Neuroglial transmitophagy and Parkinson's disease.

Mitophagy is essential for the health of dopaminergic neurons because mitochondrial damage is a keystone of Parkinson's disease. The aim of the present work was to study the degradation of mitochondria in the degenerating dopaminergic synapse. Adult Sprague-Dawley rats and YFP-Mito-DAn mice with fluorescent mitochondria in dopaminergic neurons were injected in the lateral ventricles with 6-hydroxydopamine, a toxic that inhibits the mitochondrial chain of dopaminergic neurons and blockades the axonal transport. Dopaminergic terminals closest to the lateral ventricle showed an axonal fragmentation and an accumulation of damaged mitochondria in 2-9 µ saccular structures (spheroids). Damaged mitochondria accumulated in spheroids initiated (showing high Pink1, parkin, ubiquitin, p-S65-Ubi, AMBRA1, and BCL2L13 immunoreactivity and developing autophagosomes) but did not complete (mitochondria were not polyubiquitinated, autophagosomes had no STX17, and no lysosomes were found in spheroids) the mitophagy process. Then, spheroids were penetrated by astrocytic processes and DAergic mitochondria were transferred to astrocytes where they were polyubiquitinated (UbiK63+) and linked to mature autophagosomes (STX17+) which became autophagolysosomes (Lamp1/Lamp2 which co-localized with LC3). Present data provide evidence that the mitophagy of degenerating dopaminergic terminals starts in the dopaminergic spheroids and finishes in the surrounding astrocytes (spheroid-mediated transmitophagy). The neuron-astrocyte transmitophagy could be critical for preventing the release of damaged mitochondria to the extracellular medium and the neuro-inflammatory activity which characterizes Parkinson's disease.

Neo-Hippocratic healthcare policies: professional or industrial healthcare delivery? A choice for doctors, patients, and their organisations.

BACKGROUND: Ethical medical practice requires managing health services to promote professionalism and secure accessibility to care. Commercially financed and industrially managed services strain the physicians' clinical autonomy and ethics because the industry's profitability depends on commercial, clinical standardisation. Private insurance companies also reduce access to care whilst fragmenting and segmenting health systems. Against this background, given the powerful, symbolic significance of their common voice, physicians' and patients' organisations could effectively leverage together political parties and employers' organisations to promote policies favouring access to professional care. MAIN TEXT: To provide a foundation for negotiations between physicians' and patients' organisations, we propose policy principles derived from an analysis of rights-holders and duty-bearers' stakes, i.e., patients, physicians and health professionals, and taxpayers. Their concerns are scrutinised from the standpoints of public health and right to health. Illustrated with post-WWII European policies, these principles are formulated as inputs for tentative action-research. The paper also identifies potential stumbling blocks for collective doctor/patient negotiations based on the authors' personal experience. The patients' concerns are care accessibility, quality, and price. Those of physicians and other professionals are problem-solving capacity, autonomy, intellectual progress, ethics, work environment, and revenue. The majority of taxpayers have an interest in taxes being progressive and public spending on health regressive. Mutual aid associations tend to under-estimate the physician's role in delivering care. Physicians' organisations often disregard the mission of financing care and its impact on healthcare quality. CONCLUSION: The proposed physicians-patients' alliance could promote policies in tune with professional ethics, prevent European policies' putting industrial concerns above suffering and death, bar care financing from the ambit of international trade treaties, and foster international cooperation policies consistent with the principles that inspire the design of healthcare policies at home and so reduce international migration. To be credible partners in this alliance, physicians' associations should promote a public health culture amongst their members and a team culture in healthcare services. To promote a universal health system, patients' organisations should strive to represent universal health interests rather than those of patients with specific diseases, ethnic groups, or social classes.

Medical heuristics and action-research: professionalism versus science.

