Oscillatory network markers of subcallosal cingulate deep brain stimulation for depression.

Identifying functional biomarkers related to treatment success can aid in expediting therapy optimization, as well as contribute to a better understanding of the neural mechanisms of the treatment-resistant depression (TRD) and subcallosal cingulate deep brain stimulation (SCC-DBS). Magnetoencephalography data were obtained from 16 individuals with SCC-DBS for TRD and 25 healthy subjects. The first objective of the study was to identify region-specific oscillatory modulations that both (i) discriminate individuals with TRD (with SCC-DBS OFF) from healthy controls, and (ii) discriminate TRD treatment responders from non-responders (with SCC-DBS ON). The second objective of this work was to further explore the effects of stimulation intensity and frequency on oscillatory activity in the identified brain regions of interest. Oscillatory power analyses led to the identification of brain regions that differentiated responders from non-responders based on modulations of increased alpha (8-12 Hz) and decreased gamma (32-116 Hz) power within nodes of the default mode, central executive, and somatomotor networks, Broca's area, and lingual gyrus. Within these nodes, it was also found that low stimulation frequency had stronger effects on oscillatory modulation than increased stimulation intensity. The identified functional network biomarkers implicate modulation of TRD-related activity in brain regions involved in emotional control/processing, motor control, and the interaction between speech, vision, and memory, which have all been implicated in depression. These electrophysiological biomarkers have the potential to be used as functional proxies for therapy optimization. Additional stimulation parameter analyses revealed that oscillatory modulations can be strengthened by increasing stimulation intensity or reducing frequency, which may represent potential avenues of direction in non-responders.

Evaluación funcional tras SARS-CoV-2 crítico. Estudio de cohortes de la unidad de rehabilitación en un hospital de tercer nivel / Functional evaluation in patient with critical SARS-CoV-2 disease: Cohort study in a third level hospital rehabilitation unit

Introducción: La neumonía por SARS-CoV-2 es una enfermedad infecciosa respiratoria altamente contagiosa que causa disfunción respiratoria, física y psicológica. Presentamos resultados de los pacientes valorados por el Servicio de Rehabilitación al alta de UCI por SARS-CoV-2. Material y método: Estudio de cohortes de pacientes ingresados en UCI por neumonía por SARS-CoV-2 desde el 01/10/2020 al 31/07/2021. Recogemos datos sociodemográficos, antecedentes personales, estancia media en UCI y hospital, Barthel, marcha (FAC) y mMRC (preingreso/valoración inicial/alta), desarrollo de patología osteomuscular y/o neurológica y necesidad de tratamiento rehabilitador. Resultados: Muestra de 341 pacientes de los cuales 224 cumplen criterios. Edad media: 63 años (68,75% hombres). Estancia media UCI/hospital: 27/44 días. Valorados por médicos rehabilitadores, facilitamos a los pacientes una guía elaborada por el equipo médico resolviendo dudas del proceso y pautando ejercicios de intensidad y dificultad progresiva, a realizar durante el ingreso y en el domicilio. El 42,86% desarrolló patología neurológica (83,33% del sistema nervioso periférico). El 100% ha realizado fisioterapia respiratoria y el 72,32% ha precisado fisioterapia motora. Conclusiones: En nuestro estudio, un elevado número de pacientes han precisado tratamiento rehabilitador para su recuperación funcional, destacando el desarrollo de patología neurológica post-COVID. El SARS-CoV-2 genera otras complicaciones, no solo respiratorias, subsidiarias de valorarse y tratarse por los Servicios de Rehabilitación para una recuperación integral que minimice las secuelas.(AU)

