Influence of Brainstem's Area A5 on Sympathetic Outflow and Cardiorespiratory Dynamics.

Area A5 is a noradrenergic cell group in the brain stem characterised by its important role in triggering sympathetic activity, exerting a profound influence on the sympathetic outflow, which is instrumental in the modulation of cardiovascular functions, stress responses and various other physiological processes that are crucial for adaptation and survival mechanisms. Understanding the role of area A5, therefore, not only provides insights into the basic functioning of the sympathetic nervous system but also sheds light on the neuronal basis of a number of autonomic responses. In this review, we look deeper into the specifics of area A5, exploring its anatomical connections, its neurochemical properties and the mechanisms by which it influences sympathetic nervous system activity and cardiorespiratory regulation and, thus, contributes to the overall dynamics of the autonomic function in regulating body homeostasis.

Central Autonomic Mechanisms Involved in the Control of Laryngeal Activity and Vocalization.

In humans, speech is a complex process that requires the coordinated involvement of various components of the phonatory system, which are monitored by the central nervous system. The larynx in particular plays a crucial role, as it enables the vocal folds to meet and converts the exhaled air from our lungs into audible sounds. Voice production requires precise and sustained exhalation, which generates an air pressure/flow that creates the pressure in the glottis required for voice production. Voluntary vocal production begins in the laryngeal motor cortex (LMC), a structure found in all mammals, although the specific location in the cortex varies in humans. The LMC interfaces with various structures of the central autonomic network associated with cardiorespiratory regulation to allow the perfect coordination between breathing and vocalization. The main subcortical structure involved in this relationship is the mesencephalic periaqueductal grey matter (PAG). The PAG is the perfect link to the autonomic pontomedullary structures such as the parabrachial complex (PBc), the Kölliker-Fuse nucleus (KF), the nucleus tractus solitarius (NTS), and the nucleus retroambiguus (nRA), which modulate cardiovascular autonomic function activity in the vasomotor centers and respiratory activity at the level of the generators of the laryngeal-respiratory motor patterns that are essential for vocalization. These cores of autonomic structures are not only involved in the generation and modulation of cardiorespiratory responses to various stressors but also help to shape the cardiorespiratory motor patterns that are important for vocal production. Clinical studies show increased activity in the central circuits responsible for vocalization in certain speech disorders, such as spasmodic dysphonia because of laryngeal dystonia.

CardioRVAR: A New R Package and Shiny Application for the Evaluation of Closed-Loop Cardiovascular Interactions.

CardioRVAR is a new R package designed for the complete evaluation of closed-loop cardiovascular interactions and baroreflex sensitivity estimated from continuous non-invasive heart rate and blood pressure recordings. In this work, we highlight the importance of this software tool in the context of human cardiovascular and autonomic neurophysiology. A summary of the main algorithms that CardioRVAR uses are reviewed, and the workflow of this package is also discussed. We present the results obtained from this tool after its application in three clinical settings. These results support the potential clinical and scientific applications of this tool. The open-source tool can be downloaded from a public GitHub repository, as well as its specific Shiny application, CardioRVARapp. The open-source nature of the tool may benefit the future continuation of this work.

Impact of music performance anxiety on cardiovascular blood pressure responses, autonomic tone and baroreceptor sensitivity to a western classical music piano-concert.

Introduction: Music Performance Anxiety (MPA) is a prevalent condition among musicians that can manifest both psychologically and physiologically, leading to impaired musical performance. Physiologically, MPA is characterized by excessive muscular and/or autonomic tone. This study focuses on the cardiovascular blood pressure responses, autonomic tone and baroreceptor sensitivity changes that occur during musical performance due to MPA. Methods: Six professional pianists perform a piece for piano written only for the left hand by Alexander Scriabin. The following parameters have been studied during the performance: ECG, non-invasive beat to beat continuous arterial blood pressure and skin conductance. Sympathetic and parasympathetic autonomic flow was studied with Wigner-Ville analysis (W-V) from R-R ECG variability, and baroreceptor sensitivity with the Continuous Wavelet Transform (CWT). Results: During the concert a significant increase of heart rate, systolic, mean and diastolic arterial pressure were observed. No significant differences were found in skin conductance. The W-V analysis, which studies frequency changes in the time domain, shows a significant increase of sympathetic flow and a decrease of parasympathetic flow during the concert which is associated with a significant decrease in sympathetic and vagal baroreceptor sensitivity. Discussion: The study of cardiac variability using the Wigner-Ville analysis may be a suitable method to assess the autonomic response in the context of MPA, and could be used as biofeedback in personalized multimodal treatments.

