expected that BoNT therapy would produce similar types of changes. The aim of this study was to quantify changes in task-related activity throughout the brain in stroke survivors undergoing BoNT therapy. Understanding the changes in cortical activity resulting from BoNT injections could help improve rehabilitation methods and predict functional outcome. Changes in cortical activation in response to BoNT injections have only been documented in a handful of studies. Of these past studies, participant pools tended to include patients with moderate to high functional ability of the affected limb. Although patients receiving BoNT injections often fall within a wide range of severity, BoNT injections have been shown to provide the biggest impact on the highly impaired population. BoNT injections have also been shown to provide greatest effects during the initial injections, and the effects on long-term spasticity treatment are less prevalent in the literature. In this study, we used a voxel-based approach to quantify neuroplastic effects and capture changes in activity throughout the brain, including regions outside the primary sensorimotor cortices. We recruited a majority of participants that presented with severe spasticity, who were scheduled to receive a round of BoNT injections as part of their standard of care. By assessing the brain activation associated with repeated injections, we obtained insight into BoNT on a long-term basis, as it is traditionally prescribed

Contextual factors, placebo and nocebo effects in physical therapy: clinical relevance and impact on research

A brief overview on placebo and nocebo effects Placebo and nocebo effects represent one of the most fascinating topics in the healthcare field. They represent complex and distinct psychoneurobiological phenomena where behavioural and neurophysiological changes occur during an interaction between the patient and the healthcare context (1). Placebo effects (Latin \u201cI shall please\u201d) are produced by a psychosocial context that is capable of positively affecting the patient's brain and therapeutic outcomes (2-4). On the contrary, nocebo effects (Latin \u201cI shall harm\u201d) are consequences of the negative perception of the ritual and therapeutic act on the patient's mind and body, so much so that it generates unwanted effects and side effects (5-7). Throughout the history of medicine, placebo and nocebo have been traditionally viewed as bothersome variables to check for in a clinical trial. In the last four decades, in light of some significant clinical and laboratory findings, they have become a source of research interest. Indeed, placebo and nocebo have been adopted as a conceptual model to examine the body-mind interaction and the human body systems, exploring their connection with different systems, mechanisms, diseases and therapeutic interventions (8, 9). In particular, placebo and nocebo effects have been studied in mood (10), cardiovascular, respiratory (11), gastrointestinal (12, 13), motor (14), immune and endocrine (15), and pain systems (16-18). Clinically, not all improvement or aggravation of patients\u2019 symptoms is due to placebo and nocebo effects. It is necessary to rule out the patients\u2019 modifications created by placebo and nocebo effects from the changes of outcomes related to other confounding elements. The elements which could create misinterpretations of the patients\u2019 clinical picture are: the spontaneous remission of the disease and symptom fluctuation (also called the natural history), the regression to the mean (a statistical phenomenon caused by selection biases), the patient\u2019s and clinician\u2019s biases during the reports of clinical conditions, and unidentified effects of concomitant co-interventions (8, 9). Different psychoneurobiological findings allowed the scientific community to begin to understand the underlying mechanisms of placebo and nocebo effects. From a theoretical perspective, two main psychological subjective constructs have been suggested to explain how placebo or nocebo effects act: the expectation and the conditioning. The social learning, reward, anxiety reduction, desire, motivation, memory, somatic focus, genetic and personality traits also represent alternative theories (19-25). \u201cAlternative\u201d however does not mean that these psychological mechanisms are mutually exclusive: they can interact simultaneously (26). Regarding the actual findings, placebo and nocebo interact with the brain modulatory systems at a neurochemical level, through the release of specific neurotransmitters. For instance, considering pain outcome as a model, the endogenous opioids, dopamine, cannabinoids, oxytocin and vasopressin are involved in placebo analgesia, while cholecystokinin, dopamine, opioid deactivation and cyclooxygenaseprostaglandins activation are implicated in nocebo hyperalgesia (27-29). Furthermore, recent advances in neuroimaging techniques, such as functional magnetic resonance imaging (fMRI) and positron emission tomography (PET), suggest an involvement of specific neural correlates during placebo and nocebo effects, mainly the pain one. In fact, placebo and nocebo are able to activate or deactivate the four key brain regions commonly associated with the descending pain processing pathway: the dorsolateral prefrontal cortex, the rostral anterior cingulate cortex, the periaqueductal gray and the dorsal horn of spine (16). Nevertheless, they represent only a part of brain areas showing a change in their activity during placebo or nocebo (30-32). Therefore, the previously described evidence suggests that placebo and nocebo effects are concrete and genuine phenomena, triggered by different contexts, and capable of impacting the patients\u2019 brain. It is necessary to define what the context is, and why its parts are important from a clinical perspective (33). The healthcare context as a trigger of placebo and nocebo effects In 1955 Balint described the context as the \u201cwhole atmosphere around the therapy\u201d (34). The context is not a vacuum, but it embodies a healing space composed by internal, external and relational elements capable of interacting with the patient\u2019s disease (35). The internal elements consist of memories, emotions, expectations and psychological characteristics of the patient. The external elements include the physical aspects of therapy, such as the kind of treatment (pharmacological or manual) and the place in which the treatment is delivered. Relational elements are represented by all the social cues that characterize the patient-clinician relationship, such as the verbal information that the clinicians give to the patient, the communication style or the body language (36). In 2001, Di Blasi et al. defined these elements as \u201ccontextual factors\u201d. These factors have been grouped, from a clinical practice point of view, in five categories: a) clinician features, b) patient features, c) patient-clinician relationship, d) intervention features, and e) healthcare setting features (37). As a whole, contextual factors constitute the therapeutic ritual and healing symbols surrounding the patient-clinician encounter, capable of producing changes in the patient at perceptual, neurophysiological and cognitive levels (38). Indeed, contextual factors convey a hidden meaning, actively detected and analysed by the patient, which is essential for the perception of care and the interpretation of the therapeutic intervention (39, 40). When these contextual stimuli and cues are filtered by the patient\u2019s perspective and mind-set (41), they are translated into a complex cascade of psycho-neuroimmunoendocrine events, thus triggering placebo and nocebo effects and influencing the course of illness (42, 43). From a clinical perspective, the contextual factors pervade every healthcare action (history taking, physical examination, therapy and prognosis) and directly affect the quality of the health-related outcome (44-46). A positive context, that is characterized by the presence of positive contextual factors, can improve therapeutic outcome by producing placebo effects, while a negative context, characterized by the presence of negative contextual factors, can aggravate therapeutic outcome by creating nocebo effects(47, 48). For example, during the same treatment delivery (e.g. painkillers), the use of positive verbal suggestion (e.g. \u201cThis therapy will help you and it will decrease pain\u201d) can improve musculoskeletal pain, while the adoption of verbal suggestion of uncertainty (e.g. \u201cThis therapy could help you and sometimes it decrease pain\u201d) can aggravate patient\u2019s pain (49). The presented studies offer a starting point for reflection about the role of the contextual factors surrounding the administration of a healthcare treatment: they can be a source of improvement of the efficacy of the therapy or implicated in the manifestation of adverse effects. The logical consequence is to wonder whether context, placebo and nocebo effects have been taken into consideration in a specific healthcare field, such as physical therapy. The link between placebo, nocebo effects and physical therapy Throughout the history of physical therapy and rehabilitation, placebo and nocebo effects have been considered as problematic phenomena for two main reasons. From a research point of view, they have represented confounding factors capable of limiting the internal validity of the study design and reducing the external validity of the findings (50). From a clinical point of view, they have embodied troublesome and nonspecific variables able to attenuate the therapeutic role of specific therapies such as massage, joint mobilization and therapeutic exercise (51, 52). As a consequence, for many years the role of placebo and nocebo effects was debated worldwide by clinicians and researchers (53-55). At the end of the first decade of the twenty-first century the scientific community began to investigate the mechanisms of action of joint, soft tissue and neural therapeutic intervention, consequently revaluing the role of placebo and nocebo effects in physiotherapy (56). Recent studies have suggested a mechanical and neurophysiological mechanism (peripheral, spinal and supraspinal) linked to the therapeutic strategies adopted by physical therapists (57). Among the supraspinal mechanisms, the placebo and nocebo effects have assumed an important top-down role in inducing changes in patient\u2019s symptoms (58), thus becoming elements that clinicians should adopt in clinical practice (59). Recently, also the context in which interventions are delivered has been suggested as a moderator of clinical effects (60). A new line of research has indicated the context as responsible for a larger non-specific component of treatment efficacy in physical therapy (61). Despite these promising advances, the following issues remain unexplored: 1) What are the contextual factors? 2) How can the contextual factors trigger placebo and nocebo effects? 3) Which therapeutic outcomes can be influenced by the contextual factors? 4) Are the physical therapists aware of the use of contextual factors in clinical practice? 5) What is the role of contextual factors in research? General organization of the research project The main goal of this PhD research project is to investigate the relevance of the contextual factors as triggers of placebo/nocebo effects and their impact on therapeutic outcomes in physiotherapy. Different studies were conducted during the 3-year period of PhD training (2015-2018). The results, relative discussions and implications are reported in the chapters of the present dissertation as follows: \u2022 Chapter I: a conceptual model regarding the role of the contextual factors as triggers of placebo, nocebo responses and influencers of physical therapy outcomes; \u2022 Chapter II: the model of contextual factors regarding musculoskeletal pain, which is a common outcome encountered by physical therapists; \u2022 Chapter III: the link between the determinants of patient satisfaction in outpatient musculoskeletal physiotherapy clinics and the contextual factors; \u2022 Chapter IV: the knowledge, attitude and behaviour of Italian physiotherapists specialized in manual therapy towards contextual factors; \u2022 Chapter V: the translational value of contextual factors and their relevance for physical therapy research