Past, Present, and Future of the Pathophysiological Model of the Basal Ganglia

The current model of basal ganglia (BG) was introduced two decades ago and has settled most of our current understanding of BG function and dysfunction. Extensive research efforts have been carried out in recent years leading to further refinement and understanding of the normal and diseased BG. Several questions, however, are yet to be resolved. This short review provides a synopsis of the evolution of thought regarding the pathophysiological model of the BG and summarizes the main recent findings and additions to this field of research. We have also tried to identify major challenges that need to be addressed and resolved in the near future. Detailed accounts and state-of-the-art developments concerning research on the BG are provided in the articles that make up this Special Issue

Neuron types in the primate striatum: stereological analysis of projection neurons and interneurons in control and parkinsonian monkeys

The striatum is mainly composed of projection neurons. It also contains interneurons, which modulate and control striatal output. The aim of the present study was to assess the percentages of projection neurons and interneuron populations in the striatum of control monkeys and of parkinsonian monkeys. Methods: Unbiased stereology was used to estimate the volume density of every neuron population in the caudate, putamen and ventral striatum of control monkeys and of monkeys treated with MPTP, which results in striatal dopamine depletion. The various neuron population phenotypes were identified by immunohistochemistry. All analyses were performed within the same subjects using similar processing and analysis parameters, thus allowing for reliable data comparisons. Results: In control monkeys, the projection neurons, which express the dopamine-and-cAMP-regulated-phosphoprotein, 32-KDa (DARPP-32), were the most abundant: ~86% of the total neurons counted. The interneurons accounted for the remaining 14%. Among the interneurons, those expressing calretinin were the most abundant (Cr+: ~57%; ~8% of the total striatal neurons counted), followed those expressing Parvalbumin (Pv+: ~18%; 2.6%), dinucleotide phosphate-diaphorase (NADPH+: ~13%; 1.8%), choline acetyltransferase (ChAT+: ~11%; 1.5%) and tyrosine hydroxylase (TH+: ~0.5%; 0.1%). No significant changes in volume densities occurred in any population following dopamine depletion, except for the TH+ interneurons, which increased in parkinsonian non-symptomatic monkeys and even more in symptomatic monkeys. Conclusions: These data are relevant for translational studies targeting specific neuron populations of the striatum. The fact that dopaminergic denervation does not cause neuron loss in any population has potential pathophysiological implication

Is Parkinson's disease a vesicular dopamine storage disorder?: Evidence from a study in isolated synaptic vesicles of human and nonhuman primate striatum

The cause of degeneration of nigrostriatal dopamine (DA) neurons in idiopathic Parkinson’s disease (PD) is still unknown. Intraneuronally, DA is largely confined to synaptic vesicles where it is protected from metabolic breakdown. In the cytoplasm, however, free DA can give rise to formation of cytotoxic free radicals. Normally, the concentration of cytoplasmic DA is kept at a minimum by continuous pumping activity of the vesicular monoamine transporter (VMAT)2. Defects in handling of cytosolic DA by VMAT2 increase levels of DA-generated oxy radicals ultimately resulting in degeneration of DAergic neurons. Here, we isolated for the first time, DA storage vesicles from the striatum of six autopsied brains of PD patients and four controls and measured several indices of vesicular DA storage mechanisms. We found that (1) vesicular uptake of DA and binding of the VMAT2-selective label [ 3H]dihydrotetrabenazine were profoundly reduced in PD by 87–90% and 71– 80%, respectively; (2) after correcting for DA nerve terminal loss, DA uptake per VMAT2 transport site was significantly reduced in PD caudate and putamen by 53 and 55%, respectively; (3) the VMAT2 transport defect appeared specific for PD as it was not present in Macaca fascicularis (7 MPTP and 8 controls) with similar degree of MPTP-induced nigrostriatal neurodegeneration; and (4) DA efflux studies and measurements of acidification in the vesicular preparations suggest that the DA storage impairment was localized at the VMAT2 protein itself. We propose that this VMAT2 defect may be an early abnormality promoting mechanisms leading to nigrostriatal DA neuron death in P

Thalamic innervation of the direct and indirect basal ganglia pathways in the rat: Ipsi- and contralateral projections

The present study describes the thalamic innervation coming from the rat parafascicular nucleus (PF) onto striatal and subthalamic efferent neurons projecting either to the globus pallidus (GP) or to the substantia nigra pars reticulata (SNr) by using a protocol for multiple neuroanatomical tracing. Both striatofugal neurons targeting the ipsilateral SNr (direct pathway) as well as striatal efferent neurons projecting to the ipsilateral GP (indirect pathway) were located within the terminal fields of the thalamostriatal afferents. In the subthalamic nucleus (STN), both neurons projecting to ipsilateral GP as well as neurons projecting to ipsilateral SNr also appear to receive thalamic afferents. Although the projections linking the caudal intralaminar nuclei with the ipsilateral striatum and STN are far more prominent, we also noticed that thalamic axons could gain access to the contralateral STN. Furthermore, a small number of STN neurons were seen to project to both the contralateral GP and PF nuclei. These ipsi- and contralateral projections enable the caudal intralaminar nuclei to modulate the activity of both the direct and the indirect pathway

