Grupos Investigadores

Miembros del Grupo

Coordinador
Rodríguez Oroz, María Cruz
(mcroroz@unav.es)
Investigadores
Iciar
Avilés Olmos
María de Aránzazu
Gorospe Osinalde
Antonio
Martin Bastida
Ana
Quiroga Varela
Marta
Zamarbide González
Colaboradores
Laura
Armengou García
Arántzazu
Belloso Iguerategui
Leire
Merino Galan

Líneas de Investigación

  • Alteración funcional y estructural de la sinapsis dopaminérgica en la enfermedad de Parkinson.
  • Demencia y deterioro cognitivo en la enfermedad de Parkinson.
  • Estimulación cerebral profunda, lesiones por HIFU (high intensity focused ultrasound) y fisiopatología de los ganglios basales en la enfermedad de Parkinson.
  • Papel de la activación glial y mecanismos inflamatorios en la muerte dopaminérgica.
  • Trastornos de control de impulsos en la enfermedad de Parkinson.
  • Trastornos de la marcha en la enfermedad de Parkinson.

Palabras Clave

  • Demencia
  • Deterioro cognitivo
  • Estimulación cerebral profunda
  • Ganglios basales
  • Glía
  • HIFU
  • Neuroinflamación
  • Parkinson
  • Sinapsis
  • Trastorno de impulsividad

Publicaciones Científicas desde 2018

  • Autores: Dileone, M.; Ammann, C.; Catanzaro, V.; et al.
    Revista: BRAIN STIMULATION
    ISSN: 1935-861X Vol.15 N° 3 2022 págs. 857 - 860
  • Autores: Mohamed, M. A.; Zeng, Z.; Gennaro, M.; et al.
    Revista: BRAIN COMMUNICATIONS
    ISSN: 2632-1297 Vol.4 N° 5 2022 págs. fcac199
    Resumen
    This is an imaging study in Parkinson's disease dementia with C-11-BU99008 PET (experimental radioligand developed to assess astrocytic distribution in the living brain). Mohamed M. and Zeng Z et al. report that astrogliosis is common with aging in a region-specific manner. Here, C-11-BU99008 PET does not differentiate these patients from healthy controls. The role of astrogliosis in the pathology of brain aging and neurodegenerative diseases has recently drawn great attention. Imidazoline-2 binding sites represent a possible target to map the distribution of reactive astrocytes. In this study, we use C-11-BU99008, an imidazoline-2 binding sites-specific PET radioligand, to image reactive astrocytes in vivo in healthy controls and patients with established Parkinson's disease dementia. Eighteen healthy controls (age: 45-78 years) and six patients with Parkinson's disease dementia (age: 64-77 years) had one C-11-BU99008 PET-CT scan with arterial input function. All subjects underwent one 3 T MRI brain scan to facilitate the analysis of the PET data and to capture individual cerebral atrophy. Regional C-11-BU99008 volumes of distribution were calculated for each subject by the two-tissue compartmental modelling. Positive correlations between C-11-BU99008 volumes of distribution values and age were found for all tested regions across the brain within healthy controls (P < 0.05); furthermore, multiple regression indicated that aging affects C-11-BU99008 volumes of distribution values in a region-specific manner. Independent samples t-test indicated that there was no significant group difference in C-11-BU99008 volumes of distribution values between Parkinson's disease dementia (n = 6; mean age = 71.97 +/- 4.66 years) and older healthy controls (n = 9; mean age = 71.90 +/- 5.51 years). Our data set shows that astrogliosis is common with aging in a region-specific manner. However, in this set-up, C-11-BU99008 PET cannot differentiate patients with Parkinson's disease dementia from healthy controls of similar age.
  • Autores: Basaia, S.; Agosta, F.; Diez, I.; et al.
    Revista: NEUROIMAGE. CLINICAL
    ISSN: 2213-1582 Vol.33 2022 págs. 102941
    Resumen
    The genetic traits that underlie vulnerability to neuronal damage across specific brain circuits in Parkinson's disease (PD) remain to be elucidated. In this study, we characterized the brain topological intersection between propagating connectivity networks in controls and PD participants and gene expression patterns across the human cortex - such as the SNCA gene. We observed that brain connectivity originated from PD-related pathology epicenters in the brainstem recapitulated the anatomical distribution of alpha-synuclein histopathology in postmortem data. We also discovered that the gene set most related to cortical propagation patterns of PDrelated pathology was primarily involved in microtubule cellular components. Thus, this study sheds light on new avenues for enhancing detection of PD neuronal vulnerability via an evaluation of in vivo connectivity trajectories across the human brain and successful integration of neuroimaging-genetic strategies.
  • Autores: Xing, Y.; Sapuan, A. H.; Martin Bastida, Antonio; et al.
    Revista: MOVEMENT DISORDERS
    ISSN: 0885-3185 Vol.37 N° 5 2022 págs. 1028 - 1039
    Resumen
    Background Clinical diagnosis and monitoring of Parkinson's disease (PD) remain challenging because of the lack of an established biomarker. Neuromelanin-magnetic resonance imaging (NM-MRI) is an emerging biomarker of nigral depigmentation indexing the loss of melanized neurons but has unknown prospective diagnostic and tracking performance in multicenter settings. Objectives The aim was to investigate the diagnostic accuracy of NM-MRI in early PD in a multiprotocol setting and to determine and compare serial NM-MRI changes in PD and controls. Methods In this longitudinal case-control 3 T MRI study, 148 patients and 97 controls were included from six UK clinical centers, of whom 140 underwent a second scan after 1.5 to 3 years. An automated template-based analysis was applied for subregional substantia nigra NM-MRI contrast and volume assessment. A point estimate of the period of prediagnostic depigmentation was computed. Results All NM metrics performed well to discriminate patients from controls, with receiver operating characteristic showing 85% accuracy for ventral NM contrast and 83% for volume. Generalizability using a priori volume cutoff was good (79% accuracy). Serial MRI demonstrated accelerated NM loss in patients compared to controls. Ventral NM contrast loss was point estimated to start 5 to 6 years before clinical diagnosis. Ventral nigral depigmentation was greater in the most affected side, more severe cases, and nigral NM volume change correlated with change in motor severity. Conclusions We demonstrate that NM-MRI provides clinically useful diagnostic information in early PD across protocols, platforms, and sites. It provides methods and estimated depigmentation rates that highlight the potential to detect preclinical PD and track progression for biomarker-enabled clinical trials. (c) 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society
  • Autores: Basaia, S.; Agosta, F.; Díez-Palacio, I.; et al.