Paraneoplastic autoimmune autonomic ganglionopathy as the first symptom of bladder cancer: a case report and review of literature.

BACKGROUND: Autoimmune autonomic ganglionopathy is a rare, immune-mediated disorder associated with anti-ganglionic α3-subunit nicotinic acetylcholine receptor (anti-α3gAChR) antibodies, which bind to acetylcholine receptor in autonomic ganglia (parasympathetic and sympathetic) leading to autonomic failure. This disorder is mostly associated with viral infections, but it can also be associated with systemic malignancies. Here, we report the case of a paraneoplastic autonomic ganglionopathy as the first symptom of bladder cancer. METHOD: Case report. RESULTS: A 47-year-old man, without medical history of interest, stated to the emergency department for progressive blurry vision with eye and mouth dryness, constipation, and dizziness upon standing for the last 2 weeks. Orthostatic hypotension was demonstrated by a drop in 13.3 mmHg mean blood pressure (BP) from supine (100/60 mmHg) to 45° reclining sitting position (80/50 mmHg). Blood tests, chest X-ray, brain MRI, and electroneuronography were unremarkable. Electrochemical skin conductance was reduced. Serological examination was positive for anti-α3gAChR antibodies. A full-body CT scan revealed a bladder tumor, which was treated by transurethral bladder resection. The pathologic study demonstrated a low-grade non-muscle-invasive bladder urothelial carcinoma. After tumor resection, and treatment with intravenous immunoglobulins and corticoids, a gradually improvement was observed. Today, the patient remains asymptomatic. CONCLUSION: Subacute panautonomic failure can be the first symptom for systemic malignancies. This case reports a paraneoplastic autonomic ganglionopathy as the first symptom of bladder cancer. This case highlights the importance of a systemic study to rule out the presence of cancer when autoimmune autonomic ganglionopathy is present.

Pontine A5 region modulation of the cardiorespiratory response evoked from the midbrain dorsolateral periaqueductal grey.

Connections between the midbrain dorsolateral periaqueductal grey (dlPAG) and the pontine A5 region have been shown. The stimulation of both regions evokes similar cardiovascular responses: tachycardia and hypertension. Accordingly, we have studied the interactions between dlPAG and A5 region in spontaneously breathing anesthetized rats. dlPAG was electrically stimulated (20-30 µA 1-ms pulses were given for 5 s at 100 Hz). Changes in the evoked cardiorespiratoy response were analysed before and after ipsilateral microinjections of muscimol (GABAergic agonist, 50 nl, 0.25 nmol, 5 s) within the A5 region. Electrical stimulation of the dlPAG produces, in the rat, a response characterized by tachypnoea (p < 0.001), hypertension (p < 0.001) and tachycardia (p < 0.001). The increase in respiratory rate was due to a decrease in expiratory time (p < 0.01). Pharmacological inhibition of the A5 region with muscimol produced a marked reduction of the tachycardia (p < 0.001) and the tachypnoea (p < 0.01) evoked from the dlPAG. Finally, to assess functional interactions between A5 and dlPAG, extracellular activity of putative A5 neurones were recorded during dlPAG electrical stimulation. Forty A5 cells were recorded, 16 of which were affected by dlPAG stimulation (40%). 4 cells showed activation, 5 cells excitation and 7 cells decreased spontaneous activity to dlPAG stimulation (p < 0.001). These results confirm a link between the A5 region and dlPAG. The potential role of these connections in the modulation of dlPAG evoked cardiorespiratory responses and their possible clinical implications are discussed.

