Nuestros investigadores

Manuel Alegre Esteban

Neurología y Neurocirugía
Facultad de Medicina. Universidad de Navarra
Clínica Universidad de Navarra. Clínica Universidad de Navarra
Líneas de investigación
Neurofisiología del control motor, Fisiopatología de la enfermedad de Parkinson
Índice H
22, (WoS, 10/05/2017)

Publicaciones científicas más recientes (desde 2010)

Autores: Sánchez-Carpintero Abad, Rocío (Autor de correspondencia); Urrestarazu Bolumburu, Elena; Cieza Ortiz, Sofía Isabel; et al.
ISSN 1090-3798  Vol. 24  2020  págs. 134 - 141
Objective: To evaluate the capability of children with Dravet syndrome to generate brain gamma-oscillatory activity in response to auditory steady-state stimulation. Methods: Fifty-one subjects were included: 13 with Dravet syndrome with SCN1A gene alterations, 26 with non-Dravet epilepsies and 12 healthy controls. Responses to auditory steady-state stimulation elicited with a chirp-modulated tone between 1 and 120 Hz were collected in subjects and compared across groups. Results: Subjects with Dravet syndrome showed weak or no responses in the 1-120 Hz frequency range. Healthy controls showed oscillatory responses following the frequency of the modulation that were maximal in the low (30-70 Hz) and high (80-120) gamma-ranges both, in the power and inter-trial coherence estimates. Non-Dravet epileptic children showed differences in the auditory responses when compared with the healthy controls but were able to generate oscillatory evoked activities following the frequency-varying stimulation. Conclusions: The ability to generate brain gamma-oscillatory activity of children with Dravet in response to a chirp-modulated auditory stimulus is highly impaired, is not due to epilepsy and is consistent with the Nav1.1 channel dysfunction affecting interneuron activity seen in Dravet mouse models. Significance: The reported deficits in the brain oscillatory activity evoked by chirp modulated tones in children with Dravet is compatible with Dravet syndrome disease mechanisms and constitutes a potential biomarker for future disease-modifying interventions. (C) 2019 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
Autores: Besné Villanueva, Guillermo Miguel; Alegre Esteban, Manuel; Podhorski, Adam; et al.
ISSN 1755-375X  Vol. 98  Nº 3  2020  págs. e397 - e399
Autores: Cocho Archiles, Borja; Manzanilla Zapata, Oscar; Horrillo Maysonnial, Alejandro; et al.
ISSN 0962-1105  Vol. 29  2020  págs. 339 - 340
Autores: Garriz Luis, Maite (Autor de correspondencia); Sánchez-Carpintero Abad, Rocío; Alegre Esteban, Manuel; et al.
ISSN 0210-0010  Vol. 66  Nº 11  2018  págs. 387 - 394
Introduction. Infantile cerebral palsy is a well-known condition, the prevalence of which has varied only slightly over the years. The most common subtype is spastic diplegia, and spasticity is the most disabling symptom. Its treatment involves a multidisciplinary intervention that includes rehabilitation, the use of drugs, and orthopaedic and nervous system surgery, where selective dorsal rhizotomy is a prominent procedure. Aim. To present a thorough review of the use, indication and long-term consequences of selective dorsal rhizotomy. Development. It is a minimally invasive procedure aimed at reducing spasticity in the lower extremities in order to improve the ability to walk, lessen pain, facilitate care in everyday life and diminish the need for orthopaedic surgery. The literature contains a wide range of criteria for its use, and the main indication is spastic diplegia with the absence of dystonia. It is routinely performed in several countries, while we have no evidence of its application in ours. Conclusions. Following the literature review, we believe there is enough experience to state that selective dorsal rhizotomy is a safe and simple technique from which many patients with spasticity of the lower limbs secondary to infantile cerebral palsy can benefit in both the short and the long term.
Autores: Serrano Mendioroz, Irantzu; Sampedro Pascual, Ana; Alegre Esteban, Manuel; et al.
ISSN 1043-0342  Vol. 29  Nº 4  2018  págs. 480 - 491
Porphobilinogen deaminase (PBGD) gene therapy represents a promising therapeutic option for acute intermittent porphyria (AIP) patients suffering recurrent acute attacks. A first-in-human Phase I clinical trial confirmed the safety and tolerability of adeno-associated virus (AAV)-AAT-PBGD gene therapy, but higher doses and/or more efficient vectors are needed to achieve therapeutic expression of the transgene. This study assayed the insertion into the promoter of a short enhancer element able to induce transgene expression during exposure to endogenous and exogenous stimuli related to the pathology of the disease. The inclusion in tandem of two elements of the minimal functional sequence of human -aminolevulinic acid synthase drug-responsive enhancing sequence (ADRES) positioned upstream of the promoter strongly induced transgene expression in the presence of estrogens, starvation, and certain drugs known to trigger attacks in porphyria patients. The inclusion of two ADRES motives in an AAV vector improved therapeutic efficacy, reducing 10-fold the effective dose in AIP mice. In conclusion, the inclusion of specific enhancer elements in the promoter of gene therapy vectors for AIP was able to overexpress the therapeutic transgene when it is most needed, at the time when porphyrinogenic factors increase the demand for hepatic heme and precipitate acute porphyria attacks.
Autores: Baptista Jardín, Peter Michael (Autor de correspondencia); Garaycochea Mendoza del Solar, Octavio; Álvarez Gómez, Laura; et al.