BACKGROUND: Professional knowledge aims at improving practice. It reduces uncertainty in decision-making, improves effectiveness in action and relevance in evaluation, stimulates reflexivity, and subjects practice to ethical standards. Heuristics is an approach to problem-solving, learning, and discovery employing a practical methodology that, although not optimal, is sufficient for achieving immediate goals. This article identifies the desirable, heuristic particularities of research in professional, medical practice; and it identifies what distinguishes this research from scientific research. MAIN TEXT: We examine the limits of biomedical and sociological research to produce professional knowledge. Then, we derive the heuristic characteristics of professional research from a meta-analysis of two action-research projects aimed at securing access to essential generic drugs in Senegal and improving physicians' self-assessment and healthcare coordination in Belgium. To study healthcare, biomedical sciences ignore how clinical decisions are implemented. Decisions are built into an articulated knowledge system, such as (clinical) epidemiology, where those studied are standardisable - while taking care of patients is an idiosyncratic, value-based, person-to-person process that largely eludes probabilistic methodologies. Social sciences also reach their limits here because descriptive, interpretative methods cannot help with gesture and speech quality, while the management of the patient's suffering and risks makes each of them unique. Research into medical professionalism is normative as it is intended to formulate recommendations. Scientific data and descriptions are useful to the practitioner randomly, only from the similarities in the environment of the authors and their readers. Such recommendations can be conceived of as strategies, i.e., multi-resource and multi-stage action models to improve clinical and public health practice. Action learning and action-research are needed to design and implement these strategies, because their complexity implies trial and error. To validate a strategy, repeated experiences are needed. Its reproducibility assumes the description of the context. To participate in medical action-research, the investigator needs professional proficiency - a frequent difficulty in academic settings. CONCLUSION: Some criteria to assess the relevance of publicly funded clinical and public health research can be derived from the difference between scientific and professional knowledge, i.e. the knowledge gained with real-life experience in the field.

Integrating clinical and public health knowledge in support of joint medical practice.

BACKGROUND: Strong relations between medicine and public health have long been advocated. Today, professional medical practice assumes joint clinical/public health objectives: GPs are expected to practice community medicine; Hospital specialists can be involved in disease control and health service organisation; Doctors can teach, coach, evaluate, and coordinate care; Clinicians should interpret protocols with reference to clinical epidemiology. Public health physicians should tailor preventive medicine to individual health risks. This paper is targeted at those practitioners and academics responsible for their teams' professionalism and the accessibility of care, where the authors argue in favour of the epistemological integration of clinical medicine and public health. MAIN TEXT: Based on empirical evidence the authors revisit the epistemological border of clinical and public health knowledge to support joint practice. From action-research and cognitive psychology, we derive clinical/public health knowledge categories that require different transmission and discovery techniques. The knowledge needed to support the universal human right to access professional care bridges both clinical and public health concepts, and summons professional ethics to validate medical decisions. To provide a rational framework for teaching and research, we propose the following categories: 'Know-how/practice techniques', corresponding a.o. to behavioural, communication, and manual skills; 'Procedural knowledge' to choose and apply procedures that meet explicit quality criteria; 'Practical knowledge' to design new procedures and inform the design of established procedures in new contexts; and Theoretical knowledge teaches the reasoning and theory of knowledge and the laws of existence and functioning of reality to validate clinical and public health procedures. Even though medical interventions benefit from science, they are, in essence, professional: science cannot standardise eco-biopsychosocial decisions; doctor-patient negotiations; emotional intelligence; manual and behavioural skills; and resolution of ethical conflicts. CONCLUSION: Because the quality of care utilises the professionals' skill-base but is also affected by their intangible motivations, health systems should individually tailor continuing medical education and treat collective knowledge management as a priority. Teamwork and coaching by those with more experience provide such opportunities. In the future, physicians and health professionals could jointly develop clinical/public health integrated knowledge. To this end, governments should make provision to finance non-clinical activities.

Objectives, methods, and results in critical health systems and policy research: evaluating the healthcare market.