Influence of repetitions on the Valsalva maneuver.

OBJECTIVE: In autonomic units, patients perform several short Valsalva maneuvers (VMs) while learning the procedure. The effects of repeated VMs on cardiovascular elicited responses were assessed. METHODS: 14 healthy volunteer subjects were selected (aged 22-26). VMs were performed every 3 min up to 6 times in a reclined sitting position. Changes in blood pressure (BP), heart rate (HR) and baroreflex sensitivity indexes were evaluated. Subjects were classified according to their adrenergic response patterns. RESULTS: VMs repetitions evoked a progressive decrease in BP during phases II and III and a reduced increase in mean BP at late phase II. Increased bradycardia at early phase II and IV was also observed. Last two VMs showed a significant increase in Valsalva ratio, while other indexes remained unaltered. Subjects with balanced adrenergic responses presented extended pressure recovery time from the third repetition and lower BP values than those with augmented or suppressed adrenergic responses. CONCLUSIONS: Significant changes in BP and HR at certain phases were observed when consecutive VMs were performed in young subjects in a reclined position. The most affected baroreflex index was the Valsalva ratio. Adrenergic response patterns showed differences that should be considered in order to avoid false positives. SIGNIFICANCE: We recommend not repeating the VM more than 4 times and revisiting the role and reliability of the Valsalva ratio.

Doppler Resistivity and Cerebral Small Vessel Disease: Hemodynamic Structural Correlation and Usefulness for the Etiological Classification of Acute Ischemic Stroke.

INTRODUCTION AND GOAL: Lacunar stroke is defined as an <1.5 cm diameter infarct located in the territory of a perforating artery, that is not accessible for direct study using conventional imaging techniques. Diagnosis requires exclusion of other causes. It usually occurs in the context of chronic cerebral small vessel disease, which can be suspected during the neurosonography study in the form of high pulsatility [PI] or resistance index [RI]. Clinical research was performed to confirm that PI and RI correlate with cerebral small vessel lesion burden and to determine whether these parameters are useful for supporting a lacunar origin (LO) in acute stroke. MATERIAL AND METHODS: We prospectively recorded internal carotid artery resistivity and the Fazekas score for all patients with acute ischemic stroke who met inclusion but not exclusion criteria over a 6-month period. RESULTS: The study population comprised 74 patients. A correlation was observed between the Fazekas score and resistivity. Both parameters predicted a LO, with an area under the curve of .78 and .696, respectively. The optimal cut-offs were PI = .96/RI = .58 for screening (sensitivity, 96%) and PI = 1.46/RI = .83 for confirmation (specificity, 89%). CONCLUSIONS: Doppler ultrasound is a useful technique for determining the LO of acute stroke.

Analysis of peripapillary choroidal thickness in non-arteritic anterior ischaemic optic neuropathy.

PURPOSE: To analyse peripapillary choroidal thickness (PCT) in non-arteritic ischaemic optic neuropathy (NAION). METHODS: 28 patients diagnosed with NAION (37 affected and 19 unaffected eyes) and 38 disease-free control individuals (38 eyes) were analysed using enhanced-depth imaging of spectral-domain optical coherence tomography. A vertical and a horizontal raster scan centred on the optic nerve were obtained per eye. PCT was measured at the superior, inferior, nasal and temporal quadrants from the posterior edge of the retinal pigment epithelium to the choroid-sclera junction at 500 µm intervals up to 2000 µm away from the optic nerve. Statistical analysis was used to compare average PCT and to correlate PCT with other ocular and systemic parameters. RESULTS: Mean PCT in NAION eyes and control group was 148.18±42.68 µm and 182.90±59.81 µm, respectively (p=0.005). Except for inferior PCT (p=0.158), superior, nasal and temporal PCT were significantly thinner in the NAION eyes than in the control group (p=0.006, 0.002 and 0.046). Thinner PCT, adjusted for refractive error, was associated with the diagnosis of NAION (p=0.048). Similarly, unaffected contralateral eyes showed a significant thinner PCT compared with the control group (p=0.024). Diagnosis of NAION was negatively associated with PCT in NAION eyes (p=0.008; OR 0.98; 95% CI 0.97 to 0.99) and in their contralateral unaffected eyes (p=0.043; OR 0.98; 95% CI 0.97 to 0.99). CONCLUSIONS: Eyes affected by NAION and contralateral unaffected eyes showed significantly thinner PCT compared with disease-free control eyes after adjusting for refractive error.