    Revista: NEUROLOGY
    ISSN: 0028-3878 Vol.98 N° 18 2022
  • Autores: Martin Bastida, Antonio; Delgado-Alvarado, M.; Navalpotro-Gómez, I.; et al.
    Revista: FRONTIERS IN NEUROLOGY
    ISSN: 1664-2295 Vol.12 2021 págs. 733570
    Resumen
    Dementia and mild forms of cognitive impairment as well as neuropsychiatric symptoms (i. e., impulse control disorders) are frequent and disabling non-motor symptoms of Parkinson's disease (PD). The identification of changes in neuroimaging studies for the early diagnosis and monitoring of the cognitive and neuropsychiatric symptoms associated with Parkinson's disease, as well as their pathophysiological understanding, are critical for the development of an optimal therapeutic approach. In the current literature review, we present an update on the latest structural and functional neuroimaging findings, including high magnetic field resonance and radionuclide imaging, assessing cognitive dysfunction and impulse control disorders in PD.
  • Autores: Ward, R. J.; Dexter, D. T.; Martin Bastida, Antonio; et al.
    Revista: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
    ISSN: 1422-0067 Vol.22 N° 7 2021 págs. 3338
    Resumen
    Iron loading in some brain regions occurs in Parkinson's Disease (PD), and it has been considered that its removal by iron chelators could be an appropriate therapeutic approach. Since neuroinflammation with microgliosis is also a common feature of PD, it is possible that iron is sequestered within cells as a result of the "anaemia of chronic disease" and remains unavailable to the chelator. In this review, the extent of neuroinflammation in PD is discussed together with the role played by glia cells, specifically microglia and astrocytes, in controlling iron metabolism during inflammation, together with the results of MRI studies. The current use of chelators in clinical medicine is presented together with a discussion of two clinical trials of PD patients where an iron chelator was administered and showed encouraging results. It is proposed that the use of anti-inflammatory drugs combined with an iron chelator might be a better approach to increase chelator efficacy.
  • Autores: Milán Tomás, Ángela; Fernández Matarrubia, Marta; Rodríguez Oroz, María Cruz (Autor de correspondencia)
    Revista: BEHAVIORAL SCIENCES
    ISSN: 2076-328X Vol.11 N° 7 2021 págs. 94
    Resumen
    Lewy body dementias (LBDs) consist of dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD), which are clinically similar syndromes that share neuropathological findings with widespread cortical Lewy body deposition, often with a variable degree of concomitant Alzheimer pathology. The objective of this article is to provide an overview of the neuropathological and clinical features, current diagnostic criteria, biomarkers, and management of LBD. Literature research was performed using the PubMed database, and the most pertinent articles were read and are discussed in this paper. The diagnostic criteria for DLB have recently been updated, with the addition of indicative and supportive biomarker information. The time interval of dementia onset relative to parkinsonism remains the major distinction between DLB and PDD, underpinning controversy about whether they are the same illness in a different spectrum of the disease or two separate neurodegenerative disorders. The treatment for LBD is only symptomatic, but the expected progression and prognosis differ between the two entities. Diagnosis in prodromal stages should be of the utmost importance, because implementing early treatment might change the course of the illness if disease-modifying therapies are developed in the future. Thus, the identification of novel biomarkers constitutes an area of active research, with a special focus on oc-synuclein markers.
  • Autores: Errea, O.; Rodríguez Oroz, María Cruz (Autor de correspondencia)
    Revista: MOVEMENT DISORDERS
    ISSN: 0885-3185 Vol.36 N° 1 2021 págs. 83
  • Autores: Neumann, W. J. (Autor de correspondencia); Rodríguez Oroz, María Cruz
    Revista: MOVEMENT DISORDERS
    ISSN: 0885-3185 Vol.36 N° 4 2021 págs. 796 - 799
  • Autores: Martin Bastida, Antonio (Autor de correspondencia); Tilley, B. S. ; Bansal, S.; et al.
    Revista: JOURNAL OF NEURAL TRANSMISSION
    ISSN: 0300-9564 Vol.128 N° 1 2021 págs. 15 - 25
    Resumen
    In these present studies, in vivo and and post-mortem studies have investigated the association between iron and inflammation. Early-stage Parkinson's disease (PD) patients, of less than 5 years disease duration, showed associations of plasmatic ferritin concentrations with both proinflammatory cytokine interleukin-6 and hepcidin, a regulator of iron metabolism as well as clinical measures. In addition ratios of plasmatic ferritin and iron accumulation in deep grey matter nuclei assessed with relaxometry T2* inversely correlated with disease severity and duration of PD. On the hand, post-mortem material of the substantia nigra compacta (SNc) divided according to Braak and Braak scores, III-IV and V-VI staging, exhibited comparable microgliosis, with a variety of phenotypes present. There was an association between the intensity of microgliosis and iron accumulation as assayed by Perl's staining in the SNc sections. In conclusion, markers of inflammation and iron metabolism in both systemic and brain systems are closely linked in PD, thus offering a potential biomarker for progression of the disease.
  • Autores: Esteban-Peñalba, T.; Paz-Alonso, P. M.; Navalpotro-Gómez, I.; et al.
    Revista: NEUROIMAGE. CLINICAL
    ISSN: 2213-1582 Vol.32 2021 págs. 102822
    Resumen
    Impulse control disorder is a prevalent side-effect of Parkinson's disease (PD) medication, with a strong negative impact on the quality of life of those affected. Although impulsivity has classically been associated with response inhibition deficits, previous evidence from PD patients with impulse control disorder (ICD) has not revealed behavioral dysfunction in response inhibition. In this study, 18 PD patients with ICD, 17 PD patients without this complication, and 15 healthy controls performed a version of the conditional Stop Signal Task during functional magnetic resonance imaging. Whole-brain contrasts, regions of interest, and functional connectivity analyses were conducted. Our aim was to investigate the neural underpinnings of two aspects of response inhibition: proactive inhibition, inhibition that has been prepared beforehand, and restrained inhibition, inhibition of an invalid inhibitory tendency. We observed that, in respect to the other two groups, PD patients with ICD exhibited hyperactivation of the stopping network bilaterally while performing proactive inhibition. When engaged in restrained inhibition, they showed hyperactivation of the left inferior frontal gyrus, an area linked to action monitoring. Restrained inhibition also resulted in changes to the functional co-activation between inhibitory regions and left inferior parietal cortex and right supramarginal gyrus. Our findings indicate that PD patients with ICD completed the inhibition task correctly, showing altered engagement of inhibitory and attentional areas. During proactive inhibition they showed bilateral hyperactivation of two inhibitory regions, while during restrained inhibition they showed additional involvement of attentional areas responsible for alerting and orienting.