BACKGROUND: Since the 1980s, markets have turned increasingly to intangible goods - healthcare, education, the arts, and justice. Over 40 years, the authors investigated healthcare commoditisation to produce policy knowledge relevant to patients, physicians, health professionals, and taxpayers. This paper revisits their objectives, methods, and results to enlighten healthcare policy design and research. MAIN TEXT: This paper meta-analyses the authors' research that evaluated the markets impact on healthcare and professional culture and investigated how they influenced patients' timely access to quality care and physicians' working conditions. Based on these findings, they explored the political economic of healthcare. In low-income countries the analysed research showed that, through loans and cooperation, multilateral agencies restricted the function of public services to disease control, with subsequent catastrophic reductions in access to care, health de-medicalisation, increased avoidable mortality, and failure to attain the narrow MDGs in Africa. The pro-market reforms enacted in middle-income countries entailed the purchaser-provider split, privatisation of healthcare pre-financing, and government contracting of health finance management to private insurance companies. To establish the materiality of a cause-and-effect relationship, the authors compared the efficiency of Latin American national health systems according to whether or not they were pro-market and complied with international policy standards. While pro-market health economists acknowledge that no market can offer equitable access to healthcare without effective regulation and control, the authors showed that both regulation and control were severely constrained in Asia by governance and medical secrecy issues. In high-income countries they questioned the interest for population health of healthcare insurance companies, whilst comparing access to care and health expenditures in the European Union vs. the U.S., the Netherlands, and Switzerland. They demonstrated that commoditising healthcare increases mortality and suffering amenable to care considerably and carries professional, cultural, and ethical risks for doctors and health professionals. Pro-market policies systems cause health systems inefficiency, inequity in access to care and strain professionals' ethics. CONCLUSION: Policy research methodologies benefit from being inductive, as health services and systems evaluations, and population health studies are prerequisites to challenge official discourse and to explore the historical, economic, sociocultural, and political determinants of public policies.

A plea to merge clinical and public health practices: reasons and consequences.

BACKGROUND: Revisiting professionalism, both as a medical ideal and educational topic, this paper asks whether, in the rise of artificial intelligence, healthcare commoditisation and environmental challenges, a rationale exists for merging clinical and public health practices. To optimize doctors' impact on community health, clinicians should introduce public health thinking and action into clinical practice, above and beyond controlling nosocomial infections and iatrogenesis. However, in the interest of effectiveness they should do everything possible to personalise care delivery. To solve this paradox, we explore why it is necessary for the boundaries between medicine and public health to be blurred. MAIN BODY: Proceeding sequentially, we derive standards for medical professionalism from care quality criteria, neo-Hippocratic ethics, public health concepts, and policy outcomes. Thereby, we formulate benchmarks for health care management and apply them to policy evaluation. During this process we justify the social, professional - and by implication, non-commercial, non-industrial - mission of healthcare financing and policies. The complexity of ethical, person-centred, biopsychosocial practice requires a human interface between suffering, health risks and their therapeutic solution - and thus legitimises the medical profession's existence. Consequently, the universal human right to healthcare is a right to access professionally delivered care. Its enforcement requires significant updating of the existing medical culture, and not just in respect of the man/machine interface. This will allow physicians to focus on what artificial intelligence cannot do, or not do well. These duties should become the touchstone of their practice, knowledge and ethics. Artificial intelligence must support medical professionalism, not determine it. Because physicians need sufficient autonomy to exercise professional judgement, medical ethics will conflict with attempts to introduce clinical standardisation as a managerial paradigm, which is what happens when industrial-style management is applied to healthcare. CONCLUSION: Public healthcare financing and policy ought to support medical professionalism, alongside integrated clinical and public health practice, and its management. Publicly-financed health management should actively promote ethics in publicly- oriented services. Commercialised healthcare is antithetical to ethical medical, and to clinical / public health practice integration. To lobby governments effectively, physicians need to appreciate the political economy of care.

In defence of a single body of clinical and public health, medical ethics.

BACKGROUND: Since some form of dual clinical/public health practice is desirable, this paper explains why their ethics should be combined to influence medical practice and explores a way to achieve that. MAIN TEXT: In our attempt to merge clinical and public health ethics, we empirically compared the individual and collective health consequences of two illustrative lists of medical and public health ethical tenets and discussed their reciprocal relevance to praxis. The studied codes share four principles, namely, 1. respect for individual/collective rights and the patient's autonomy; 2. cultural respect and treatment that upholds the patient's dignity; 3. honestly informed consent; and 4. confidentiality of information. However, they also shed light on the strengths and deficiencies of each other's tenets. Designing a combined clinical and public health code requires fleshing out three similar principles, namely, beneficence, medical and public health engagement in favour of health equality, and community and individual participation; and adopting three stand-alone principles, namely, professional excellence, non-maleficence, and scientific excellence. Finally, we suggest that eco-biopsychosocial and patient-centred care delivery and dual clinical/public health practice should become a doctor's moral obligation. We propose to call ethics based on non-maleficence, beneficence, autonomy, and justice - the values upon which, according to Pellegrino and Thomasma, the others are grounded and that physicians and ethicists use to resolve ethical dilemmas - "neo-Hippocratic". The neo- prefix is justified by the adjunct of a distributive dimension (justice) to traditional Hippocratic ethics. CONCLUSION: Ethical codes ought to be constantly updated. The above values do not escape the rule. We have formulated them to feed discussions in health services and medical associations. Not only are these values fragmentary and in progress, but they have no universal ambition: they are applicable to the dilemmas of modern Western medicine only, not Ayurvedic or Shamanic medicine, because each professional culture has its own philosophical rationale. Efforts to combine clinical and public health ethics whilst resolving medical dilemmas can reasonably be expected to call upon the physician's professional identity because they are intellectual challenges to be associated with case management.