Introduction: SARS-COV-2 pneumonia is a highly contagious respiratory disease that causes respiratory, physical and psychological dysfunctions. We present the results of patient assessment when they were discharged from the ICU. Material and method: Cohort study of patients affected by SARS-COV-2 pneumonia admitted to the intensive care unit from 01/10/2020 to 31/07/2021. We collect sociodemographic data, personal history, ICU and hospital stay, Barthel, FAC and mMRC (pre-admission/initial assessment/discharge), development of osteomuscular and/or neurological pathology and need for rehabilitation treatment. Results: A total of 341 patients were evaluated, of which 224 met criteria. The average age was 63 years (68.75% men). Mean ICU/hospital stay were 27/44 days. They were assessed by physiatry, after that, we provide a guide developed by physiatry, solving doubts about the disease and setting exercises of intensity and progressive difficulty, to be carried out during the admission and at home. Neurological pathology was present at 42.86% patients, of whom a 83.33% were peripheral nervous system disease. The total of the sample needed respiratory physiotherapy and a 72.32% motor physiotherapy. Conclusions: In our study, a high number of patients have needed rehabilitation treatment in order to get functional recovery, highlighting the development of post-COVID neurological pathology. SARS-COV-2 generates other complications, not only respiratory, subsidiary to be assessed and treated by rehabilitation services for a comprehensive recovery that minimizes sequelae.(AU)

[Functional evaluation in patient with critical SARS-CoV-2 disease: Cohort study in a third level hospital rehabilitation unit]. / Evaluación funcional tras SARS-CoV-2 crítico. Estudio de cohortes de la unidad de rehabilitación en un hospital de tercer nivel.

INTRODUCTION: SARS-COV-2 pneumonia is a highly contagious respiratory disease that causes respiratory, physical and psychological dysfunctions. We present the results of patient assessment when they were discharged from the ICU. MATERIAL AND METHOD: Cohort study of patients affected by SARS-COV-2 pneumonia admitted to the intensive care unit from 01/10/2020 to 31/07/2021. We collect sociodemographic data, personal history, ICU and hospital stay, Barthel, FAC and mMRC (pre-admission/initial assessment/discharge), development of osteomuscular and/or neurological pathology and need for rehabilitation treatment. RESULTS: A total of 341 patients were evaluated, of which 224 met criteria. The average age was 63 years (68.75% men). Mean ICU/hospital stay were 27/44 days. They were assessed by physiatry, after that, we provide a guide developed by physiatry, solving doubts about the disease and setting exercises of intensity and progressive difficulty, to be carried out during the admission and at home. Neurological pathology was present at 42.86% patients, of whom a 83.33% were peripheral nervous system disease. The total of the sample needed respiratory physiotherapy and a 72.32% motor physiotherapy. CONCLUSIONS: In our study, a high number of patients have needed rehabilitation treatment in order to get functional recovery, highlighting the development of post-COVID neurological pathology. SARS-COV-2 generates other complications, not only respiratory, subsidiary to be assessed and treated by rehabilitation services for a comprehensive recovery that minimizes sequelae.

Does conventional early life academic excellence predict later life scientific discovery? An assessment of the lives of great medical innovators.

BACKGROUND: Perhaps, as never before, we need innovators. With our growing population numbers, and with increasing pressures on our education systems, are we in danger of becoming more rigid and formulaic and increasingly inhibiting innovation? When young can we predict who will become the great innovators? For example, in medicine, who will change clinical practice? AIMS: We therefore determined to assess whether the current academic excellence approach to medical school entrance would have captured previous great innovators in medicine, assuming that they should all have well fulfilled current entrance requirements. METHODS: The authors assembled a list of 100 great medical innovators which was then approved, rejected or added to by a jury of 12 MD fellows of the Royal Society of Canada. Two reviewers, who had taken both the past and present Medical College Admission Test as part of North American medical school entrance requirements, independently assessed each innovator's early life educational history in order to predict the innovator's likely success at medical school entry, assuming excellence in all entrance requirements. RESULTS: Thirty-one percent of the great medical innovators possessed no medical degree and 24% would likely be denied entry to medical school by today's standards (e.g. had a history of poor performance, failure, dropout or expulsion) with only 24% being guaranteed entry. Even if excellence in only one topic was required, the figure would only rise to 41% certain of medical school entry. CONCLUSION: These data show that today's medical school entry standards would have barred many great innovators and raise questions about whether we are losing medical innovators as a consequence. Our findings have important implications for promoting flexibility and innovation for medical education, and for promoting an environment for innovation in general.

Synaptic activity protects against AD and FTD-like pathology via autophagic-lysosomal degradation.