  • Autores: Parkin, B. L.; Daws, R. E.; Das-Neves, I.; et al.
    Revista: BRAIN COMMUNICATIONS
    ISSN: 2632-1297 Vol.3 N° 3 2021 págs. fcab175
    Resumen
    The cognitive deficits associated with Parkinson's disease vary across individuals and change across time, with implications for prognosis and treatment. Key outstanding challenges are to define the distinct behavioural characteristics of this disorder and develop diagnostic paradigms that can assess these sensitively in individuals. In a previous study, we measured different aspects of attentional control in Parkinson's disease using an established fMRI switching paradigm. We observed no deficits for the aspects of attention the task was designed to examine; instead those with Parkinson's disease learnt the operational requirements of the task more slowly. We hypothesized that a subset of people with early-to-mid stage Parkinson's might be impaired when encoding rules for performing new tasks. Here, we directly test this hypothesis and investigate whether deficits in instruction-based learning represent a characteristic of Parkinson's Disease. Seventeen participants with Parkinson's disease (8 male; mean age: 61.2 years), 18 older adults (8 male; mean age: 61.3 years) and 20 younger adults (10 males; mean age: 26.7 years) undertook a simple instruction-based learning paradigm in the MRI scanner. They sorted sequences of coloured shapes according to binary discrimination rules that were updated at two-minute intervals. Unlike common reinforcement learning tasks, the rules were unambiguous, being explicitly presented; consequently, there was no requirement to monitor feedback or estimate contingencies. Despite its simplicity, a third of the Parkinson's group, but only one older adult, showed marked increases in errors, 4 SD greater than the worst performing young adult. The pattern of errors was consistent, reflecting a tendency to misbind discrimination rules. The misbinding behaviour was coupled with reduced frontal, parietal and anterior caudate activity when rules were being encoded, but not when attention was initially oriented to the instruction slides or when discrimination trials were performed. Concomitantly, Magnetic Resonance Spectroscopy showed reduced gamma-Aminobutyric acid levels within the mid-dorsolateral prefrontal cortices of individuals who made misbinding errors. These results demonstrate, for the first time, that a subset of early-to-mid stage people with Parkinson's show substantial deficits when binding new task rules in working memory. Given the ubiquity of instruction-based learning, these deficits are likely to impede daily living. They will also confound clinical assessment of other cognitive processes. Future work should determine the value of instruction-based learning as a sensitive early marker of cognitive decline and as a measure of responsiveness to therapy in Parkinson's disease.
  • Autores: Pagonabarraga, J. (Autor de correspondencia); Arbelo, J. M.; Grandas, F.; et al.
    Revista: BRAIN SCIENCES
    ISSN: 2076-3425 Vol.10 N° 3 2020 págs. 176
    Resumen
    Safinamide is an approved drug for the treatment of motor fluctuations in Parkinson's disease (PD). Scarce data are available on its use in clinical practice. A group of Spanish movement disorders specialists was convened to review the use of safinamide across different clinical scenarios that may guide neurologists in clinical practice. Eight specialists with recognized expertise in PD management elaborated the statements based on available evidence in the literature and on their clinical experience. The RAND/UCLA method was carried, with final conclusions accepted after a 2-round modified Delphi process. Higher level of agreement between panellists was reached for the following statements. Safinamide significantly improves mean daily OFF time without troublesome dyskinesias. Adjunctive treatment with safinamide is associated with motor improvements in patients with mid-to-late PD. The efficacy of safinamide on motor fluctuations is maintained at long-term, with no increase over time in dyskinesias severity. The clinical benefits of safinamide on pain and depression remain unclear. Safinamide presents a similar incidence of adverse events compared with placebo. The efficacy and safety of safinamide shown in the pivotal clinical trials are reproduced in clinical practice, with improvement of parkinsonian symptoms, decrease of daily OFF time, control of dyskinesias at the long term, and good tolerability and safety.
  • Autores: Pagonabarraga, J. (Autor de correspondencia); Arbelo, J. M.; Grandas, F. ; et al.
    Revista: BRAIN SCIENCES
    ISSN: 2076-3425 Vol.10 N° 5 2020 págs. 313
  • Autores: Navalpotro-Gómez, I.; Kim, J. ; Paz-Alonso, P. M.; et al.
    Revista: PARKINSONISM AND RELATED DISORDERS
    ISSN: 1353-8020 Vol.70 2020 págs. 74 - 81
    Resumen
    Background: Dynamic functional network analysis may add relevant information about the temporal nature of the neurocognitive alterations in PD patients with impulse control disorders (PD-ICD). Our aim was to investigate changes in dynamic functional network connectivity (dFNC) in PD-ICD patients, and topological properties of such networks. Methods: Resting state fMRI was performed on 16 PD PD-ICD patients, 20 PD patients without ICD and 17 healthy controls, whose demographic, clinical and behavioral scores were assessed. We conducted a group spatial independent component analysis, sliding window and graph-theory analyses. Results: PD-ICD patients, in contrast to PD-noICD and HC subjects, were engaged across time in a brain configuration pattern characterized by a lack of between-network connections at the expense of strong within-network connections (State III) in temporal, frontoinsular and cingulate cortices, all key nodes of the salience network. Moreover, this increased maintenance of State III in PD-ICD patients was positively correlated with the severity of impulsivity and novelty seeking as measured by specific scales. While in State III, these patients also exhibited increased local efficiency in all the aforementioned areas. Conclusions: Our findings show for the first time that PD-ICD patients have a dynamic functional engagement of local connectivity involving the limbic circuit, leading to the inefficient modulation in emotional processing and reward-related decision-making. These results provide new insights into the pathophysiology of ICD in PD padents and indicate that the dFC study of fMRI could be a useful biomarker to identify patients at risk to develop ICD.