The astrocytic response to the dopaminergic denervation of the striatum.

Increasing evidence suggests that the dopaminergic degeneration which characterizes Parkinson's disease starts in the striatal dopamine terminals and progresses retrogradely to the body of dopamine cells in the substantia nigra. The role of striatal astrocytes in the striatal initiation of the dopaminergic degeneration is little known. This work was aimed at studying the astrocytic response to the dopaminergic denervation of the striatum. The injection of 6-hydroxydopamine (25 µg) in the lateral ventricle of adult Sprague-Dawley rats induced a fast (4 h) and selective (unaccompanied by unspecific lesions of striatal tissue or microgliosis) degeneration of the dopaminergic innervation of the striatum which was followed by a selective astrocytosis unaccompanied by microgliosis. This astrocytosis was severe and had a specific profile which included some (e.g. up-regulation of glial fibrillary acidic protein, GS, S100ß, NDRG2, vimentin) but not all (e.g. astrocytic proliferation or differentiation from NG2 cells, astrocytic scars, microgliosis) the characteristics observed after the non-selective lesion of the striatum. This astrocytosis is similar to those observed in the parkinsonian striatum and, because it is was unaccompanied by changes in other striatal cells (e.g. by microgliosis), it may be suitable to study the role of striatal astrocytes during the dopaminergic denervation which characterizes the first stages of Parkinson's disease. The dopaminergic denervation of the striatum induced a severe astrogliosis with a specific profile which included some (e.g. up-regulation of GFAP, GS, S100ß, NDRG2, vimentin) but not all (e.g. astrocytic proliferation or differentiation from NG2 cells, astrocytic scars, microgliosis) the characteristics observed after the non-selective striatal lesions. This response may help to understand the role of striatal astrocytes during the dopaminergic denervation which characterizes the first stages of PD. Cover Image for this issue: doi: 10.1111/jnc.13336.

The functional connectivity of intralaminar thalamic nuclei in the human basal ganglia.

Projections of the centromedian-parafasicularis neurons of the intralaminar thalamus are major inputs of the striatum. Their functional role in the activity of human basal ganglia (BG) is not well known. The aim of this work was to study the functional connectivity of intralaminar thalamic nuclei with other BG by using the correlations of the BOLD signal recorded during "resting" and a motor task. Intralaminar nuclei showed a marked functional connectivity with all the tested BG, which was observed during "resting" and did not change with the motor task. As regards the intralaminar nuclei, BG connectivity was much lower for the medial dorsal nucleus (a thalamic nucleus bordering the intralaminar nuclei) and for the default mode network (although intralaminar nuclei showed a negative correlation with the default mode network). After the "regression" of intralaminar nuclei activity (partial correlation), the functional connectivity of the caudate and putamen nuclei with other BG decreased (but not with the primary sensorimotor cortex). Present data provide evidence that intralaminar nuclei are not only critical for striatal activity but also for the global performance of human BG, an action involving subcortical BG loops more than cortico-subcortical loops. The high correlation found between BG suggest that, similarly to that reported in other brain centers, the very-slow frequency fluctuations are relevant for the functional activity of these centers.

Causality methods to study the functional connectivity in brain networks: the basal ganglia - thalamus causal interactions.