ISSN 0001-6519  Vol. 69  Nº 1  2018  págs. 42 - 47
The objective of this communication is to describe our preliminary results in upper airway stimulation surgery via hypoglossal nerve stimulation implantation for obstructive sleep apnoea. We describe 4 cases and the outcomes of the surgery were analysed using the Epworth scale, apnoea-hypopnoea index, minimal 02 Sat, average 02 Sat and snoring intensity. In all cases a significant reduction in Epworth scale values and apnoea-hypopnoea index were obtained (P<.05). The minimum and average oxygen saturation had better values after the surgery, however, there was no statistically significant difference. The snoring severity measured subjectively changed from "intense" to "absent", in all cases. The preliminary results obtained with the upper airway stimulation surgery via hypoglossal nerve stimulation showed objective and subjective improvement after the implant activation. (C) 2017 Elsevier Espana, S.L.U. and Sociedad Espanola de Otorrinolaringologia y Cirugia de Cabeza y Cuello. All rights reserved.
Autores: Montiel Terrón, Veronica; Muiños Lopez, Emma; Granero Molto, Froilan; et al.
ISSN 2240-4554  Vol. 8  Nº 2  2018  págs. 261-275
Conclusion: Animal models for muscular degeneration after rotator cuff tears have been well established and described. The next challenge is the achievement of a therapeutic target that could be transferred to the clinical setting.
Autores: Jiang, L. ; Berraondo López, Pedro; Jerico, D.; et al.
ISSN 1078-8956  Vol. 24  Nº 12  2018  págs. 1899 - 1909
Acute intermittent porphyria (AIP) results from haploinsufficiency of porphobilinogen deaminase (PBGD), the third enzyme in the heme biosynthesis pathway. Patients with AIP have neurovisceral attacks associated with increased hepatic heme demand. Phenobarbital-challenged mice with AIP recapitulate the biochemical and clinical characteristics of patients with AIP, including hepatic overproduction of the potentially neurotoxic porphyrin precursors. Here we show that intravenous administration of human PBGD (hPBGD) mRNA (encoded by the gene HMBS) encapsulated in lipid nanoparticles induces dose-dependent protein expression in mouse hepatocytes, rapidly normalizing urine porphyrin precursor excretion in ongoing attacks. Furthermore, hPBGD mRNA protected against mitochondrial dysfunction, hypertension, pain and motor impairment. Repeat dosing in AIP mice showed sustained efficacy and therapeutic improvement without evidence of hepatotoxicity. Finally, multiple administrations to nonhuman primates confirmed safety and translatability. These data provide proof-of-concept for systemic hPBGD mRNA as a potential therapy for AIP.
Autores: Cordon Medrano, Ivan; Nicolás Apesteguía, María Jesús; Arrieta Eguren, Sandra; et al.
ISSN 1935-861X  Vol. 11  Nº 1  2018  págs. 231 - 238
Background: High-frequency deep brain stimulation (DBS) has become a widespread therapy used in the treatment of Parkinson's Disease (PD) and other diseases. Although it has proved beneficial, much recent attention has been centered around the potential of new closed-loop DBS implementations. Objective: Here we present a new closed-loop DBS scheme based on the phase of the theta activity recorded from the motor cortex. By testing the implementation on freely moving 6-OHDA lesioned and control rats, we assessed the behavioral and neurophysiologic effects of this implementation and compared it against the classical high-frequency DBS. Results: Results show that both stimulation modalities produce significant and opposite changes on the movement and neurophysiological activity. Close-loop stimulation, far from improving the animals' behavior, exert contrary effects to those of high-frequency DBS which reverts the parkinsonian symptoms. Motor improvement during open-loop, high-frequency DBS was accompanied by a reduction in the amount of cortical beta oscillations while akinetic and disturbed behavior during close-loop stimulation coincided with an increase in the amplitude of beta activity. Conclusion: Cortical-phase-dependent close-loop stimulation of the STN exerts significant behavioral and oscillatory changes in the rat model of PD. Open-loop and close-loop stimulation outcomes differed dramatically, thus suggesting that the scheme of stimulation determines the output of the modulation even if the target structure is maintained. The current framework could be extended in future studies to identify the correct parameters that would provide a suitable control signal to the system. It may well be that with other stimulation parameters, this sort of DBS could be beneficial. (C) 2017 Elsevier Inc. All rights reserved.
Autores: Bonkovsky, H. L.; Bissell, D. M. ; Ventura, P.; et al.
ISSN 0270-9139  Vol. 68  Nº Supl. 1  2018  págs. 723A - 724A
Autores: Guridi Legarra, Jorge; Alegre Esteban, Manuel
ISSN 0885-3185  Vol. 32  Nº 1  2017  págs. 64 - 69
Over the past 10 years, research into the neurophysiology of the basal ganglia has provided new insights into the pathophysiology of movement disorders. The presence of pathological oscillations at specific frequencies has been linked to different signs and symptoms in PD and dystonia, suggesting a new model to explain basal ganglia dysfunction. These advances occurred in parallel with improvements in imaging and neurosurgical techniques, both of which having facilitated the more widespread use of DBS to modulate dysfunctional circuits. High-frequency stimulation is thought to disrupt pathological activity in the motor cortex/ basal ganglia network; however, it is not easy to explain all of its effects based only on changes in network oscillations. In this viewpoint, we suggest that a return to (C) 2016 International Parkinson and Movement Disorder Society
Autores: Martínez Simón, Antonio (Autor de correspondencia); Alegre Esteban, Manuel; Honorato Cia, María Cristina; et al.