  • Autores: Meles, S. K.; Renken, R. J.; Pagani, M.; et al.
    Revista: EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING
    ISSN: 1619-7070 Vol.47 N° 2 2020 págs. 437 - 450
    Resumen
    Rationale In Parkinson's disease (PD), spatial covariance analysis of F-18-FDG PET data has consistently revealed a characteristic PD-related brain pattern (PDRP). By quantifying PDRP expression on a scan-by-scan basis, this technique allows objective assessment of disease activity in individual subjects. We provide a further validation of the PDRP by applying spatial covariance analysis to PD cohorts from the Netherlands (NL), Italy (IT), and Spain (SP). Methods The PDRPNL was previously identified (17 controls, 19 PD) and its expression was determined in 19 healthy controls and 20 PD patients from the Netherlands. The PDRPIT was identified in 20 controls and 20 "de-novo" PD patients from an Italian cohort. A further 24 controls and 18 "de-novo" Italian patients were used for validation. The PDRPSP was identified in 19 controls and 19 PD patients from a Spanish cohort with late-stage PD. Thirty Spanish PD patients were used for validation. Patterns of the three centers were visually compared and then cross-validated. Furthermore, PDRP expression was determined in 8 patients with multiple system atrophy. Results A PDRP could be identified in each cohort. Each PDRP was characterized by relative hypermetabolism in the thalamus, putamen/pallidum, pons, cerebellum, and motor cortex. These changes co-varied with variable degrees of hypometabolism in posterior parietal, occipital, and frontal cortices. Frontal hypometabolism was less pronounced in "de-novo" PD subjects (Italian cohort). Occipital hypometabolism was more pronounced in late-stage PD subjects (Spanish cohort). PDRPIT, PDRPNL, and PDRPSP were significantly expressed in PD patients compared with controls in validation cohorts from the same center (P < 0.0001), and maintained significance on cross-validation (P < 0.005). PDRP expression was absent in MSA. Conclusion The PDRP is a reproducible disease characteristic across PD populations and scanning platforms globally. Further study is needed to identify the topography of specific PD subtypes, and to identify and correct for center-specific effects.
  • Autores: Rodríguez-Chinchilla, T.; Quiroga Varela, Ana; Molinet-Dronda, F.; et al.
    Revista: EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING
    ISSN: 1619-7070 Vol.47 N° 11 2020 págs. 2602 - 2612
  • Autores: Jimenez-Urbieta, H.; Gago, B.; Quiroga Varela, Ana; et al.
    Revista: PSYCHOPHARMACOLOGY
    ISSN: 0033-3158 Vol.237 N° 8 2020 págs. 2419 - 2431
    Resumen
    Rationale Impulse control disorders (ICD) and other impulsive-compulsive behaviours are frequently found in Parkinson's disease (PD) patients treated with dopaminergic agonists. To date, there are no available animal models to investigate their pathophysiology and determine whether they can be elicited by varying doses of dopaminergic drugs. In addition, there is some controversy regarding the predispositional pattern of striatal dopaminergic depletion. Objectives To study the effect of two doses of pramipexole (PPX) on motor impulsivity, delay intolerance and compulsive-like behaviour. Methods Male rats with mild dopaminergic denervation in the dorsolateral striatum (bilateral injections of 6-hydroxidopamine (6-OHDA)) treated with two doses of PPX (0.25 mg/kg and 3 mg/kg) and tested in the variable delay-to-signal paradigm. Results Partial (50%) dopaminergic depletion did not induce significant changes in motor impulsivity or delay intolerance. However, 0.25 mg/kg of PPX increased motor impulsivity, while 3 mg/kg of PPX increased both motor impulsivity and delay intolerance. These effects were independent of the drug's antiparkinsonian effects. Importantly, impulsivity scores before and after dopaminergic lesion were positively associated with the impulsivity observed after administering 3 mg/kg of PPX. No compulsive-like behaviour was induced by PPX administration. Conclusions We described a rat model, with a moderate dorsolateral dopaminergic lesion resembling that suffered by patients with early PD, that develops different types of impulsivity in a dose-dependent manner dissociated from motor benefits when treated with PPX. This model recapitulates key features of abnormal impulsivity in PD and may be useful for deepening our understanding of the pathophysiology of ICD.
  • Autores: Li, WH. (Autor de correspondencia); Lao-Kaim, NP. ; Roussakis, A. A. ; et al.
    Revista: NEUROIMAGE. CLINICAL
    ISSN: 2213-1582 Vol.28 2020 págs. 102409
    Resumen
    Background: Resting-state functional magnetic resonance imaging (fMRI) studies have demonstrated that basal ganglia functional connectivity is altered in Parkinson's disease (PD) as compared to healthy controls. However, such functional connectivity alterations have not been related to the dopaminergic deficits that occurs in PD over time. Objectives: To examine whether functional connectivity impairments are correlated with dopaminergic deficits across basal ganglia subdivisions in patients with PD both cross-sectionally and longitudinally. Methods: We assessed resting-state functional connectivity of basal ganglia subdivisions and dopamine transporter density using C-11-PE2I PET in thirty-four PD patients at baseline. Of these, twenty PD patients were rescanned after 19.9 +/- 3.8 months. A seed-based approach was used to analyze resting-state fMRI data. C-11-PE2I binding potential (BPND) was calculated for each participant. PD patients were assessed for disease severity. Results: At baseline, PD patients with greater dopaminergic deficits, as measured with C-11-PE2I PET, showed larger decreases in posterior putamen functional connectivity with the midbrain and pallidum. Reduced functional connectivity of the posterior putamen with the thalamus, midbrain, supplementary motor area and sensorimotor cortex over time were significantly associated with changes in DAT density over the same period. Furthermore, increased motor disability was associated with lower intraregional functional connectivity of the posterior putamen. Conclusions: Our findings suggest that basal ganglia functional connectivity is related to integrity of dopaminergic system in patients with PD. Application of resting-state fMRI in a large cohort and longitudinal scanning may be a powerful tool for assessing underlying PD pathology and its progression.
  • Autores: Paz-Alonso, P. M. (Autor de correspondencia); Navalpotro-Gomez, I. ; Boddy, P.; et al.