This study uses methods recently developed to study the complex evolution of atmospheric phenomena which have some similarities with the dynamics of the human brain. In both cases, it is possible to record the activity of particular centers (geographic regions or brain nuclei) but not to make an experimental modification of their state. The study of "causality", which is necessary to understand the dynamics of these complex systems and to develop robust models that can predict their evolution, is hampered by the experimental restrictions imposed by the nature of both systems. The study was performed with data obtained in the thalamus and basal ganglia of awake humans executing different tasks. This work studies the linear, non-linear and more complex relationships of these thalamic centers with the cortex and main BG nuclei, using three complementary techniques: the partial correlation regression method, the Gaussian process regression/distance correlation and a model-free method based on nearest-neighbor that computes the conditional mutual information. These causality methods indicated that the basal ganglia present a different functional relationship with the anterior-ventral (motor), intralaminar and medio-dorsal thalamic centers, and that more than 60% of these thalamus-basal ganglia relationships present a non-linear dynamic (35 of the 57 relationships found). These functional interactions were observed for basal ganglia nuclei with direct structural connections with the thalamus (primary somatosensory and motor cortex, striatum, internal globus pallidum and substantia nigra pars reticulata), but also for basal ganglia without structural connections with the thalamus (external globus pallidum and subthalamic nucleus). The motor tasks induced rapid modifications of the thalamus-basal ganglia interactions. These findings provide new perspectives of the thalamus - BG interactions, many of which may be supported by indirect functional relationships and not by direct excitatory/inhibitory interactions.

Striatal glutamate induces retrograde excitotoxicity and neuronal degeneration of intralaminar thalamic nuclei: their potential relevance for Parkinson's disease.

An over-stimulation of nigral glutamate (GLU) receptors has been proposed as a cause of the progression of the dopamine (DA) cell degeneration (excitotoxicity) which characterizes Parkinson's disease. The possible toxic action of striatal GLU (retrograde excitotoxicity) on these cells, and on other neurons which innervate the striatum and which also degenerate in Parkinson's disease (thalamostriatal cells of the intralaminar thalamic nuclei), is still practically unexplored. The retrograde excitotoxicity of striatal GLU on DAergic mesostriatal and GLUergic thalamostriatal cells was tested here by studying these cells 6 weeks after striatal perfusion of GLU by reverse microdialysis. GLU perfusion induced the striatal denervation of thalamic inputs (as revealed by vesicular glutamate transporter 2) and the remote degeneration of intralaminar neurons. In both centres, these effects were accompanied by microglial activation. Similar responses were not observed for nigrostriatal neurons, which showed no dopaminergic striatal denervation, no microglial activation in the substantia nigra and no changes in the number of dopaminergic cells in the substantia nigra. The inhibition of DAergic transmission increased the extrasynaptic GLU levels in the striatum (evaluated by microdialysis), an effect observed after the local administration of agonists and antagonists of DAergic transmission, and after the peripheral administration of levodopa (which increased the DA and decreased the GLU levels in the striatum of rats with an experimental DAergic denervation of this centre). The data presented show that striatal GLU induced a retrograde excitotoxicity which did not affect all striatal inputs in the same way and which could be involved in the cell degeneration of the intralaminar nuclei of the thalamus generally observed in Parkinson's disease.

Ascorbate prevents cell death from prolonged exposure to glutamate in an in vitro model of human dopaminergic neurons.

Ascorbate (vitamin C) is a nonenzymatic antioxidant highly concentrated in the brain. In addition to mediating redox balance, ascorbate is linked to glutamate neurotransmission in the striatum, where it renders neuroprotection against excessive glutamate stimulation. Oxidative stress and glutamatergic overactivity are key biochemical features accompanying the loss of dopaminergic neurons in the substantia nigra that characterizes Parkinson's disease (PD). At present, it is not clear whether antiglutamate agents and ascorbate might be neuroprotective agents for PD. Thus, we tested whether ascorbate can prevent cell death from prolonged exposure to glutamate using dopaminergic neurons of human origin. To this purpose, dopamine-like neurons were obtained by differentiation of SH-SY5Y cells and then cultured for 4 days without antioxidant (antiaging) protection to evaluate glutamate toxicity and ascorbate protection as a model system of potential factors contributing to dopaminergic neuron death in PD. Glutamate dose dependently induced toxicity in dopaminergic cells largely by the stimulation of AMPA and metabotropic receptors and to a lesser extent by N-methyl-D-aspartate and kainate receptors. At relatively physiological levels of extracellular concentration, ascorbate protected cells against glutamate excitotoxicity. This neuroprotection apparently relies on the inhibition of oxidative stress, because ascorbate prevented the pro-oxidant action of the scavenging molecule quercetin, which occurred over the course of prolonged exposure, as is also seen with glutamate. Our findings show the relevance of ascorbate as a neuroprotective agent and emphasize an often underappreciated role of oxidative stress in glutamate excitotoxicity. Occurrence of a glutamate-ascorbate link in dopaminergic neurons may explain previous contradictions regarding their putative role in PD.