Vol. 126  Nº 6  2017  págs. 1033 - 1042
Autores: Alegre Esteban, Manuel; Molero Santos, Patricio; Valencia Ustárroz, Miguel; et al.
ISSN 0165-1781  Vol. 247  2017  págs. 214 - 221
The symptoms of schizophrenia might be mediated by a cortical network disconnection which may disrupt the cortical oscillatory activity. Steady-state responses are an easy and consistent way to explore cortical oscillatory activity. A chirp-modulated tone (increasing the frequency of the modulation in a linear manner) allows a fast measure of the steady-state response to different modulation rates. With this approach, we studied the auditory steady-state responses in two groups of patients with schizophrenia (drug-naive and treated with atypical antipsychotic drugs), in order to assess the differences in their responses with respect to healthy subjects, and study any potential effect of medication. Drug-naive patients had reduced amplitude and inter-trial phase coherence of the response in the 30-50Hz range, and reduced amplitude of the response in the 90-100Hz range, when compared to controls. In the treated patients group, the response in the 30-50Hz range was normalized to values similar to the control group, but the reduction in amplitude in the 90-100Hz range remained as in the drug-naive group. These results suggest that gamma activity impairment in schizophrenia is a complex phenomenon that affects a wide band of frequencies and may be influenced by antipsychotic treatment.
Autores: Honorato Cia, María Cristina; Martínez Simón, Antonio; Guridi Legarra, Jorge; et al.
ISSN 1878-8750  Vol. 101  2017  págs. 114 - 121
BACKGROUND: The anesthetic management of patients requiring surgery for movement disorders needs to balance microrecording quality and patient cooperation with safety and comfort. Anesthetics can alter microrecording, although the effect on outcome is debatable. They also provide a rested and cooperative patient and minimize complications such as intracranial hemorrhage by providing better hemodynamic control. Most teams use local anesthesia with monitored anesthesia care or conscious sedation with propofol. Recently, dexmedetomidine has emerged as an alternative that, at low doses, does not affect microrecording, and that does not impair respiratory drive. METHODS: In the past 15 years, we have used in our institution local anesthesia, remifentanil, or dexmedetomidine sedation. We compared functional outcome and rate of complications in a group of 145 patients with similar characteristics. RESULTS: We found 5 (3.4%) intracranial hemorrhages. Two (1.4%) were symptomatic. The remifentanil group had the highest risk of having systolic blood pressure > 160 mm Hg during surgery (odds ratio [OR], 2.8; 95% confidence interval [CI], 0.9-9.9), whereas the dexmedetomidine group had the lowest (OR, 0.7; 95% CI, 0.2-1.8), compared with the local anesthesia group. Surgical time was shortest with dexmedetomidine (mean, 283 minutes) and longest with local anesthesia only (mean, 328 minutes). Functional outcome (Unified Parkinson's Disease Rating Scale, Part III motor component scale) was similar among groups. The dexmedetomidine group had a statistically significant lower risk of perioperative neurologic events compared with the local anesthesia group (OR, 0.09; 95% CI, 0.002-0.68). CONCLUSIONS: Sedation can be used safely without affecting outcome, and dexmedetomidine provides better hemodynamic management. Clinical significance remains unclear and larger studies need to be undertaken.
Autores: Rodríguez Díez, María Cristina; Alegre Esteban, Manuel; Díez Goñi, María de las Nieves; et al.
ISSN 1472-6920  Vol. 16  Nº 1  2016  págs. 47
The formal quality of the MIR exam items has improved over the last five years with regard to testwiseness. A more detailed revision of the items submitted, checking systematically for the presence of technical flaws, could improve the validity and discriminatory power of the exam, without increasing its difficulty.
Autores: García García, David; Guridi Legarra, Jorge; Toledo Atucha, Jon; et al.
ISSN 0022-3085  Vol. 125  Nº 5  2016  págs. 1068 - 1079
OBJECTIVE Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is widely used in patients with Parkinson's disease (PD). However, which target area of this region results in the highest antiparkinsonian efficacy is still a matter of debate. The aim of this study was to develop a more accurate methodology to locate the electrodes and the contacts used for chronic stimulation (active contacts) in the subthalamic region, and to determine the position at which stimulation conveys the greatest clinical benefit. METHODS The study group comprised 40 patients with PD in whom bilateral DBS electrodes had been implanted in the STN. Based on the Morel atlas, the authors created an adaptable 3D atlas that takes into account individual anatomical variability and divides the STN into functional territories. The locations of the electrodes and active contacts were obtained from an accurate volumetric assessment of the artifact using preoperative and postoperative MR images. Active contacts were positioned in the 3D atlas using stereotactic coordinates and a new volumetric method based on an ellipsoid representation created from all voxels that belong to a set of contacts. The antiparkinsonian benefit of the stimulation was evaluated by the reduction in the Unified Parkinson's Disease Rating Scale Part III (UPDRS-III) score and in the levodopa equivalent daily dose (LEDD) at 6 months. A homogeneous group classification for contact position and the respective clinical improvement was applied using a hierarchical clustering method. RESULTS Subthalamic stimulation induced a significant reduction of 58.0% ± 16.5% in the UPDRS-III score (p < 0.001) and 64.9% ± 21.0% in the LEDD (p < 0.001). The greatest reductions in the total and contralateral UPDRS-III scores (64% and 76%, respectively) and in the LEDD (73%) were obtained when the active contacts were placed approximately 12 mm lateral to the midline, with no influence of the position being observed in the anteroposterior and dorsoventral axes. In contrast, contacts located about 10 mm from the midline only reduced the global and contralateral UPDRS-III scores by 47% and 41%, respectively, and the LEDD by 33%. Using the ellipsoid method of location, active contacts with the highest benefit were positioned in the rostral and most lateral portion of the STN and at the interface between this subthalamic region, the zona incerta, and the thalamic fasciculus. Contacts placed in the most medial regions of the motor STN area provided the lowest clinical efficacy. CONCLUSIONS The authors report an accurate new methodology to assess the position of electrodes and contacts used for chronic subthalamic stimulation. Using this approach, the highest antiparkinsonian benefit is achieved when active contacts are located within the rostral and the most lateral parts of the motor region of the STN and at the interface of this region and adjacent areas (zona incerta and thalamic fasciculus).