    Revista: MOVEMENT DISORDERS
    ISSN: 0885-3185 Vol.35 N° 2 2020 págs. 316 - 325
    Resumen
    BACKGROUND: Impulse control disorders related to alterations in the mesocorticolimbic dopamine network occur in Parkinson's disease (PD). Our objective was to investigate the functional neural substrates of reward processing and inhibitory control in these patients. METHODS: Eighteen PD patients with impulse control disorders, 17 without this complication, and 18 healthy controls performed a version of the Iowa Gambling Task during functional magnetic resonance scanning under 3 conditions: positive, negative, and mixed feedback. Whole-brain contrasts, regions of interest, time courses, functional connectivity analyses, and brain-behavior associations were examined. RESULTS: PD patients with impulse control disorders exhibited hyperactivation in subcortical and cortical regions typically associated with reward processing and inhibitory control compared with their PD and healthy control counterparts. Time-course analyses revealed that only PD patients with impulse control disorders exhibited stronger signal intensity during the initial versus final periods of the negative-feedback condition in bilateral insula, and right ventral striatum. Interestingly, hyperactivation of all the examined right-lateralized frontostriatal areas during negative feedback was positively associated with impulse control disorder severity. Importantly, positive associations between impulse control disorder severity and regional activations in the right insula and right inferior frontal gyrus, but not the right subthalamic nucleus, were mediated by functional connectivity with the right ventral striatum. CONCLUSIONS: During a reward-based task, PD patients with impulse control disorders showed hyperactivation in a right-lateralized network of regions including the subthalamic nucleus that was strongly associated with impulse control disorder severity. In these patients, the right ventral striatum in particular played a critical role in modulating the functional dynamics of right-lateralized inhibitory-control frontal regions when facing penalties. © 2019 International Parkinson and Movement Disorder Society.
  • Autores: van Veen, R. (Autor de correspondencia); Gurvits, V.; Kogan, R. V.; et al.
    Revista: COMPUTER METHODS AND PROGRAMS IN BIOMEDICINE
    ISSN: 0169-2607 Vol.197 2020 págs. 105708
    Resumen
    Background and objective: Neurodegenerative diseases like Parkinson's disease often take several years before they can be diagnosed reliably based on clinical grounds. Imaging techniques such as MRI are used to detect anatomical (structural) pathological changes. However, these kinds of changes are usually seen only late in the development. The measurement of functional brain activity by means of [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) can provide useful information, but its interpretation is more difficult. The scaled sub-profile model principal component analysis (SSM/PCA) was shown to provide more useful information than other statistical techniques. Our objective is to improve the performance further by combining SSM/PCA and prototype-based generalized matrix learning vector quantization (GMLVQ). Methods: We apply a combination of SSM/PCA and GMLVQ as a classifier. In order to demonstrate the combination's validity, we analyze FDG-PET data of Parkinson's disease (PD) patients collected at three different neuroimaging centers in Europe. We determine the diagnostic performance by performing a ten times repeated ten fold cross validation. Additionally, discriminant visualizations of the data are included. The prototypes and relevance of GMLVQ are transformed back to the original voxel space by exploiting the linearity of SSM/PCA. The resulting prototypes and relevance profiles have then been assessed by three neurologists. Results: One important finding is that discriminative visualization can help to identify disease-related properties as well as differences which are due to center-specific factors. Secondly, the neurologist assessed the interpretability of the method and confirmed that prototypes are similar to known activity profiles of PD patients. Conclusion: We have shown that the presented combination of SSM/PCA and GMLVQ can provide useful means to assess and better understand characteristic differences in FDG-PET data from PD patients and HCs. Based on the assessments by medical experts and the results of our computational analysis we conclude that the first steps towards a diagnostic support system have been taken successfully. Keywords: Parkinson¿s disease (PD); Scaled sub-profile scaling model principal component analysis (SSM/PCA); [(18)F]Fluorodeoxyglucose positron emission tomography (FDG-PET); generalized matrix learning vector quantization (GMLVQ).
  • Autores: Valentí Azcárate, Rafael; Martinez, I. ; Amat, I. ; et al.
    Revista: MOVEMENT DISORDERS
    ISSN: 0885-3185 Vol.35 2020 págs. S372 - S372
  • Autores: Martí Andrés, Gloria María; Perovnik, M. ; Rebec, E.; et al.
    Revista: MOVEMENT DISORDERS
    ISSN: 0885-3185 Vol.35 2020 págs. S114 - S116
  • Autores: Martínez Valbuena, Iván; Valentí Azcárate, Rafael; Caballero, C.; et al.
    Revista: MOVEMENT DISORDERS
    ISSN: 0885-3185 Vol.35 N° SUPPL 1 2020 págs. S156 - S156
  • Autores: Armengou García, Laura; Martí Andrés, Gloria María; Valentí Azcárate, Rafael; et al.
    Revista: MOVEMENT DISORDERS
    ISSN: 0885-3185 Vol.35 2020 págs. S436 - S437
  • Autores: Martin Bastida, Antonio; Suárez Vega, Victor Manuel; Domínguez Echávarri, Pablo Daniel; et al.
    Revista: MOVEMENT DISORDERS
    ISSN: 0885-3185 Vol.35 2020 págs. S254 - S255
  • Autores: Martin Bastida, Antonio; Delgado-Alvarado, M. ; Navalpotro-Gomez, I.; et al.
    Revista: MOVEMENT DISORDERS
    ISSN: 0885-3185 Vol.35 N° Supl. 1 2020 págs. S254
  • Autores: Gasca Salas, Carmen; Garcia-Lorenzo, D.; García García, David; et al.