Self-induced accumulation of glutamate in striatal astrocytes and basal ganglia excitotoxicity.

Excitotoxicity induced by high levels of extracellular glutamate (GLU) has been proposed as a cause of cell degeneration in basal ganglia disorders. This phenomenon is normally prevented by the astrocytic GLU-uptake and the GLU-catabolization to less dangerous molecules. However, high-GLU can induce reactive gliosis which could change the neuroprotective role of astrocytes. The striatal astrocyte response to high GLU was studied here in an in vivo rat preparation. The transient striatal perfusion of GLU (1 h) by reverse microdialysis induced complex reactive gliosis which persisted for weeks and which was different for radial-like glia, protoplasmic astrocytes and fibrous astrocytes. This gliosis was accompanied by a persistent cytosolic accumulation of GLU (immunofluorescence quantified by confocal microscope), which persisted for weeks (self-induced glutamate accumulation), and which was associated to a selective decrease of glutamine synthetase activity. This massive and persistent self-induced glutamate accumulation in striatal astrocytes could be an additional factor for the GLU-induced excitotoxicity, which has been implicated in the progression of different basal ganglia disorders.

Integrating mechanical sensor readouts into organ-on-a-chip platforms.

Organs-on-a-chip have emerged as next-generation tissue engineered models to accurately capture realistic human tissue behaviour, thereby addressing many of the challenges associated with using animal models in research. Mechanical features of the culture environment have emerged as being critically important in designing organs-on-a-chip, as they play important roles in both stimulating realistic tissue formation and function, as well as capturing integrative elements of homeostasis, tissue function, and tissue degeneration in response to external insult and injury. Despite the demonstrated impact of incorporating mechanical cues in these models, strategies to measure these mechanical tissue features in microfluidically-compatible formats directly on-chip are relatively limited. In this review, we first describe general microfluidically-compatible Organs-on-a-chip sensing strategies, and categorize these advances based on the specific advantages of incorporating them on-chip. We then consider foundational and recent advances in mechanical analysis techniques spanning cellular to tissue length scales; and discuss their integration into Organs-on-a-chips for more effective drug screening, disease modeling, and characterization of biological dynamics.

Studying the functional connectivity of the primary motor cortex with the binarized cross recurrence plot: The influence of Parkinson's disease.

Two new recurrence plot methods (the binary recurrence plot and binary cross recurrence plot) were introduced here to study the long-term dynamic of the primary motor cortex and its interaction with the primary somatosensory cortex, the anterior motor thalamus of the basal ganglia motor loop and the precuneous nucleus of the default mode network. These recurrence plot methods: 1. identify short-term transient interactions; 2. identify long-lasting delayed interactions that are common in complex systems; 3. work with non-stationary blood oxygen level dependent (BOLD) data; 4. may study the relationship of centers with non-linear functional interactions; 5 may compare different experimental groups performing different tasks. These methods were applied to BOLD time-series obtained in 20 control subjects and 20 Parkinson´s patients during the execution of motor activity and body posture tasks (task-block design). The binary recurrence plot showed the task-block BOLD response normally observed in the primary motor cortex with functional magnetic resonance imaging methods, but also shorter and longer BOLD-fluctuations than the task-block and which provided information about the long-term dynamic of this center. The binary cross recurrence plot showed short-lasting and long-lasting functional interactions between the primary motor cortex and the primary somatosensory cortex, anterior motor thalamus and precuneous nucleus, interactions which changed with the resting and motor tasks. Most of the interactions found in healthy controls were disrupted in Parkinson's patients, and may be at the basis of some of the motor disorders and side-effects of dopaminergic drugs commonly observed in these patients.

The Influence of Aging on the Functional Connectivity of the Human Basal Ganglia.