Ardeola, a scientific journal of ornithology: cooperative survivorship within the red queen game

Editorial.-- et al.[EN]: Ardeola is the scientific journal of the Spanish Ornithological Society. We analyse historical changes in citation, topics and foreign authorship of articles published in Ardeola from its first publication in 1954 up to last year, 2015, to test to what extent the persistence of the journal during the last 61 years has been due to support of authors, Society members, readers, editors or the whole ornithological community. Analyses were done within the context of the Red Queen game played by scientific journals competing for the best and more cited articles. The impact factor of Ardeola has increased from 1985 onwards both in absolute and relative terms. Thematic changes have followed trends of the general ornithological literature, without the journal specialising in particular topics or geographical regions. Foreign authorship decreased from 1954 up to the end of the 20 century, subsequently increasing again, a trend fuelled by coverage by Current Contents and the JCR, the establishment of English as the language of publication and recent Internet access through the BioOne platform. Ardeola is a traditional scientific journal, backed by a scientific society, whose future will be guaranteed by a reputation for rigour and quality sought by authors, reviewers and editors, supported by the members of the Spanish Ornithological Society and retaining its original objective: 'to be a journal at the level of the best..., looking for a strong collaboration with foreign authors to promote the benefit of the Ornithology'.[ES]: Ardeola es la revista científica de la Sociedad Española de Ornitología (SEO/BirdLife). Analizamos los cambios históricos en citación, temática y contribución de autores extranjeros a los artículos publicados en Ardeola desde sus inicios en 1954 hasta el año pasado, 2015, con el objetivo de evaluar si el mantenimiento de la revista a lo largo de los últimos 61 años se ha debido al apoyo de los autores, de los miembros de SEO/BirdLife, de los lectores, de los editores de la revista, o de los ornitólogos en general. Los análisis de este mantenimiento se realizan en el contexto del juego de la reina roja en el que están implicadas las revistas científicas, que compiten por publicar los mejores artículos más citados. El factor de impacto de Ardeola ha aumentado desde 1985 en adelante, tanto en términos absolutos como relativos. En la actualidad es de 0,6–0,8, situándose en el tercer cuartil de las revistas de ornitología cubiertas por el Journal Citation Reports (JCR). Los cambios temáticos han seguido en general los del resto de la literatura ornitológica, sin especializarse en temas o áreas geográficas particulares. La proporción de autores extranjeros disminuyó desde 1954 hasta finales del siglo pasado, recuperándose a continuación a niveles del 30%–40%, una tendencia que sin duda se ha acelerado por la cobertura de Ardeola por Current Contents y el JCR, el establecimiento del inglés como idioma de publicación y el acceso reciente por Internet a través de BioOne. Ardeola es una revista científica clásica, sostenida por una sociedad científica, cuyo futuro será garantizado por el sello riguroso de calidad mantenido por autores, revisores y editores, y mantenido por los miembros de SEO/BirdLife con el mismo espíritu con el que fue creada in 1954: ‘para ser una revista del nivel de las mejores…, buscando una intensa colaboración con autores extranjeros para promover el beneficio de la Ornitología’.Peer Reviewe

Clinical features, pathophysiology, and treatment of levodopa-induced dyskinesias in Parkinson's disease

Dyskinetic disorders are characterized by excess of motor activity that may interfere with normal movement control. In patients with Parkinson's disease, the chronic levodopa treatment induces dyskinetic movements known as levodopa-induced dyskinesias (LID). This paper analyzed the pathophysiology, clinical manifestations, pharmacological treatments, and surgical procedures to treat hyperkinetic disorders. Surgery is currently the only treatment available for Parkinson's disease that may improve both parkinsonian motor syndrome and LID. However, this paper shows the different mechanisms involved are not well understood

Involvement of the subthalamic nucleus in impulse control disorders associated with Parkinson’s disease

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 2–8mm 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 0–2mm 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

Slow oscillatory activity and levodopa-induced dyskinesias in Parkinson’s disease

The pathophysiology of levodopa-induced dyskinesias (LID) in Parkinson’s disease is not well understood. We have recorded local field potentials (LFP) from macroelectrodes implanted in the subthalamic nucleus (STN) of 14 patients with Parkinson’s disease following surgical treatment with deep brain stimulation. Patients were studied in the ‘Off’ medication state and in the ‘On’ motor state after administration of levodopa– carbidopa (po) or apomorphine (sc) that elicited dyskinesias in 11 patients. The logarithm of the power spectrum of the LFP in selected frequency bands (4–10, 11–30 and 60–80 Hz) was compared between the ‘Off’ and ‘On’ medication states. A peak in the 11–30 Hz band was recorded in the ‘Off’ medication state and reduced by 45.2% (P < 0.001) in the ‘On’ state. The ‘On’ was also associated with an increment of 77. 6% (P < 0.001) in the 4–10 Hz band in all patients who showed dyskinesias and of 17.8% (P < 0.001) in the 60–80 Hz band in the majority of patients. When dyskinesias were only present in one limb (n = 2), the 4–10 Hz peak was only recorded in the contralateralSTN. These findings suggest that the 4–10 Hz oscillation is associated with the expression of LID in Parkinson’s disease