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.

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.

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.

Evaluación y utilidad del cuestionario DASI (duke activity score index) para la estimación de capacidad funcional en población chilena / A spanish version of the DASI questionnaire for estimation of functional capacity and cardiovascular risk applied to a chilean population

RESUMEN: El Duke Activity Status Index (DASI) es un cuestionario inglés utilizado para la estimación de capacidad funcional, que se ha correlacionado con equivalentes metabólicos (METs) y con consumo de oxígeno (VO2max). No existe información de su aplicación en población chilena. El objetivo fue evaluar la utilidad de una versión de DASI traducida al español y adaptada a población local, para predecir capacidad funcional determinada en prueba de esfuerzo máxima. Método: Se tradujo al español el DASI junto con adaptación de preguntas para población local. El cuestionario fue auto administrado previo a la realización de una prueba de esfuerzo máximo, sólo detenida por síntomas y percepción de esfuerzo de ≥17 /20 en escala de Borg. Se correlacionó METs con VO2max logrados en esfuerzo versus los estimados por DASI. Resultados: Se incorporaron 480 sujetos (edad x:50.9 ±15.3 años). La mediana (IQ) de METS estimados por DASI fue 9,2 (8,2-9,8). El valor α de Cronbach y Formula 20 de Kuder Richardson fue 0,72. El cuestionario fue de rápida aplicación. Se observó correlación significativa entre METs (r: 0.44; p< 0.001) y VO2max (r: 0,37; p< 0.001) determinados por cuestionario DASI y prueba de esfuerzo máxima. Conclusión: El DASI traducido y adaptado a población chilena es un instrumento sencillo de completar, que se correlaciona positivamente con capacidad funcional de forma similar a lo descrito en otros países, entregando una herramienta útil para la evaluación y predicción de riesgo cardiovascular.

ABSTRACT: The Duke Activity Status Index (DASI) is an English questionnaire used to estimate functional capacity and physical fitness that correlates with peak oxygen uptake (VO2max) and metabolic equivalents (METs). There is no available information of its application in Chilean population. Aim: to assess the efficacy of a Spanish version of the DASI questionnaire in predicting functional capacity in a Chilean population. Methods: DASI was translated into a Spanish version and adapted to local population and culture. The questionnaire was self-administered prior to carrying out a treadmill exercise stress testing, stopped only by symptoms or a perception of stress ≥17 / 20 on the Borg scale. Internal consistency was estimated with two tests. A correlation was performed between the METs and VO2max achieved in treadmill stress testing versus those estimated by DASI. Results: 480 subjects were enrolled (age x: 50.9 ±15.3 years old). The median (IQ) DASI score was 9,2 (8,2-9,8). Both Cronbach´s α and Kuder Richardson Formula 20 were 0,72. DASI was easy and quick to apply. A significant correlation was observed between METS by DASI and those estimated by stress testing (r: 0.44: p<0.001); the same was true for the estimation of VO2max (r:0.37: p<0.001). Conclusion: The Spanish DASI translation adapted to Chilean population is an easy instrument to apply. Results are similar those obtained in other countries in the estimation of functional capacity.

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 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.

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.

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 dynamic of basal ganglia activity with a multiple covariance method: influences of Parkinson's disease.

The closed-loop cortico-subcortical pathways of basal ganglia have been extensively used to describe the physiology of these centres and to justify the functional disorders of basal ganglia diseases. This approach justifies some experimental and clinical data but not others, and furthermore, it does not include a number of subcortical circuits that may produce a more complex basal ganglia dynamic than that expected for closed-loop linear networks. This work studied the functional connectivity of the main regions of the basal ganglia motor circuit with magnetic resonance imaging and a new method (functional profile method), which can analyse the multiple covariant activity of human basal ganglia. The functional profile method identified the most frequent covariant functional status (profiles) of the basal ganglia motor circuit, ordering them according to their relative frequency and identifying the most frequent successions between profiles (profile transitions). The functional profile method classified profiles as input profiles that accept the information coming from other networks, output profiles involved in the output of processed information to other networks and highly interconnected internal profiles that accept transitions from input profiles and send transitions to output profiles. Profile transitions showed a previously unobserved functional dynamic of human basal ganglia, suggesting that the basal ganglia motor circuit may work as a dynamic multiple covariance network. The number of internal profiles and internal transitions showed a striking decrease in patients with Parkinson's disease, a fact not observed for input and output profiles. This suggests that basal ganglia of patients with Parkinson's disease respond to requirements coming from other neuronal networks, but because the internal processing of information is drastically weakened, its response will be insufficient and perhaps also self-defeating. These marked effects were found in patients with few motor disorders, suggesting that the functional profile method may be an early procedure to detect the first stages of the Parkinson's disease when the motor disorders are not very evident. The multiple covariance activity found presents a complementary point of view to the cortico-subcortical closed-loop model of basal ganglia. The functional profile method may be easily applied to other brain networks, and it may provide additional explanations for the clinical manifestations of other basal ganglia disorders.