Although basal ganglia (BG) are involved in the motor disorders of aged people, the effect of aging on the functional interaction of BG is not well-known. This work was aimed at studying the influence of aging on the functional connectivity of the motor circuit of BG (BGmC). Thirty healthy volunteers were studied (young-group 26.4 ± 5.7 years old; aged-group 63.1 ± 5.8 years old) with a procedure planned to prevent the spurious functional connectivity induced by the closed-loop arrangement of the BGmC. BG showed different functional interactions during the inter-task intervals and when subjects did not perform any voluntary task. Aging induced marked changes in the functional connectivity of the BGmC during these inter-task intervals. The finger movements changed the functional connectivity of the BG, these modifications were also different in the aged-group. Taken together, these data show a marked effect of aging on the functional connectivity of the BGmC, and these effects may be at the basis of the motor handicaps of aged people during the execution of motor-tasks and when they are not performing any voluntary motor task.

The causal interaction in human basal ganglia.

The experimental study of the human brain has important restrictions, particularly in the case of basal ganglia, subcortical centers whose activity can be recorded with fMRI methods but cannot be directly modified. Similar restrictions occur in other complex systems such as those studied by Earth system science. The present work studied the cause/effect relationships between human basal ganglia with recently introduced methods to study climate dynamics. Data showed an exhaustive (identifying basal ganglia interactions regardless of their linear, non-linear or complex nature) and selective (avoiding spurious relationships) view of basal ganglia activity, showing a fast functional reconfiguration of their main centers during the execution of voluntary motor tasks. The methodology used here offers a novel view of the human basal ganglia which expands the perspective provided by the classical basal ganglia model and may help to understand BG activity under normal and pathological conditions.

Astrocytes and retrograde degeneration of nigrostriatal dopaminergic neurons in Parkinson's disease: removing axonal debris.

OBJECTIVE: The dopaminergic nigrostriatal neurons (DA cells) in healthy people present a slow degeneration with aging, which produces cellular debris throughout life. About 2%-5% of people present rapid cell degeneration of more than 50% of DA cells, which produces Parkinson's disease (PD). Neuroinflammation accelerates the cell degeneration and may be critical for the transition between the slow physiological and the rapid pathological degeneration of DA cells, particularly when it activates microglial cells of the medial forebrain bundle near dopaminergic axons. As synaptic debris produced by DA cell degeneration may trigger the parkinsonian neuroinflammation, this study investigated the removal of axonal debris produced by retrograde degeneration of DA cells, paying particular attention to the relative roles of astrocytes and microglia. METHODS: Rats and mice were injected in the lateral ventricles with 6-hydroxydopamine, inducing a degeneration of dopaminergic synapses in the striatum which was not accompanied by non-selective tissue damage, microgliosis or neuroinflammation. The possible retrograde degeneration of dopaminergic axons, and the production and metabolization of DA-cell debris were studied with immunohistochemical methods and analyzed in confocal and electron microscopy images. RESULTS: The selective degeneration of dopaminergic synapses in the striatum was followed by a retrograde degeneration of dopaminergic axons whose debris was found within spheroids of the medial forebrain bundle. These spheroids retained mitochondria and most (e.g., tyrosine hydroxylase, the dopamine transporter protein, and amyloid precursor protein) but not all (e.g., α-synuclein) proteins of the degenerating dopaminergic axons. Spheroids showed initial (autophagosomes) but not late (lysosomes) components of autophagy (incomplete autophagy). These spheroids were penetrated by astrocytic processes of the medial forebrain bundle, which provided the lysosomes needed to continue the degradation of dopaminergic debris. Finally, dopaminergic proteins were observed in the cell somata of astrocytes. No microgliosis or microglial phagocytosis of debris was observed in the medial forebrain bundle during the retrograde degeneration of dopaminergic axons. CONCLUSIONS: The present data suggest a physiological role of astrocytic phagocytosis of axonal debris for the medial forebrain bundle astrocytes, which may prevent the activation of microglia and the spread of retrograde axonal degeneration in PD.

Astrocytes, a Promising Opportunity to Control the Progress of Parkinson's Disease.

At present, there is no efficient treatment to prevent the evolution of Parkinson's disease (PD). PD is generated by the concurrent activity of multiple factors, which is a serious obstacle for the development of etio-pathogenic treatments. Astrocytes may act on most factors involved in PD and the promotion of their neuroprotection activity may be particularly suitable to prevent the onset and progression of this basal ganglia (BG) disorder. The main causes proposed for PD, the ability of astrocytes to control these causes, and the procedures that can be used to promote the neuroprotective action of astrocytes will be commented upon, here.