Autores: Rodríguez Díez, María Cristina; Tejedor, J. ; Alegre Esteban, Manuel; et al.
ISSN 0212-6567  Vol. 48  Nº 7  2016  págs. 501 - 502
Autores: Iriarte Franco, Jorge; Campo Ezquibela, Aránzazu; Alegre Esteban, Manuel; et al.
ISSN 1556-407X  Vol. 16  Nº 7  2015  págs. 827 - 830
The International Classification of Sleep Disorders-Third Edition (ICSD-3) classifies catathrenia among the respiratory disorders and not as a parasomnia as in ICSD-2. Few patients have been reported during these years, and the clinical description of the sound is different from group to group. In fact, there is no full agreement about its nature, origin, meaning, and treatment.
Autores: Jahanshahi, M. ; Obeso, I. ; Baunez, C. ; et al.
ISSN 0885-3185  Vol. 30  Nº 2  2015  págs. 128 - 140
Although Parkinson's disease (PD) is primarily considered a disorder of initiation of actions, patients also have deficits in inhibitory control, both in the motor and cognitive domains. Impulse control disorders, which can develop in association with dopaminergic medication in a small proportion of patients with PD, are the symptoms most commonly considered as representing inhibitory deficits. However, there is now also a body of evidence suggesting a role for the subthalamic nucleus (STN), which is ordinarily hyperactive in PD, in inhibitory control. Here, we review evidence from animal studies, imaging studies, and investigations recording STN activity intra- or perioperatively in patients with PD having surgery for DBS of the STN (STN-DBS). We also highlight relevant hypotheses about the role of the STN and consider evidence from studies that have examined the effect of STN-DBS in patients with PD on performance of experimental tasks requiring inhibition of prepotent or habitual responses or decision making under conflict, as well as the psychiatric side effects of STN-DBS. Though the results are not always consistent, nevertheless, this body of evidence supports the role of the STN in inhibitory and executive control.
Autores: Cordon Medrano, Ivan; Nicolás Apesteguía, María Jesús; Arrieta Eguren, Sandra; et al.
ISSN 0924-977X  Vol. 25  Nº 8  2015  págs. 1375 - 1387
Recent studies have suggested the implication of the basal ganglia in the pathogenesis of schizophrenia. To investigate this hypothesis, here we have used the ketamine model of schizophrenia to determine the oscillatory abnormalities induced in the rat motor circuit of the basal ganglia. The activity of free moving rats was recorded in different structures of the cortico-basal ganglia circuit before and after an injection of a subanesthesic dose of ketamine (10mg/kg). Spectral estimates of the oscillatory activity, phase-amplitude cross-frequency coupling interactions (CFC) and imaginary event-related coherence together with animals¿ behavior were analyzed. Oscillatory patterns in the cortico-basal ganglia circuit were highly altered by the effect of ketamine. CFC between the phases of low-frequency activities (delta, 1-4; theta 4-8Hz) and the amplitude of high-gamma (~80Hz) and high-frequency oscillations (HFO) (~150Hz) increased dramatically and correlated with the movement increment shown by the animals. Between-structure analyses revealed that ketamine had also a massive effect in the low-frequency mediated synchronization of the HFO's across the whole circuit. Our findings suggest that ketamine administration results in an aberrant hypersynchronization of the whole cortico-basal circuit where the tandem theta/HFO seems to act as the main actor in the hyperlocomotion shown by the animals. Here we stress the importance of the basal ganglia circuitry in the ketamine model of schizophrenia and leave the door open to further investigations devoted to elucidate to what extent these abnormalities also reflect the prominent neurophysiological deficits observed in schizophrenic patients.
Autores: Honorato Cia, María Cristina; Martínez Simón, Antonio; Alegre Esteban, Manuel; et al.
ISSN 1011-6125  Vol. 93  Nº 6  2015  págs. 393-399
Dexmedetomidine provides adequate sedation during surgery for PD, but it might affect motor signs making intraoperative testing difficult or even impossible. Dosage appears not to be the determining factor in motor changes, whose cause remains unclear.
Autores: Palma Carazo, José Alberto; Iriarte Franco, Jorge; Fernández González, Secundino; et al.