[Healthcare management of an epilepsy clinic: factors involved in the demand for health care and clinical situation of patients]. / Gestion sanitaria de una consulta de epilepsia: factores implicados en la demanda asistencial y situacion clinica de los pacientes.

INTRODUCTION: Epilepsy is a chronic illness that requires a long-term periodic follow-up of the patient and this means that as time goes by the number of patients attended increases, with the ensuing added cost for the healthcare system. AIM: To determine the factors involved in the time until an epileptic patient's next visit. PATIENTS AND METHODS: Our sample consisted of a selection of patients who visited the epilepsy clinic at our hospital consecutively during one year. Their clinical situation and relationship with the medical advice they were given, together with the factors involved in the time elapsed until the next visit, were analysed by means of predictive econometric models. RESULTS: There is a clear association between the patient's clinical situation and the modification of the treatment proposed by the neurologist in the previous visit. The factors involved in the time until the next visit were the frequency of seizures, adverse side effects from medicines -above all those that affect cognition- and the medical advice given to the patient. Polytherapy, psychoaffective disorders or the patient's social situation were not found to be significant. CONCLUSIONS: Follow-up visits in a specific epilepsy clinic improves the patient's situation. This is the first analysis of the demand for healthcare in patients with epilepsy conducted by means of econometric methods and from a mixed physician-patient perspective. Since the factors that determine the time until the next visit can be modified, the number of visits per year could be reduced, thus improving patients' clinical situation. We suggest a greater amount of time should be spent per visit so as to be able to have a bearing on it and thereby cut costs in the long term.

TITLE: Gestion sanitaria de una consulta de epilepsia: factores implicados en la demanda asistencial y situacion clinica de los pacientes.Introduccion. La epilepsia es una enfermedad cronica que implica un seguimiento periodico del paciente a largo plazo, lo que supone un aumento del numero de pacientes visitados con el tiempo y, por tanto, un coste al sistema sanitario. Objetivo. Determinar los factores implicados en el tiempo para la siguiente visita de un paciente epileptico. Pacientes y metodos. Seleccion de pacientes durante un ano que acuden consecutivamente a consulta de epilepsia de nuestro hospital. Se analiza su situacion clinica y relacion con el consejo medico dado, y los factores implicados en el tiempo transcurrido hasta la siguiente visita mediante modelos econometricos predictivos. Resultados. Existe una clara asociacion entre la situacion clinica del paciente y la modificacion del tratamiento propuesta por el neurologo en la visita anterior. Los factores implicados en el tiempo hasta la siguiente visita fueron frecuencia de crisis, efectos adversos medicamentosos, sobre todo los que afectan a la cognicion, y consejo medico al paciente. No resultaron significativos la politerapia, los trastornos psicoafectivos ni la situacion social del paciente. Conclusiones. El seguimiento en una consulta especifica de epilepsia mejora la situacion del paciente. Se trata del primer analisis de demanda asistencial en pacientes con epilepsia realizado mediante metodos econometricos y desde una perspectiva mixta medico-paciente. Dado que los factores que determinan el tiempo para la siguiente visita son modificables, podria disminuir el numero de visitas al ano, mejorando la situacion clinica de los pacientes. Proponemos una mayor duracion por visita para poder incidir en ello y reducir costes a largo plazo.