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.

The functional interaction of the brain default network with motor networks is modified by aging.

Motor disturbance is a major source of injury in older adults, a fact facilitated by the interfering action of cognitive activities on ongoing motor tasks. The present work studies the influence of aging on the functional interaction of the default mode network(DMN) and two key networks for motion, the somato-motor network(SMN) and the posterior motor circuit of basal ganglia(BGmC). The relationship between these networks was explored in young (31.3 ±â€¯5.2;n = 12) and aged (58.7 ±â€¯5.4;n = 15) groups by studying the co-activation (positive correlation)/co-inactivation (negative correlation) and unrelated fluctuations (no significant correlation) of the BOLD-signals recorded by functional magnetic resonance imaging in the motor/somatosensory primary cortex, basal ganglia(BG) centers, and the posterior cingulate cortex(DMN) which projects to the SMN and BGmC. Two experimental conditions were used, one with subjects performing hand movements (a condition which should activate the motor networks and block the DMN) and a resting condition with subjects not performing any particular task (a condition where the DMN is recruited and the motor networks should be less active). In the young group, the DMN showed co-inactivation with the SMN and a non-significant correlation with the BGmC. However, in the aged-group the DMN-BGmC co-inactivation decreased (particularly during the motor action), and the DMN-SMN co-inactivation was replaced by a co-activation (during both the resting and motor action). Present data show a marked effect of age on the functional relationship of DMN with these cortical (SMN) and subcortical(BG) motor networks, suggesting that a disorder of the DMN-motor network co-inactivation may facilitate the motor disturbances that often accompany aging.

The influence of Parkinson's disease on the functional connectivity of the motor loop of human basal ganglia.

Current basal ganglia models integrate information obtained from humans and animals to explain motor disorders in Parkinson's disease. These models explain some motor disturbances of Parkinson's disease (PD), but different clinical observations which remain unexplained have promoted the development of new basal ganglia (BG) models. The present study uses the time-relationship (partial correlation) of the BOLD-signal fluctuations to study the influence of PD on BG interactions of 17 age-matched controls (58.7 ±â€¯5.3 years of age) and 24 PD patients (56.7 ±â€¯8.4 years of age). Controls showed a complex functional connectivity of BG with a positive correlation between some nuclei (synchrony) and a negative correlation between other nuclei (anti-synchrony). This functional connectivity was different in PD-patients who showed: 1. an increased synchrony between the primary motor cortex(M1)-external pallidum(GPe), putamen(Put)-GPe, Put-subthalamic nucleus (STN), STN-internal pallidum (GPi), STN-motor thalamus (Tal), STN-GPi substantia nigra (SN) and SN-Tal, 2. a decreased synchrony between Put-GPi, GPe-STN, GPe-SN, STN-SN and GPi-SN, and 3. an increased anti-synchrony between GPe-SN and GPi-Tal. In control subjects, the motor-task increased the Put-Tal, GPi-SN and STN-Tal synchrony, decreased the STN-GPi and STN-SN synchrony and decreased the M1-GPe and the GPe-GPi anti-synchrony. The effect of the motor-task was very different in PD-patients, in whom it induced a decrease of the M1-GPe, STN-GPi and SN-Tal synchrony and a decrease of the GPe-Tal and GPe-SN anti-synchrony. Functional connectivity imaging methods may provide data that cannot be obtained by other methods in humans, and that may help to understand the physiology of BG and its deterioration in PD.

The organization of the basal ganglia functional connectivity network is non-linear in Parkinson's disease.

The motor symptoms in Parkinson's disease (PD) have been linked to changes in the excitatory/inhibitory interactions of centers involved in the cortical-subcortical closed-loop circuits which connect basal ganglia (BG) and the brain cortex. This approach may explain some motor symptoms of PD but not others, which has driven the study of BG from new perspectives. Besides their cortical-subcortical linear circuits, BG have a number of subcortical circuits which directly or indirectly connect each BG with all the others. This suggests that BG may work as a complex network whose output is the result of massive functional interactions between all of their nuclei (decentralized network; DCN), more than the result of the linear excitatory/inhibitory interactions of the cortical-subcortical closed-loops. The aim of this work was to study BG as a DCN, and to test whether the DCN behavior of BG changes in PD. BG activity was recorded with MRI methods and their complex interactions were studied with a procedure based on multiple correspondence analysis, a data-driven multifactorial method which can work with non-linear multiple interactions. The functional connectivity of twenty parkinsonian patients and eighteen age-matched controls were studied during resting and when they were performing sequential hand movements. Seven functional configurations were identified in the control subjects during resting, and some of these interactions changed with motor activity. Five of the seven interactions found in control subjects changed in Parkinson's disease. The BG response to the motor task was also different in PD patients and controls. These data show the basal ganglia as a decentralized network where each region can perform multiple functions and each function is performed by multiple regions. This framework of BG interactions may provide new explanations concerning motor symptoms of PD which are not explained by current BG models.