ISSN 0959-9851  Vol. 25  Nº 4  2015  págs. 225 - 232
BACKGROUND: Cardiac autonomic tone after long-term continuous positive airway pressure therapy in patients with obstructive sleep apnea remains unexplored. METHODS: Thirty patients with obstructive sleep apnea (14 with moderate and 16 with severe obstructive sleep apnea) were studied during a baseline polysomnographic study, after a full night of acute continuous positive airway pressure treatment, and after long-term (~2 years) chronic continuous positive airway pressure therapy. Twenty age- and gender-matched controls with baseline sleep study were selected for comparison purposes. Cross-spectral analysis and the low-frequency (LF) and high-frequency (HF) components of the heart rate variability were computed separately over 10-min ECG epochs during rapid eye movement sleep, non-rapid eye movement sleep, and wakefulness. RESULTS: During the baseline study, obstructive sleep apnea patients exhibited increased LF, decreased HF, and increased LF/HF ratio during sleep when compared to controls. In a multiple regression model, the mean oxygen saturation explained the increased LF during rapid and non-rapid eye movement sleep in obstructive sleep apnea patients. Acute continuous positive airway pressure therapy decreased the LF modulations and the LF/HF ratio and increased the HF modulations during sleep in patients with severe obstructive sleep apnea. Long-term continuous positive airway pressure therapy decreased LF modulations and LF/HF ratio with increased HF modulations during sleep in patients with moderate and severe obstructive sleep apnea. CONCLUSIONS: Long-term continuous positive airway pressure reduces the sympathovagal imbalance in patients with moderate and severe obstructive sleep apnea, both during rapid and non-rapid eye movement sleep. Continuous positive airway pressure seems to exert its changes in cardiac autonomic modulation by decreasing the burden of nocturnal hypoxia.
Autores: Rodríguez Díez, María Cristina; Díez Goñi, María de las Nieves; Alegre Esteban, Manuel; et al.
ISSN 0212-6567  Vol. 48  Nº 3  2015  págs. 210 - 212
Autores: Palma Carazo, José Alberto; Iriarte Franco, Jorge (Autor de correspondencia); Fernández González, Secundino; et al.
ISSN 1388-2457  Vol. 125  Nº 9  2014  págs. 1783 - 1791
OBJECTIVE: The pathophysiological basis of obstructive sleep apnea (OSA) is not completely understood and likely varies among patients. In this regard, some patients with OSA do not exhibit hypoxemia. We aimed to analyze the clinical, sleep, and autonomic features of a group of patients with severe OSA without hypoxia (OSA-h) and compare to OSA patients with hypoxia (OSA+h) and controls. METHODS: Fifty-six patients with OSA-h, 64 patients with OSA+h, and 44 control subjects were studied. Clinical and sleep features were analyzed. Besides, time- and frequency-domain heart rate variability (HRV) measures comprising the mean R-R interval, the standard deviation of the RR intervals (SDNN), the low frequency (LF) oscillations, the high frequency (HF) oscillations, and the LF/HF ratio, were calculated across sleep stages during a one-night polysomnography. RESULTS: OSA-h patients had a lower body mass index, a lower waist circumference, lower apnea duration, and a higher frequency of previous naso-pharyngeal surgery when compared to OSA+h patients. In terms of heart rate variability, OSA+h had increased LF oscillations (i.e., baroreflex function) during N1-N2 and rapid eye movement (REM) sleep when compared to OSA-h and controls. Both OSA+h and OSA-h groups had decreased HF oscillations (i.e., vagal inputs) during N1-N2, N3 and REM sleep when compared to controls. The LF/HF ratio was increased during N1-N2 and REM sleep, only in patients with OSA+h. CONCLUSIONS: Patients with OSA-h exhibit distinctive clinical, sleep, and autonomic features when compared to OSA with hypoxia. SIGNIFICANCE: OSA is a heterogeneous entity. These differences must be taken into account in future studies when analyzing therapeutic approaches for sleep apnea patients.
Autores: Palma Carazo, José Alberto (Autor de correspondencia); Alegre Esteban, Manuel; Valencia Ustárroz, Miguel; et al.
Vol. 121  Nº 4  2014  págs. 385 - 390
Autores: Toledo Atucha, Jon; lopez azcarate, Jon; García García, David; et al.
Vol. 64  2014  págs. 60 - 65
Autores: Palma Carazo, José Alberto (Autor de correspondencia); Iriarte Franco, Jorge; Alegre Esteban, Manuel; et al.
ISSN 1872-8952  Vol. 125  Nº 1  2014  págs. 208 - 210
Autores: Pastrana Delgado, Juan Carlos; Campo Ezquibela, Aránzazu; González Hernández, Álvaro; et al.
ISSN 0014-2565  Vol. 214  Nº Esp. Congr.  2014  págs. 1185
Objetivos: Las pruebas ECOE (Evaluación clínica objetiva y estructurada) permiten conocer el nivel de adquisición de competencias clínicas en la formación médica. El proyecto de troncalidad plantea la conveniencia de valorar el grado de adquisición de estas competencias tras los primeros años de especialización. El objetivo de nuestro estudio, fue valorar la viabilidad y resultados de un ECOE sobre competencias clínicas troncales básicas, realizado en residentes de segundo año de especialidades médicas.
Autores: Palma Carazo, José Alberto; Urrestarazu Bolumburu, Elena; Alegre Esteban, Manuel; et al.