    Revista: BRAIN IMAGING AND BEHAVIOR
    ISSN: 1931-7557 Vol.13 N° 1 2019 págs. 180 - 188
    Resumen
    Mild cognitive impairment (MCI) in Parkinson's disease (PD) is a risk factor for dementia and thus, it is of interest to elucidate if specific patterns of atrophy in PD-MCI patients are associated with a higher risk of developing dementia. We aim to define pattern(s) of regional atrophy in PD-MCI patients who developed dementia during 31months of follow-up using cortical thickness analysis Twenty-three PD-MCI patients and 18 controls underwent brain MRI and completed a neuropsychological examination at baseline, PD-MCI patients were followed after a 31month follow-up in order to assess their progression to dementia. At follow up, 8 PD-MCI patients had converted to dementia (PD-MCI converters) whereas 15 remained as PD-MCI (PD-MCI non-converters). All patients were at least 60years old and suffered PD10years. There were no baseline differences between the two groups of patients in clinical and neuropsychological variables. The cortex of PD-MCI converters was thinner than that of PD-MCI non-converters, bilaterally in the frontal, insula and the left middle temporal areas, also displaying a more widespread pattern of cortical thinning relative to the controls. This study shows that aged and long-term PD patients with MCI who convert to dementia in the short-mid term suffer a thinning of the cortex in several areas (frontal cortex, and middle temporal lobe and insula), even when their cognitive impairment was similar to that of PD-MCI non-converters. Thus, MRI analysis of cortical thickness may represent a useful measure to identify PD-MCI patients at a higher risk of developing dementia.
  • Autores: Navalpotro-Gomez, I.; Dacosta-Aguayo, R.; Molinet-Dronda, F.; et al.
    Revista: EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING
    ISSN: 1619-7070 Vol.46 N° 10 2019 págs. 2065 - 2076
    Resumen
    PurposePrevious studies in patients with Parkinson's disease (PD) and impulse control disorders (ICDs) have produced heterogeneous results regarding striatal dopamine transporter (DaT) binding and activity in the mesocorticolimbic network. Our aim here was to study the relationship between striatal DaT availability and cortical metabolism, as well as motor, behavioural and cognitive features of PD patients with ICD.MethodsIn a group of PD patients with ICD (PD-ICD, n=16) and 16 matched PD patients without ICD (PD-noICD, n=16), DaT single-photon emission computed tomography (SPECT) imaging (DaTSCAN) was used to study DaT availability in predefined striatal volumes of interest (VOIs): putamen, caudate nucleus and ventral striatum (VS). In addition, the specific association of striatal DaT binding with cortical limbic and associative metabolic activity was evaluated by F-18-fluorodeoxyglucose (FDG) positron emission tomography (PET) in PD-ICD patients and investigated using statistical parametric mapping (SPM8). Finally, associations between DaT availability and motor, behavioural and cognitive features were assessed.ResultsPD-ICD patients had a significantly lower DaT density in the VS than PD-noICD patients, which was inversely associated with ICD severity. Lower DaT availability in the VS was associated with lower FDG uptake in several cortical areas belonging to the limbic and associative circuits, and in other regions involved in reward and inhibition processes (p<0.0001 uncorrected; k>50 voxels). No significant results were observed using a higher conservative threshold (p<0.05; FDR corrected). PD-ICD patients also displayed impairment in interference and attentional Stroop Task execution, and more anxiety, all associated with reduced DaT availability in the VS and caudate nucleus.ConclusionsICDs in PD patients are related to reduced DaT binding in the VS, which accounts for dysfunction in a complex cortico-subcortical network that involves areas of the mesolimbic and mesocortical systems, being associated with reward evaluation, salience attribution and inhibitory control processes.
  • Autores: de Iure A; Napolitano F; Beck G; et al.
    Revista: MOVEMENT DISORDERS
    ISSN: 0885-3185 Vol.34 N° 6 2019 págs. 832 - 844
  • Autores: Jimenez-Urbieta, H.; Gago, B. ; Quiroga Varela, Ana; et al.
    Revista: NEUROBIOLOGY OF AGING
    ISSN: 0197-4580 Vol.75 2019 págs. 126 - 135
    Resumen
    Treatment with dopaminergic agonists such as pramipexole (PPX) contributes to the development of impulse control disorders (ICDs) in patients with Parkinson's disease (PD). As such, animal models of abnormal impulse control in PD are needed to better study the pathophysiology of these behaviors. Thus, we investigated impulsivity and related behaviors using the 5-choice serial reaction time task, as well as FosB/Delta FosB expression, in rats with mild parkinsonism induced by viral-mediated substantia nigra overexpression of human A53T mutated alpha-synuclein, and following chronic PPX treatment (0.25 mg/kg/d) for 4 weeks. The bilateral loss of striatal dopamine transporters (64%) increased the premature response rate of these rats, indicating enhanced waiting impulsivity. This behavior persisted in the OFF state after the second week of PPX treatment and it was further exacerbated in the ON state throughout the treatment period. The enhanced rate of premature responses following dopaminergic denervation was positively correlated with the premature response rate following PPX treatment (both in the ON and OFF states). Moreover, the striatal dopaminergic deficit was negatively correlated with the premature response rate at all times (pretreatment, ON and OFF states) and it was positively correlated with the striatal FosB/Delta FosB expression. By contrast, PPX treatment was not associated with changes in compulsivity (perseverative responses rate). This model recapitulates some features of PD with ICD, namely the dopaminergic deficit of early PD and the impulsivity traits provoked by dopaminergic loss in association with PPX treatment, making this model a useful tool to study the pathophysiology of ICDs. (C) 2018 Elsevier Inc. All rights reserved.
  • Autores: Durante V.; De Iure A.; Loffredo V.; et al.
    Revista: BRAIN
    ISSN: 0006-8950 Vol.142 N° 5 2019 págs. 1365 - 1385
  • Autores: Martin Bastida, Antonio; Lao-Kaim, N. R.; Roussakis, A. A.; et al.