Changes in synaptic excitability and reduced brain metabolism are among the earliest detectable alterations associated with the development of Alzheimer's disease (AD). Stimulation of synaptic activity has been shown to be protective in models of AD beta-amyloidosis. Remarkably, deep brain stimulation (DBS) provides beneficial effects in AD patients, and represents an important therapeutic approach against AD and other forms of dementia. While several studies have explored the effect of synaptic activation on beta-amyloid, little is known about Tau protein. In this study, we investigated the effect of synaptic stimulation on Tau pathology and synapses in in vivo and in vitro models of AD and frontotemporal dementia (FTD). We found that chronic DBS or chemically induced synaptic stimulation reduced accumulation of pathological forms of Tau and protected synapses, while chronic inhibition of synaptic activity worsened Tau pathology and caused detrimental effects on pre- and post-synaptic markers, suggesting that synapses are affected. Interestingly, degradation via the proteasomal system was not involved in the reduction of pathological Tau during stimulation. In contrast, chronic synaptic activation promoted clearance of Tau oligomers by autophagosomes and lysosomes. Chronic inhibition of synaptic activity resulted in opposite outcomes, with build-up of Tau oligomers in enlarged auto-lysosomes. Our data indicate that synaptic activity counteracts the negative effects of Tau in AD and FTD by acting on autophagy, providing a rationale for therapeutic use of DBS and synaptic stimulation in tauopathies.

Past, present, and future of Parkinson's disease: A special essay on the 200th Anniversary of the Shaking Palsy.

This article reviews and summarizes 200 years of Parkinson's disease. It comprises a relevant history of Dr. James Parkinson's himself and what he described accurately and what he missed from today's perspective. Parkinson's disease today is understood as a multietiological condition with uncertain etiopathogenesis. Many advances have occurred regarding pathophysiology and symptomatic treatments, but critically important issues are still pending resolution. Among the latter, the need to modify disease progression is undoubtedly a priority. In sum, this multiple-author article, prepared to commemorate the bicentenary of the shaking palsy, provides a historical state-of-the-art account of what has been achieved, the current situation, and how to progress toward resolving Parkinson's disease. © 2017 International Parkinson and Movement Disorder Society.

Lack of depotentiation at basal ganglia output neurons in PD patients with levodopa-induced dyskinesia.

Parkinson's disease (PD), characterized by the loss of dopaminergic nigrostriatal projections, is a debilitating neurodegenerative disease which produces bradykinesia, rigidity, tremor and postural instability. The dopamine precursor levodopa (L-Dopa) is the most effective treatment for the amelioration of PD signs and symptoms, but long-term administration can lead to disabling motor fluctuations and L-Dopa-induced dyskinesias. In animal models of PD, a form of plasticity called depotentiation, or the reversal of previous potentiation, is selectively lost after the development of dyskinetic movements following L-Dopa treatment. We investigated whether low frequency stimulation (LFS) in the globus pallidus internus (GPi) and substantia nigra pars reticulata (SNr) could induce depotentiation at synapses that had already undergone high frequency stimulation (HFS)-induced potentiation. To do so, we measured the field potentials (fEPs) evoked by stimulation from a nearby microelectrode in 28 patients undergoing implantation of deep brain stimulating (DBS) electrodes in the subthalamic nucleus (STN) or GPi. We found that GPi and SNr synapses in patients with less severe dyskinesia underwent greater depotentiation following LFS than in patients with more severe dyskinesia. This demonstration of impaired depotentiation in basal ganglia output nuclei in PD patients with dyskinesia is an important validation of animal models of levodopa-induced dyskinesia. The ability of a synapse to reverse previous potentiation may be crucial to the normal function of the BG, perhaps by preventing saturation of the storage capacity required in motor learning and optimal motor function. Loss of this ability at the output nuclei may underlie, or contribute to the cellular basis of dyskinetic movements.

Reduced paired pulse depression in the basal ganglia of dystonia patients.