ISSN 1388-2457  Vol. 124  Nº 6  2013  págs. 1163 - 1168
OBJECTIVE: Cardiac physiology during sleep in Parkinson's disease (PD) remains poorly explored. We studied heart rate variability (HRV) across sleep stages in PD patients and correlated the results with clinical features. METHODS: Cross-sectional study comprising 33 patients with PD and 29 controls matched for age, gender, and number of apneas/hypopneas per hour. HRV measures, (mean R-R interval, SDNN, ULF, VLF, LF, HF and LF/HF) were calculated separately for all sleep stages as well as wakefulness just before and after sleep during one-night polysomnography. Correlation analysis was performed between HRV values and PD patients' characteristics. RESULTS: The mean R-R interval was lower in all sleep stages in PD patients when compared with controls. VLF and LF were lower during REM sleep in PD patients. HF during N1-N2 stage was higher in PD. We found inverse correlations between VLF and LF during REM sleep and UPDRS-ON and UPDRS-OFF. CONCLUSION: VLF and LF during REM sleep might constitute surrogate markers of disease severity. SIGNIFICANCE: These findings provide additional clinical evidence of the autonomic impairment commonly observed in PD, and prove that cardiac autonomic dysfunction during REM sleep is correlated with disease severity.
Autores: Iriarte Franco, Jorge; Palma Carazo, José Alberto; Fernández González, Secundino; et al.
ISSN 1389-9457  Vol. 14  Nº 2  2013  págs. 217 - 219
Objectives This is a video case report of a 58-year-old male patient with severe obstructive sleep apnea (OSA) who underwent a pharyngo-laryngoscopy during non-drug-induced sleep. Methods The pharyngo-laryngoscopy was performed transnasally during a 30-minute nap, in the afternoon, with a flexible endoscope in supine position. During the procedure, the patient was monitored with polysomnography. Results The patient slept for 20 minutes in supine position, reaching N2 sleep stage. During the sleep, 15 respiratory events (apneas or hypopneas) were recorded. The video-recording showed that, during apneas, the obstruction at the pharyngeal level was never complete, although the nasal sensor showed a total stop in the nasal airflow. Conclusions This case highlights that OSA could not be as obstructive as generally thought, at least during N2 sleep; moreover, it suggests that apneic episodes are not a totally passive and monomorphic phenomenon, but a rather complex event.
Autores: Palma Carazo, José Alberto; Urrestarazu Bolumburu, Elena; lopez azcarate, Jon; et al.
Revista: SLEEP
ISSN 0161-8105  Vol. 36  Nº 6  2013  págs. 933 - 940
OBJECTIVE: To assess autonomic function by heart rate variability (HRV) during sleep in patients with sleep related alveolar hypoventilation (SRAH) and to compare it with that of patients with obstructive sleep apnea (OSA) and control patients. DESIGN: Cross-sectional study. SETTING: Sleep Unit, University Hospital of University of Navarra. PATIENTS: Fifteen idiopathic and obesity related-SRAH patients were studied. For each patient with SRAH, a patient with OSA, matched in age, sex, body mass index (BMI), minimal oxygen saturation (SatO2), and mean SatO2 was selected. Control patients were also matched in age, sex, and BMI with patients with OSA and those with SRAH, and in apnea/hypopnea index (AHI) with patients with SRAH. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: Time- and frequency-domain HRV measures (R-R, standard deviation of normal-to-normal RR interval [SDNN], very low frequency [VLF], low frequency [LF], high frequency [HF], LF/HF ratio) were calculated across all sleep stages as well as during wakefulness just before and after sleep during a 1-night polysomnography. In patients with SRAH and OSA, LF was increased during rapid eye movement (REM) when compared with control patients, whereas HF was decreased during REM and N1-N2 sleep stages. The LF/HF ratio was equally increased in patients with SRAH and OSA during REM and N1-N2. Correlation analysis showed that LF and HF values during REM sleep were correlated with minimal SatO2 and mean SatO2. CONCLUSIONS: Patients with SRAH exhibited an abnormal cardiac tone during sleep. This fact appears to be related to the severity of nocturnal oxygen desaturation. Moreover, there were no differences between OSA and SRAH, supporting the hypothesis that autonomic changes in OSA are primarily related to a reduced nocturnal oxygen saturation, rather than a consequence of other factors such as nocturnal respiratory events.
Autores: Alegre Esteban, Manuel (Autor de correspondencia); Valencia Ustárroz, Miguel
ISSN 00144886  Vol. 248  2013  págs. 183 - 186
Autores: lopez azcarate, Jon; Nicolas, Maria Jesus; Cordón, Iván; et al.
ISSN 1662-5110  Vol. 7  2013  págs. 155
Autores: Alegre Esteban, Manuel; lopez azcarate, Jon; Obeso Martin, I.; et al.
ISSN 0014-4886  Vol. 239  2013  págs. 1 - 12
Normal actions and behaviors often require inhibition of unwanted and inadequate movements. Motor inhibition has been studied using the stop signal task, in which participants are instructed to respond to a go signal. Sporadically, a stop signal is also delivered after a short interval following the go signal, prompting participants to inhibit their already started response to the go signal. Functional MRI studies using this paradigm have implicated the activation of the subthalamic nucleus in motor inhibition. We directly recorded subthalamic nucleus activity from bilaterally implanted deep brain stimulation electrodes in a group of 10 patients with Parkinson's disease, during performance of the stop signal task. Response inhibition was associated with specific changes in subthalamic activity in three different frequency bands. Response preparation was associated with a decrease in power and cortico-subthalamic coherence in the beta band (12-30 Hz), which was smaller and shorter when the response was successfully inhibited. In the theta band, we observed an increase in frontal cortico-subthalamic coherence related to the presence of the stop signal, which was highest when response inhibition was unsuccessful. Finally, a specific differential pattern of gamma activity was observed in the "on" motor state. Performance of the response was associated with a significant increase in power and cortico-subthalamic coherence, while successful inhibition of the response was associated with a bilateral decrease in subthalamic power and cortico-subthalamic coherence. Importantly, this inhibition-related decrease in gamma activity was absent in the four patients with dopamine-agonist related impulse-control disorders. Our results provide direct support for the involvement of the subthalamic nucleus in response inhibition and suggest that this function may be mediated by a specific reduction in gamma oscillations in the cortico-subthalamic connection.