    Revista: BRAIN
    ISSN: 0006-8950 Vol.142 2019 págs. 2023 - 2036
    Resumen
    Parkinson's disease is characterized by the progressive loss of pigmented dopaminergic neurons in the substantia nigra and associated striatal deafferentation. Neuromelanin content is thought to reflect the loss of pigmented neurons, but available data characterizing its relationship with striatal dopaminergic integrity are not comprehensive or consistent, and predominantly involve heterogeneous samples. In this cross-sectional study, we used neuromelanin-sensitive MRI and the highly specific dopamine transporter PET radioligand, C-11-PE2I, to assess the association between neuromelanin-containing cell levels in the substantia nigra pars compacta and nigrostriatal terminal density in vivo, in 30 patients with bilateral Parkinson's disease. Fifteen healthy control subjects also underwent neuromelanin-sensitive imaging. We used a novel approach taking into account the anatomical and functional subdivision of substantia nigra into dorsal and ventral tiers and striatal nuclei into pre- and post-commissural subregions, in accordance with previous animal and post-mortem studies, and consider the clinically asymmetric disease presentation. In vivo, Parkinson's disease subjects displayed reduced neuromelanin levels in the ventral (-30 +/- 28%) and dorsal tiers (-21 +/- 24%) as compared to the control group [F(1,43) = 11.95, P = 0.001]. Within the Parkinson's disease group, nigral pigmentation was lower in the ventral tier as compared to the dorsal tier [F(1,29) = 36.19, P < 0.001] and lower in the clinically-defined most affected side [F(1,29) = 4.85, P = 0.036]. Similarly, lower dopamine transporter density was observed in the ventral tier [F(1,29) = 76.39, P < 0.001] and clinically-defined most affected side [F(1,29) = 4.21, P = 0.049]. Despite similar patterns, regression analysis showed no significant association between nigral pigmentation and nigral dopamine transporter density. However, for the clinically-defined most affected side, significant relationships were observed between pigmentation of the ventral nigral tier with striatal dopamine transporter binding in pre-commissural and post-commissural striatal subregions known to receive nigrostriatal projections from this tier, while the dorsal tier correlated with striatal projection sites in the pre-commissural striatum (P < 0.05, Benjamini-Hochberg corrected). In contrast, there were no statistically significant relationships between these two measures in the clinically-defined least affected side. These findings provide important insights into the topography of nigrostriatal neurodegeneration in Parkinson's disease, indicating that the characteristics of disease progression may fundamentally differ across hemispheres and support post-mortem data showing asynchrony in the loss of neuromelanin-containing versus tyrosine hydroxylase positive nigral cells.
  • Autores: Garcia-Ruiz, P. J.; Sanz-Cartagena, P. (Autor de correspondencia); Martinez-Castrillo, J. C.; et al.
    Revista: REVISTA DE NEUROLOGIA
    ISSN: 0210-0010 Vol.66 N° 5 2018 págs. 163 - 172
    Resumen
    Introduction. Botulinum toxin type A (BTA) is a bacterial endotoxin, whose therapeutic use has had a dramatic impact on different neurological disorders, such as dystonia and spasticity. Aim. To analyze and summarize different questions about the use of BTA in our clinical practice. Development. A group of experts in neurology developed a list of topics related with the use of BTA. Two groups were considered: neuropharmacology and dystonia. A literature search at PubMed, mainly for English language articles published up to June 2016 was performed. The manuscript was structured as a questionnaire that includes those questions that, according to the panel opinion, could generate more controversy or doubt. The initial draft was reviewed by the expert panel members to allow modifications, and after subsequent revisions for achieving the highest degree of consensus, the final text was then validated. Different questions about diverse aspects of neuropharmacology, such as mechanism of action, bioequivalence of the different preparations, immunogenicity, etc. were included. Regarding dystonia, the document included questions about methods of evaluation, cervical dystonia, blepharospasm, etc. Conclusion. This review does not pretend to be a guide, but rather a tool for continuous training of residents and specialists in neurology, about different specific areas of the management of BTA.
  • Autores: Dranca, L. ; de Mendarozketa, L. D. R.; Goñi, A.; et al.
    Revista: BMC BIOINFORMATICS
    ISSN: 1471-2105 Vol.19 N° 1 2018 págs. 471
    Resumen
    BackgroundParkinson's Disease (PD) is a chronic neurodegenerative disease associated with motor problems such as gait impairment. Different systems based on 3D cameras, accelerometers or gyroscopes have been used in related works in order to study gait disturbances in PD. Kinect (?) has also been used to build these kinds of systems, but contradictory results have been reported: some works conclude that Kinect does not provide an accurate method of measuring gait kinematics variables, but others, on the contrary, report good accuracy results.MethodsIn this work, we have built a Kinect-based system that can distinguish between different PD stages, and have performed a clinical study with 30 patients suffering from PD belonging to three groups: early PD patients without axial impairment, more evolved PD patients with higher gait impairment but without Freezing of Gait (FoG), and patients with advanced PD and FoG. Those patients were recorded by two Kinect devices when they were walking in a hospital corridor. The datasets obtained from the Kinect were preprocessed, 115 features identified, some methods were applied to select the relevant features (correlation based feature selection, information gain, and consistency subset evaluation), and different classification methods (decision trees, Bayesian networks, neural networks and K-nearest neighbours classifiers) were evaluated with the goal of finding the most accurate method for PD stage classification.ResultsThe classifier that provided the best results is a particular case of a Bayesian Network classifier (similar to a Naive Bayesian classifier) built from a set of 7 relevant features selected by the correlation-based on feature selection method. The accuracy obtained for that classifier using 10-fold cross validation is 93.40%. The relevant features are related to left shin angles, left humerus angles, frontal and lateral bents, left forearm angles and the number of steps during spin.ConclusionsIn this paper, it is shown that using Kinect is adequate to build a inexpensive and comfortable system that classifies PD into three different stages related to FoG. Compared to the results of previous works, the obtained accuracy (93.40%) can be considered high. The relevant features for the classifier are: a) movement and position of the left arm, b) trunk position for slightly displaced walking sequences, and c) left shin angle, for straight walking sequences. However, we have obtained a better accuracy (96.23%) for a classifier that only uses features extracted from slightly displaced walking steps and spin walking steps. Finally, the obtained set of relevant features may lead to new rehabilitation therapies for PD patients with gait problems.
  • Autores: Viedma-Guiard, E.; Aguero, P.; Crespo-Araico, L.; et al.
    Revista: NEUROLOGIA
    ISSN: 1578-1968 Vol.33 N° 2 2018 págs. 107-111
    Resumen
    Implementing an e-mail-based consultation system is feasible in MD units. It facilitates both communication between neurologists and patients and continued care in the primary care setting.
  • Autores: Delgado-Alvarado, M.; Dacosta-Aguayo, R.; Navalpotro-Gomez, I.; et al.