Gestión sanitaria de una consulta de epilepsia: factores implicados en la demanda asistencial y situación clínica de los pacientes / Healthcare management of an epilepsy clinic: factors involved in the demand for health care and clinical

Introducción. La epilepsia es una enfermedad crónica que implica un seguimiento periódico del paciente a largo plazo, lo que supone un aumento del número de pacientes visitados con el tiempo y, por tanto, un coste al sistema sanitario. Objetivo. Determinar los factores implicados en el tiempo para la siguiente visita de un paciente epiléptico. Pacientes y métodos. Selección de pacientes durante un año que acuden consecutivamente a consulta de epilepsia de nuestro hospital. Se analiza su situación clínica y relación con el consejo médico dado, y los factores implicados en el tiempo transcurrido hasta la siguiente visita mediante modelos econométricos predictivos. Resultados. Existe una clara asociación entre la situación clínica del paciente y la modificación del tratamiento propuesta por el neurólogo en la visita anterior. Los factores implicados en el tiempo hasta la siguiente visita fueron frecuencia de crisis, efectos adversos medicamentosos, sobre todo los que afectan a la cognición, y consejo médico al paciente. No resultaron significativos la politerapia, los trastornos psicoafectivos ni la situación social del paciente. Conclusiones. El seguimiento en una consulta específica de epilepsia mejora la situación del paciente. Se trata del primer análisis de demanda asistencial en pacientes con epilepsia realizado mediante métodos econométricos y desde una perspectiva mixta médico-paciente. Dado que los factores que determinan el tiempo para la siguiente visita son modificables, podría disminuir el número de visitas al año, mejorando la situación clínica de los pacientes. Proponemos una mayor duración por visita para poder incidir en ello y reducir costes a largo plazo (AU)

Introduction. Epilepsy is a chronic illness that requires a long-term periodic follow-up of the patient and this means that as time goes by the number of patients attended increases, with the ensuing added cost for the healthcare system. Aim. To determine the factors involved in the time until an epileptic patient’s next visit. Patients and methods. Our sample consisted of a selection of patients who visited the epilepsy clinic at our hospital consecutively during one year. Their clinical situation and relationship with the medical advice they were given, together with the factors involved in the time elapsed until the next visit, were analysed by means of predictive econometric models. Results. There is a clear association between the patient’s clinical situation and the modification of the treatment proposed by the neurologist in the previous visit. The factors involved in the time until the next visit were the frequency of seizures, adverse side effects from medicines –above all those that affect cognition– and the medical advice given to the patient.Polytherapy, psychoaffective disorders or the patient’s social situation were not found to be significant. Conclusions. Follow-up visits in a specific epilepsy clinic improves the patient’s situation. This is the first analysis of the demand for healthcare in patients with epilepsy conducted by means of econometric methods and from a mixed physicianpatient perspective. Since the factors that determine the time until the next visit can be modified, the number of visits per year could be reduced, thus improving patients’ clinical situation. We suggest a greater amount of time should be spent per visit so as to be able to have a bearing on it and thereby cut costs in the long term (AU)

Prevalence and clinical characteristics of epilepsy in the South of Spain.

PURPOSE: Epilepsy is a common neurological disorder found in all societies. There are extensive epidemiologic studies of different European areas. However, not much information about the South-West of Europe exists. In Málaga, Health Care is free and there are only two public hospitals with Neurological Services that assist Eastern or Western areas depending on the case. The purpose is to estimate the epidemiology in Málaga through a hospital-based study and compare it to the other European studies. METHODS: Review on the hospital data base and gathering of consecutive patients with a diagnosis of active epilepsy served by the Epilepsy outpatient clinic in Virgen de la Victoria Hospital throughout a year. RESULTS: 2 281 patients fulfilled the criteria and 515 patients were recruited in order to study the epidemiologic characteristics. Male gender and focal onset seizures predominate (75.5%). Medium age 40. 58% of patients have been seizure-free in the last year. Known etiology in half of the patients. 54% of patients are treated with monotherapy. Valproic acid is the commonest drug. Other epidemiologic and demographic important data are provided. Data are analysed and compared to other European studies. CONCLUSIONS: Prevalence rate in Western Málaga is 4.79 cases/1000 inhabitants. Characteristics of the sample are similar to those of other European studies. Although this is a hospital-based study, the particular characteristics of the Health Care System in our region enable us to gather real data concerning epidemiology and prevalence.