Autores: Valencia Ustárroz, Miguel; lopez azcarate, Jon; Nicolas, Maria Jesus; et al.
Vol. 45  Nº 5  2012  págs. 619 - 628
Autores: Alegre Esteban, Manuel (Autor de correspondencia); lopez azcarate, Jon; Alonso-Frech, F.; et al.
ISSN 0885-3185  Vol. 27  Nº 9  2012  págs. 1176 - 1179
From a neurophysiological viewpoint, patients exhibited oscillatory activity typical of the "on" medication state during diphasic dyskinesias. The minimal presence of gamma activity during diphasic dyskinesias, however, suggests that this "on" state might be incomplete or limited to dopaminergic mechanisms affecting the lower limbs.
Autores: Kufoy, E.; Palma Carazo, José Alberto; lopez azcarate, Jon; et al.
Revista: PLOS ONE
ISSN 1932-6203  Vol. 7  Nº 3  2012  págs. e33769
Introduction: Obstructive Sleep Apnea (OSA) is a major risk factor for cardiovascular disease. The goal of this study was to demonstrate whether the use of CPAP produces significant changes in the heart rate or in the heart rate variability of patients with OSA in the first night of treatment and whether gender and obesity play a role in these differences. Methods: Single-center transversal study including patients with severe OSA corrected with CPAP. Only patients with total correction after CPAP were included. Patients underwent two sleep studies on consecutive nights: the first night a basal study, and the second with CPAP. We also analyzed the heart rate changes and their relationship with CPAP treatment, sleep stages, sex and body mass index. Twenty-minute segments of the ECG were selected from the sleep periods of REM, no-REM and awake. Heart rate (HR) and heart rate variability (HRV) were studied by comparing the R-R interval in the different conditions. We also compared samples from the basal study and CPAP nights. Results: 39 patients (15 females, 24 males) were studied. The mean age was 50.67 years old, the mean AHI was 48.54, and mean body mass index was 33.41 kg/m(2) (31.83 males, 35.95 females). Our results showed that HRV (SDNN) decreased after the use of CPAP during the first night of treatment, especially in non-REM sleep. Gender and obesity did not have any influence on our results. Conclusions: These findings support that cardiac variability improves as an acute effect, independently of gender or weight, in the first night of CPAP use in severe OSA patients, supporting the idea of continuous use and emphasizing that noncompliance of CPAP treatment should be avoided even if it is just once.
Autores: Guridi Legarra, Jorge; Rodríguez Oroz, María Cruz; Alegre Esteban, Manuel; et al.
ISSN 1353-8020  Vol. 18  Nº 6  2012  págs. 765-769
It is important to identify this hardware problem in view of the growing number of patients receiving this therapy. A protocol for patients with loss of stimulation efficacy and electrode impedance increment needs to be created in clinical visits in order to detect the failed stimulation mechanism.
Autores: Nicolás Apesteguía, María Jesús; lopez azcarate, Jon; Valencia Ustárroz, Miguel; et al.
Revista: PLOS ONE
ISSN 1932-6203  Vol. 6  Nº 7  2011  págs. e21814-
Autores: Iriarte Franco, Jorge; Fernández González, Secundino; Fernández-Arrechea, Natalia; et al.
ISSN 1520-9512  Vol. 15  Nº 2  2011  págs. 229 - 235
Purpose: Catathrenia (nocturnal groaning) is a rare and relatively little-understood parasomnia. The characteristics of the sound and the recordings are not similar in all the relevant research papers. Indeed, there is currently some discussion regarding whether or not this is a single entity. For some authors, catathrenia is a particular form of parasomnia; for others, it may be a variant of snoring or a respiratory problem. The goal is to establish whether or not catathrenia may be regarded as an expiratory vocal sound. An attempt was made to classify the origin of this sound according to its sound structure. Methods: We present the sound analysis of two patients, a man and a woman, with clinically diagnosed catathrenia and we compared them with the analysis of snoring. We use the spectrogram and the oscillogram. We classified the sounds according to the Yanagihara criteria. Results: The vocal nature of the sound was confirmed, and several significant differences to some snoring sounds were discovered. The analysis of the catathrenia samples demonstrated that these signals are type II according to Yanagihara classification; these signals had a very short jitter, and had formants and harmonics. However, snoring is a type III, very irregular and had formants but not harmonics. Conclusions: The oscillogram and the spectrogram in these patients show that the origins of the sounds are clearly different: catathrenia is laryngeal, while snoring is guttural. Catathrenia cannot be considered as expiratory snoring.
Autores: Rodríguez Oroz, María Cruz; lopez azcarate, Jon; García García, David; et al.