    Revista: MOVEMENT DISORDERS
    ISSN: 0885-3185 Vol.33 N° 11 2018 págs. 1809 - 1814
    Resumen
    Background: There is a need for biomarkers of dementia in PD. Objectives: To determine if the levels of the main CSF proteins and their ratios are associated with deterioration in cognition and progression to dementia in the short to mid term. Methods: The Parkinson's Progression Markers Initiative database was used as an exploratory cohort, and a center-based cohort was used as a replication cohort. Amyloid ss 1-42, total tau, threonine-181 phosphorylated tau, and alpha-synuclein in the CSF and the ratios of these proteins were assessed. Results: In the Parkinson's Progression Markers Initiative cohort (n = 281), the total tau/amyloid ss 1-42, total tau/alpha-synuclein, total tau/amyloid ss 1-42+alpha-synuclein, and amyloid ss 1-42/total tau ratios were associated with a risk of progression to dementia over a 3-year follow-up. In the replication cohort (n = 40), the total tau/alpha-synuclein and total tau/amyloid ss 1-42+alpha-synuclein ratios were associated with progression to dementia over a 41-month follow-up. Conclusion: Ratios of the main proteins found in PD patient brain inclusions that can be measured in the CSF appear to have value as short- to mid-term predictors of dementia. (c) 2018 International Parkinson and Movement Disorder Society

Proyectos desde 2018

  • Título: RodríguezOroz_GN2022/28_Restauración de la función sináptica en el estado premotor de la enfermedad de Parkinson mediantemodulación proteica con terapia génica y terapias moleculares
    Código de expediente: GN2022/28
    Investigador principal: MARIA CRUZ RODRIGUEZ OROZ.
    Financiador: GOBIERNO DE NAVARRA. DEPARTAMENTO DE SALUD
    Convocatoria: 2022 GN Proyectos de Investigación en salud
    Fecha de inicio: 22-12-2022
    Fecha fin: 21-12-2025
    Importe concedido: 79.349,14€
    Otros fondos: -
  • Título: 0011-4001-2022-000042 Gn_Investigo_2021
    Código de expediente: 0011-4001-2022-000042
    Investigador principal: MARIA CRUZ RODRIGUEZ OROZ.
    Financiador: GOBIERNO DE NAVARRA
    Convocatoria: 2021 GN Investigo
    Fecha de inicio: 18-11-2022
    Fecha fin: 17-11-2023
    Importe concedido: 33.108,92€
    Otros fondos: Fondos MRR
  • Título: 0011-4001-2022-000001 Programa Investigo de Gobierno de Navarra 2021
    Código de expediente: 0011-4001-2022-000001
    Investigador principal: MARIA CRUZ RODRIGUEZ OROZ.
    Financiador: GOBIERNO DE NAVARRA
    Convocatoria: 2021 GN Investigo
    Fecha de inicio: 14-03-2022
    Fecha fin: 13-03-2023
    Importe concedido: 33.108,92€
    Otros fondos: Fondos MRR
  • Título: Desarrollo de terapias nasales inmunomoduladoras en envejecimiento y neurodegeneración (INNOLFACT)
    Código de expediente: 0011-1411-2020-000049
    Investigador principal: JUAN JOSE LASARTE SAGASTIBELZA.
    Financiador: GOBIERNO DE NAVARRA
    Convocatoria: FIMA 2020 GN PROYECTOS ESTRATEGICOS DE I+D 2020-2022
    Fecha de inicio: 01-07-2020
    Fecha fin: 30-11-2022
    Importe concedido: 399.103,16€
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  • Título: INNOLFACT: Implementación de Medicina de Precisión Olfatoria y Desarrollo de terapias nasales
    Código de expediente: 0011-1411-2020-000036
    Investigador principal: MARIA CRUZ RODRIGUEZ OROZ.
    Financiador: GOBIERNO DE NAVARRA
    Convocatoria: 2020 GN PROYECTOS ESTRATEGICOS DE I+D 2020-2022
    Fecha de inicio: 01-07-2020
    Fecha fin: 30-11-2022
    Importe concedido: 601.228,00€
    Otros fondos: -
  • Título: Alteraciones de la sinapsis en el estriado y en la corteza frontal en la disfunción ejecutiva de la enfermedad de Parkinson
    Código de expediente: PI19/01915
    Investigador principal: MARIA CRUZ RODRIGUEZ OROZ.
    Financiador: INSTITUTO DE SALUD CARLOS III
    Convocatoria: 2019 AES Proyectos de investigación
    Fecha de inicio: 01-01-2020
    Fecha fin: 30-06-2024
    Importe concedido: 123.420,00€
    Otros fondos: Fondos FEDER
  • Título: GENEURONA. Implantación del diagnóstico genómico de la epilepsia y la migraña en Navarra
    Código de expediente: 0011-1411-2018-000044
    Investigador principal: ANA MARIA GARCIA OSTA.
    Financiador: GOBIERNO DE NAVARRA
    Convocatoria: 2018- GN PROY. ESTRATEGICOS DE I+D 2018-2020
    Fecha de inicio: 01-04-2018
    Fecha fin: 30-11-2020
    Importe concedido: 476.239,53€
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  • Título: Implantación del diagnóstico de la epilepsia y la migraña en Navarra (Geneurona)
    Código de expediente: 0011-1411-2018-000053
    Investigador principal: MARIA CRUZ RODRIGUEZ OROZ.
    Financiador: GOBIERNO DE NAVARRA
    Convocatoria: 2018 GN PROYECTOS ESTRATEGICOS DE I+D 2018-2020
    Fecha de inicio: 01-04-2018
    Fecha fin: 30-11-2020
    Importe concedido: 18.481,69€
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  • Título: GOB. VASCO PREDOCTORAL Arantzazu Bellosos (MCRO)
    Código de expediente:
    Investigador principal: ARANTZAZU BELLOSO IGUERATEGUI.
    Financiador: GOBIERNO VASCO
    Convocatoria: 2016 - GV PREDOCTORAL FIMA 2019 - GV PREDOCTORAL FIMA 2019 - GV PREDOCTORAL 2018 - GV PREDOCTORAL
    Fecha de inicio: 07-02-2018
    Fecha fin: 31-12-2020
    Importe concedido: 66.979,16€
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  • Título: Evaluación mediante RMN de pacientes tratados mediante talat
    Investigador principal: MARIA CRUZ RODRIGUEZ OROZ
    Fecha de inicio: 13-02-2020
    Fecha fin: 30-04-2023
    Importe: 0
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  • Título: Directional stimulation of the subthalamic nucleus.Parkinson
    Investigador principal: MARIA CRUZ RODRIGUEZ OROZ
    Fecha de inicio: 01-09-2019
    Fecha fin: 15-09-2022
    Importe: 0
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