Acetylcholinesterase inhibitors and the risk of hip fracture in Alzheimer's disease patients: a case-control study.

Recent studies have reported the presence of acetylcholine (ACh) receptor subtypes in bone tissue, and have demonstrated that inhibition of the ACh receptors has negative effects on bone mass and fracture healing capacity. However, little is known about the potential clinical effects that increased ACh signaling might have on bone. Accordingly, this study was designed to determine whether the use of acetylcholinesterase inhibitors (AChEIs), a group of drugs that stimulate ACh receptors and are used to treat Alzheimer's disease (AD), is associated with a decreased risk of hip fracture in AD patients. To accomplish this objective, a case-control analysis was performed using the AD population, aged above 75 years, based in the local health area of the Carlos Haya Hospital, in Malaga, Spain. The cases were 80 AD patients that suffered a hip fracture between January 2004 and December 2008. The controls were 2178 AD patients without hip fracture followed at our health care area during the same period of time. Compared with patients who did not use AChEIs, the hip fracture adjusted odds ratio (OR) for users of AChEIs was 0.42 (95% confidence interval [CI], 0.24-0.72), for users of rivastigmine was 0.22 (95% CI, 0.10-0.45), and for users of donepezil was 0.39 (95% CI, 0.19-0.76). Data were adjusted for the following parameters: body mass index, fall risk, smoking habits, cognition, dependence, degree of AD, comorbidity score, treatment with selective serotonin reuptake inhibitors, age, and gender. Our data suggests that use of AChEIs donepezil and rivastigmine is associated with a reduced risk of fractures in AD patients. Many elderly patients with AD disease who are at risk of developing osteoporosis may potentially benefit from therapy with the AChEIs donepezil and rivastigmine.

Role of the parabrachial complex in the cardiorespiratory response evoked from hypothalamic defense area stimulation in the anesthetized rat.

To analyze the role of parabrachial complex (PBc) in the modulation of cardiorespiratory response evoked from the hypothalamic defense area (HDA), cardiorespiratory changes were analyzed in spontaneously breathing anesthetised rats in response to electrical stimulation of the HDA (1 ms pulses, 30-50 microA, 100 Hz for 5 s) before and after the microinjection of muscimol (50 nl, 0.25 nmol, 5 s) within the PBc. HDA stimulation evoked an inspiratory facilitatory response, consisting of an increase in respiratory rate (p<0.001) due to a decrease in expiratory time (p<0.01). The respiratory response was accompanied by a pressor (p<0.001) and a tachycardic (p<0.001) response. Muscimol microinjection within the lateral parabrachial region (lPB) abolished the respiratory response to HDA stimulation (p<0.01) and decreased the pressor response (p<0.05). Muscimol within the medial parabrachial region and Kölliker-Fuse (mPB-KF) decreased the magnitude of the pressor (p<0.01) and tachycardic (p<0.05) responses to HDA stimulation. The respiratory response persisted unchanged. Finally, extracellular recording of putative neurons from these regions were obtained during HDA stimulation to confirm functional interaction between HDA and parabrachial regions. 105 pontine cells were recorded during HDA stimulation, 57 from the lPB and 48 from the mPB-KF. In mPB-KF 34/48 (71%) and in lPB 38/57 (67%) cells were influenced from HDA. The results indicate that neurons from different regions of the PBc have an important function in mediating the cardiorespiratory response evoked from the HDA. The possible mechanisms involved in these interactions are discussed.