Revista: BRAIN
ISSN 0006-8950  Vol. 134  Nº 1  2011  págs. 36-49
Behavioural abnormalities such as impulse control disorders may develop when patients with Parkinson's disease receive dopaminergic therapy, although they can be controlled by deep brain stimulation of the subthalamic nucleus. We have recorded local field potentials in the subthalamic nucleus of 28 patients with surgically implanted subthalamic electrodes. According to the predominant clinical features of each patient, their Parkinson's disease was associated with impulse control disorders (n = 10), dyskinesias (n = 9) or no dopaminergic mediated motor or behavioural complications (n = 9). Recordings were obtained during the OFF and ON dopaminergic states and the power spectrum of the subthalamic activity as well as the subthalamocortical coherence were analysed using Fourier transform-based techniques. The position of each electrode contact was determined in the postoperative magnetic resonance image to define the topography of the oscillatory activity recorded in each patient. In the OFF state, the three groups of patients had similar oscillatory activity. By contrast, in the ON state, the patients with impulse control disorders displayed theta-alpha (4-10 Hz) activity (mean peak: 6.71 Hz) that was generated 2-8 mm below the intercommissural line. Similarly, the patients with dyskinesia showed theta-alpha activity that peaked at a higher frequency (mean: 8.38 Hz) and was generated 0-2 mm below the intercommissural line. No such activity was detected in patients that displayed no dopaminergic side effects. Cortico-subthalamic coherence was more frequent in the impulsive patients in the 4-7.5 Hz range in scalp electrodes placed on the frontal regions anterior to the primary motor cortex, while in patients with dyskinesia it was in the 7.5-10 Hz range in the leads overlying the primary motor and supplementary motor area. Thus, dopaminergic side effects in Parkinson's disease are associated with oscillatory activity in the theta-alpha band, but at different frequencies and with different topography for the motor (dyskinesias) and behavioural (abnormal impulsivity) manifestations. These findings suggest that the activity recorded in parkinsonian patients with impulse control disorders stems from the associative-limbic area (ventral subthalamic area), which is coherent with premotor frontal cortical activity. Conversely, in patients with l-dopa-induced dyskinesias such activity is recorded in the motor area (dorsal subthalamic area) and it is coherent with cortical motor activity. Consequently, the subthalamic nucleus appears to be implicated in the motor and behavioural complications associated with dopaminergic drugs in Parkinson's disease, specifically engaging different anatomo-functional territories
Autores: Alegre Esteban, Manuel; Guridi Legarra, Jorge; Artieda González-Granda, Julio
Revista: Journal of the Neurological Sciences
ISSN 0022-510X  Vol. 310  Nº 1-2  2011  págs. 194 - 196
Autores: Alegre Esteban, Manuel; Urrestarazu Bolumburu, Elena
ISSN 0736-0258  Vol. 122  Nº 8  2011  págs.  1480 - 1481
Autores: Arrondo Ostíz, Gonzalo; Alegre Esteban, Manuel; Villoslada Díaz, Pablo
ISSN 2041-8000  Vol. 1  2010  págs. 1 - 8
Memantine, an uncompetitive, low-affinity N-methyl-D-aspartate (NMDA) receptor antagonist, is an approved compound for use inmoderate to severe Alzheimer¿s disease. Its pharmacological features allow it to block excessive neuronal activation produced by glutamate,while permitting normal activation of the NMDA receptor channel. A review of the trials that have evaluated the use of the compound invascular dementia, Alzheimer¿s disease, or both shows that it is well tolerated and has mild but statistically significant positive effects oncognition and other domains of patients with advanced Alzheimer¿s disease. Recently, a double-blind, placebo-controlled trial in patients withmultiple sclerosis reported neurological worsening in several patients similar to the typical pseudoexacerbations of this disease. Also, the useof memantine in patients with Lewy body disease produces adverse effects. Although the mechanisms of such side-effects are unknown, wesuggest that they could be due to the impairment of synaptic transmission in the demyelinated pathways.
Autores: Pérez Alcázar, Marta; Nicolas, Maria Jesus; Valencia Ustárroz, Miguel; et al.
ISSN 1872-6240  Vol. 1310  2010  págs. 58 - 67
Autores: lopez azcarate, Jon; Tainta, Mikel; Rodríguez Oroz, María Cruz; et al.
ISSN 1529-2401  Vol. 30  Nº 19  2010  págs. 6667 - 6677
Autores: Unzu Ezquerro, Carmen María; Sampedro Pascual, Ana; Mauleón Mayora, Itsaso; et al.
Revista: Molecular Therapy
ISSN 1525-0016  Vol. 19  Nº 2  2010  págs. 243 - 250
Acute intermittent porphyria (AIP) is characterized by a hereditary deficiency of hepatic porphobilinogen deaminase (PBGD) activity. Clinical features are acute neurovisceral attacks accompanied by overproduction of porphyrin precursors in the liver. Recurrent life-threatening attacks can be cured only by liver transplantation. We developed recombinant adeno-associated virus (rAAV) vectors expressing human PBGD protein driven by a liver-specific promoter to provide sustained protection against induced attacks in a predictive model for AIP. Phenobarbital injections in AIP mice induced porphyrin precursor accumulation, functional block of nerve conduction, and progressive loss of large-caliber axons in the sciatic nerve. Hepatocyte transduction showed no gender variation after rAAV2/8 injection, while rAAV2/5 showed lower transduction efficiency in females than males. Full protection against induced phenobarbital-attacks was achieved in animals showing over 10% of hepatocytes expressing high amounts of PBGD. More importantly, sustained hepatic expression of hPBGD protected against loss of large-caliber axons in the sciatic nerve and disturbances in nerve conduction velocity as induced by recurrent phenobarbital administrations. These data show for the first time that porphyrin precursors generated in the liver interfere with motor function. rAAV2/5-hPBGD vector can be produced in sufficient quantity for an intended gene therapy trial in patients with recurrent life-threatening porphyria attacks.