Decreased inhibition and aberrant plasticity are key features in the pathophysiology of dystonia. Impaired short interval cortical inhibition and resultant increased excitability have been described for various forms of dystonia using paired pulse methods with transcranial magnetic stimulation of motor cortex. It is hypothesized that, in addition to cortical abnormalities, impairments in basal ganglia function may lead to dystonia but a deficit of inhibition within the basal ganglia has not been demonstrated to date. To examine the possibility that impaired inhibition and synaptic plasticity within the basal ganglia play a role in dystonia, the present study used a pair of microelectrodes to test paired pulse inhibition in the globus pallidus interna (GPi) and substantia nigra pars reticulata (SNr) of dystonia and PD patients undergoing implantation of deep brain stimulating (DBS) electrodes. We found that there was less paired pulse depression of local field evoked potentials in the basal ganglia output nuclei of dystonia patients compared with Parkinson's disease patients on dopaminergic medication. Paired pulse depression could be restored following focal high frequency stimulation (HFS). These findings suggest that abnormalities exist in synaptic function of striatopallidal and/or striatonigral terminals in dystonia patients and that these abnormalities may contribute to the pathophysiology of dystonia, either independent of, or in addition to the increased excitability and plasticity observed in cortical areas in dystonia patients. These findings also suggest that HFS is capable of enhancing striatopallidal and striatonigral GABA release in basal ganglia output nuclei, indicating a possible mechanism for the therapeutic benefits of DBS in the GPi of dystonia patients.

Deep brain stimulation effects on memory.

As the population of many countries ages, disorders of cognition and memory-such as Alzheimer's Disease (AD) and dementia associated with Parkinson's Disease-will become a major societal burden. At present, few effective medical therapies against these conditions are available. Deep brain stimulation (DBS) may be a potential therapeutic option, because it can directly target and modulate the activity of structures implicated in circuits subserving memory function. In this article, we review the scientific literature to address some of the mechanisms by which DBS may impact memory and cognition. We then summarize the results of recent clinical experience with DBS in AD and Parkinsonian dementia.

A psychiatric primer for the functional neurosurgeon.

There is increasing attention in the neurosurgical literature towards surgery, specifically deep brain stimulation (DBS), for psychiatric indications. Several positive trials have spurred intense investigation and research in this area, owing to rapid advances in the neurosciences. As a result, the scope of neurosurgical practice is evolving to now include disorders that weren't traditionally in the purview of the average functional neurosurgeon. Further, functional neurosurgeons are now being charged with taking care of patients as part of a multi-disciplinary group that includes psychologists and psychiatrists. As DBS for psychiatry continues to evolve, and as further indications are explored, it is incumbent on neurosurgeons who treat these disorders to familiarize themselves with current standards of diagnosis and treatment. Just as the movement disorder surgeon should be familiar with the biology, physiology, diagnosis and treatment of Parkinson's disease, so they should become familiar with similar aspects of commonly referred psychiatric conditions. Specifically, much of the interest in the DBS literature currently surrounds major depression, obsessive-compulsive disorder and Tourette's syndrome. Here, we review the epidemiology, diagnostic criteria, hypothesized neurocircuitry and current treatments, both medical and surgical of each of these conditions to serve as a centralized, introductory primer for the practicing functional neurosurgeon.

Subthalamic deep brain stimulation at individualized frequencies for Parkinson disease.

OBJECTIVES: The oscillation model of Parkinson disease (PD) states that, in the subthalamic nucleus (STN), increased θ (4-10 Hz) and ß (11-30 Hz) frequencies were associated with worsening whereas γ frequencies (31-100 Hz) were associated with improvement of motor symptoms. However, the peak STN frequency in each band varied widely from subject to subject. We hypothesized that STN deep brain stimulation (DBS) at individualized γ frequencies would improve whereas θ or ß frequencies would worsen PD motor signs. METHODS: We prospectively studied 13 patients with PD. STN local field potential (LFP) was recorded after electrode implantations, in the OFF and then in ON dopaminergic medication states while patients performed wrist movements. Six individual peak frequencies of the STN LFP power spectra were obtained: the greatest decrease in θ and ß and greatest increase in γ frequencies in the ON state (MED) and during movements (MOVE). Eight DBS frequencies were applied including 6 MED and MOVE frequencies, high frequency (HF) used for chronic stimulation, and no stimulation. The patients were assessed using the motor Unified Parkinson's Disease Rating Scale (mUPDRS). RESULTS: STN DBS at γ frequencies (MED and MOVE) and HF significantly improved mUPDRS scores compared to no stimulation and both γ frequencies were not different from HF. DBS at θ and ß frequencies did not worsen mUPDRS scores compared to no stimulation. CONCLUSION: Short-term administration of STN DBS at peak dopamine-dependent or movement-related γ frequencies were as effective as HF for reducing parkinsonian motor signs but DBS at θ and ß frequencies did not worsen PD motor signs. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that STN DBS at patient-specific γ frequencies and at usual high frequencies both improved mUPDRS scores compared to no stimulation and did not differ in effect.

Evidence for synergism between cell death mechanisms in a cellular model of neurodegeneration in Parkinson's disease.

Delineation of how cell death mechanisms associated with Parkinson's disease (PD) interact and whether they converge would help identify targets for neuroprotective therapies. The purpose of this study was to use a cellular model to address these issues. Catecholaminergic SH-SY5Y neuroblastoma cells were exposed to a range of compounds (dopamine, rotenone, 5,8-dihydroxy-1,4-naphtho-107 quinone [naphthazarin], and Z-Ile-Glu(OBut)-Ala-Leu-al [PSI]) that are neurotoxic when applied to these cells for extended periods of times at specific concentrations. At the concentrations used, these compounds cause cellular stress via mechanisms that mimic those associated with causing neurodegeneration in PD, namely oxidative stress (dopamine), mitochondrial dysfunction (rotenone), lysosomal dysfunction (naphthazarin), and proteasomal dysfunction (PSI). The compounds were applied to the SH-SY5Y cells either alone or in pairs. When applied separately, the compounds produced a significant decrease in cell viability confirming that oxidative stress, mitochondrial, proteosomal, or lysosomal dysfunction can individually result in catecholaminergic cell death. When the compounds were applied in pairs, some of the combinations produced synergistic effects. Analysis of these interactions indicates that proteasomal, lysosomal, and mitochondrial dysfunction is exacerbated by dopamine-induced oxidative stress. Furthermore, inhibition of the proteasome or lysosome or increasing oxidative stress has a synergistic effect on cell viability when combined with mitochondrial dysfunction, suggesting that all cell death mechanisms impair mitochondrial function. Finally, we show that there are reciprocal relationships between oxidative stress, proteasomal dysfunction, and mitochondrial dysfunction, whereas lysosome dysfunction appears to mediate cell death via an independent pathway. Given the highly interactive nature of the various cell death mechanisms linked with PD, we predict that effective neuroprotective strategies should target multiple sites in these pathways, for example oxidative stress and mitochondria.

[Horner syndrome as a manifestation of carotid artery dissection]. / Síndrome de Horner como manifestación de disección carotídea.

CLINICAL CASE: A 42-year-old man presented with ptosis and miosis in his left eye and a history of headache over the last 20 days. An angioresonance showed dissection of internal carotid artery. DISCUSSION: "Painful Horner's Syndrome" is considered to be a medical emergency due possible onset of an internal carotid artery dissection. We consider that awareness of neuro-ophthalmologic emergencies is very important in the clinical praxis of an ophthalmologist. Multidisciplinary treatment and follow-up of these patients is required.

Involvement of the human pedunculopontine nucleus region in voluntary movements.

OBJECTIVE: The pedunculopontine nucleus region (PPNR) is being investigated as a target for deep brain stimulation (DBS) in Parkinson disease (PD), particularly for gait and postural impairment. A greater understanding of how PPNR activities and oscillations are modulated with voluntary movements is crucial to the development of neuromodulation strategies. METHODS: We studied 7 patients with PD who underwent DBS electrode implantations in the PPNR. PPNR local field potential and EEG were recorded while patients performed self-paced wrist and ankle movements. RESULTS: Back-averaging of the PPNR recording showed movement-related potentials before electromyography onset. Frequency analysis showed 2 discrete movement-related frequency bands in the theta (6- to 10-Hz) and beta (14- to 30-Hz) ranges. The PPNR theta band showed greater event-related desynchronization with movements in the ON than in the OFF medication state and was coupled with the sensorimotor cortices in the ON state only. Beta event-related desynchronization was observed in the PPNR during the premovement and movement execution phases in the OFF state. In contrast, premovement PPNR beta event-related synchronization occurred in the ON state. Moreover, beta band coherence between the PPNR and the midline prefrontal region was observed during movement preparation in the ON but not the OFF state. CONCLUSIONS: Activities of PPNR change during movement preparation and execution in patients with PD. Dopaminergic medications modulate PPNR activities and promote the interactions between the cortex and PPNR. Beta oscillations may have different functions in the basal ganglia and PPNR, and may be prokinetic rather than antikinetic in the PPNR.

Apomorphine reduces subthalamic neuronal entropy in parkinsonian patients.

Dopamine depletion in Parkinson's disease (PD) alters the neuronal activity in basal ganglia circuits. Characterizing these changes in network activity is an important step in understanding the disease and how therapies mitigate symptoms. Non-linear analysis methods can complement the traditional description of neuronal firing characteristics. Here we examine the entropy of subthalamic neurons in PD patients undergoing stereotactic surgery for deep brain stimulation (DBS). The activity of 8 neurons was recorded prior to, during, and following systemic administration of the dopamine agonist apomorphine at clinically effective doses. Apomorphine induced a decrease in entropy measured in the inter-spike intervals of sub-thalamic neurons in 6 of the 8 neurons. This is the first report that anti-parkinsonian drugs affect non-linear features of neuronal firing in the basal ganglia of parkinsonian patients.

Gestión del conocimiento I: formación universitaria, especializada y formación continuada / Management of knowledge I: university, specializaed training and continuing education

La actividad desarrollada por profesionales y docentes universitarios es primordial para establecer los cauces que coordinen el sistema sanitario y universitario. Las unidades de gestión clínica (UGC) deben promover la participación del profesional en el ámbito asistencial, de gestión, docente e investigador. En la Universidad de Sevilla, la asignatura de principios de medicina física y rehabilitación (MEFYR), vinculada al área de conocimiento de radiología y medicina física, es impartida por 8 profesores especialistas en MEFYR. Una de las máximas preocupaciones de los facultativos dedicados a la MEFYR es la formación de nuevos especialistas. La UGC de Rehabilitación lleva a cabo su actividad docente mediante el desarrollo de un programa tutelado para los residentes, con unos contenidos específicos de formación teóricos (sesión clínica tipo Critical Apraisal Topics [CAT], sesiones clásicas y bibliográficas) y prácticos (manipulaciones). La formación continuada es un proceso de enseñanza y aprendizaje activo y permanente destinado a actualizar y mejorar los conocimientos, habilidades y actitudes de los profesionales sanitarios. La UGC de Rehabilitación, a través de la Comisión de Docencia, organiza e imparte cursos anuales de formación continuada de 30 horas lectivas, contribuyendo a la difusión y conocimiento de nuestra especialidad. Consideramos que las UGC, en el plano docente y formativo, nos proporcionan las herramientas necesarias para mejorar el conocimiento y la calidad de la formación. Desde estas unidades se incentiva: participar en la docencia universitaria, elaborar tesis doctorales y contribuir a la formación especializada y continuada. Se promueven las publicaciones en revistas de impacto y la investigación (AU)

The activity developed by professionals and university teachers is essential to establish the pathways that coordinate the health care and university system. The Clinical Management Units (CMU) should promote the participation of the professional in the areas of care, management, teaching and investigator. In the University of Seville, eight professors who are specialized in Physical and Rehabilitation Medicine Principles (PRMP) teach the subjects of (PRMP) link to the area of knowledge of Radiology and Physical Medicine is given by. One of the maximum concerns of the professionals dedicated to the PRMP is the training of new specialists. The CMU of rehabilitation performs its teaching activities through the development of a tutelary program for the residents, with some specific contents on theoretical training (clinical session type Critical Appraisal Topics (CAT), classical sessions and be a graphical ones) unpractical training (manipulations). The continuing education is an active and permanent teaching and learning process aimed at updating and improving knowledge, skills and attitudes of the health care professionals. The CMU of Rehabilitation, through the Teaching Committee, organizes and gives yearly courses on continuing education with 13 teaching hours contributing to the spreading and knowledge of our specialty (AU)