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.

Estudio longitudinal del efecto del confinamiento por COVID-19 en la aparición de trastornos del sueño en una muestra clínica de niños y adolescentes españoles / Longitudinal study of the impact of confinement in a sample of Spanish children and adolescents

Aunque abundantes estudios aportan evidencia sobre el impacto del confinamiento en el sueño en población adulta, ésta resulta escasa en población infanto-juvenil. Así, el estudio surge de la necesidad de ampliar el conocimiento al respecto para amortiguar la urgencia clínica actual. El presente trabajo se propone estudiar el efecto de las restricciones debidas a la COVID-19 en las alteraciones del sueño de una muestra de niños y adolescentes que fueron atendidos en la consulta de psicología clínica del servicio público de salud. Se contó con una muestra de pacientes de entre 3 y 16 años, (Medad = 10.51, DT = 3.28). Como instrumentos de medida se utilizaron la Escala de Alteraciones del Sueño de Bruni, en tres momentos de medida, y un cuestionario con variables sociodemográficas. Se realiza un análisis descriptivo de evolución de la prevalencia y comparaciones de proporciones. Los resultados muestran que un 82% de la muestra tenía una alteración del sueño, que se mantuvo 6 meses y un descenso significativo al 22% un año después, coincidiendo con la flexibilización de las medidas. También se encuentran diferencias significativas entre la presencia o la ausencia de alteración del sueño y algunas de las variables recogidas: consumo de psicofármacos de los padres y uso de pantallas. Estos datos sugieren que el confinamiento tuvo un impacto emocional en la población infanto-juvenil, en concreto sobre el sueño. (AU)

This study highlights the need to expand the evidence on the impact of lockdown on the sleep of children and adolescents. Although several studies provide evidence in this regard, research on child and adolescent population is still scarce. The paper also aims at exploring whether the possible effects vanish over time. The sample is formed by patients ranging from 3 to 16 years old. The mean age was 10.51 and the SD was 3.28. Two assessment instruments were used: the Sleep Disturbances Scale for Children (SDSC) and a socieconomic questionnaire. The SDSC was measured three times during one year and a descriptive analysis of the sample and the evolution of the prevalence according to the results of the scale was executed. A comparison of proportions was made in those patients who exceeded the cut-off point in the different variables collected. The results indicate that 82% of the sample had a sleep disorder, which remained for 6 months and it experienced a significant decrease to 22% after one year, when COVID-19 restrictions were relaxed. There are also significant differences between sleep disorder and some of the variables collected: parents’ use of psychotropic drugs and use of screens. This data suggests that lockdown had an emotional impact on children and adolescent population, specifically on their sleep. (AU)

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.

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.

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.

Striatal astrocytes engulf dopaminergic debris in Parkinson's disease: A study in an animal model.

The role of astrocytes in Parkinson's disease is still not well understood. This work studied the astrocytic response to the dopaminergic denervation. Rats were injected in the lateral ventricles with 6-hydroxydopamine (25µg), inducing a dopaminergic denervation of the striatum not accompanied by non-selective tissue damage. The dopaminergic debris were found within spheroids (free-spheroids) which retained some proteins of dopaminergic neurons (e.g., tyrosine hydroxylase, the dopamine transporter protein, and APP) but not others (e.g., α-synuclein). Free-spheroids showed the initial (LC3-autophagosomes) but not the late (Lamp1/Lamp2-lysosomes) components of autophagy (incomplete autophagy), preparing their autophagosomes for an external phagocytosis (accumulation of phosphatidylserine). Free-spheroids were penetrated by astrocyte processes (fenestrated-spheroids) which made them immunoreactive for GFAP and S100ß, and which had some elements needed to continue the debris degradation (Lamp1/Lamp2). Finally, proteins normally found in neurons (TH, DAT and α-synuclein) were observed within astrocytes 2-5 days after the dopaminergic degeneration, suggesting that the intracellular contents of degenerated cells had been transferred to astrocytes. Taken together, present data suggest phagocytosis as a physiological role of striatal astrocytes, a role which could be critical for cleaning striatal debris during the initial stages of Parkinson's disease.

The Multiple Correspondence Analysis Method and Brain Functional Connectivity: Its Application to the Study of the Non-linear Relationships of Motor Cortex and Basal Ganglia.

The complexity of basal ganglia (BG) interactions is often condensed into simple models mainly based on animal data and that present BG in closed-loop cortico-subcortical circuits of excitatory/inhibitory pathways which analyze the incoming cortical data and return the processed information to the cortex. This study was aimed at identifying functional relationships in the BG motor-loop of 24 healthy-subjects who provided written, informed consent and whose BOLD-activity was recorded by MRI methods. The analysis of the functional interaction between these centers by correlation techniques and multiple linear regression showed non-linear relationships which cannot be suitably addressed with these methods. The multiple correspondence analysis (MCA), an unsupervised multivariable procedure which can identify non-linear interactions, was used to study the functional connectivity of BG when subjects were at rest. Linear methods showed different functional interactions expected according to current BG models. MCA showed additional functional interactions which were not evident when using lineal methods. Seven functional configurations of BG were identified with MCA, two involving the primary motor and somatosensory cortex, one involving the deepest BG (external-internal globus pallidum, subthalamic nucleus and substantia nigral), one with the input-output BG centers (putamen and motor thalamus), two linking the input-output centers with other BG (external pallidum and subthalamic nucleus), and one linking the external pallidum and the substantia nigral. The results provide evidence that the non-linear MCA and linear methods are complementary and should be best used in conjunction to more fully understand the nature of functional connectivity of brain centers.

The functional connectivity in the motor loop of human basal ganglia.

Basal ganglia interact in a complex way which is still not completely understood. The model generally used to explain basal ganglia interactions is based on experimental data in animals, but its validation in humans has been hampered by methodological restrictions. The time-relationship (partial correlation) of the fluctuations of the blood-oxygen-level-dependent signals recorded in the main basal ganglia was used here (32 healthy volunteers; 18-72 years of age; 16 males and 16 females) to test whether the interaction of the main basal ganglia in humans follows the pattern of functional connectivity in animals. Data showed that most basal ganglia have a functional connectivity which is compatible with that of the established closed-loop model. The strength of the connectivity of some basal ganglia changed with finger motion, suggesting that the functional interactions between basal ganglia are quickly restructured by the motor tasks. The present study with the motor cortico-BG loop centers supports the circling dynamic of the basal ganglia model in humans, showing that motor tasks may change the functional connectivity of these centers.

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 degeneration of dopaminergic synapses in Parkinson's disease: A selective animal model.

Available evidence increasingly suggests that the degeneration of dopamine neurons in Parkinson's disease starts in the striatal axons and synaptic terminals. A selective procedure is described here to study the mechanisms involved in the striatal denervation of dopaminergic terminals. This procedure can also be used to analyze mechanisms involved in the dopaminergic re-innervation of the striatum, and the role of astrocytes and microglia in both processes. Adult Sprague-Dawley rats were injected in the lateral ventricles with increasing doses of 6-hydroxydopamine (12-50 µg), which generated a dose-dependent loss of dopaminergic synapses and axons in the striatum, followed by an axonal sprouting (weeks later) and by a progressive recovery of striatal dopaminergic synapses (months later). Both the degeneration and regeneration of the dopaminergic terminals were accompanied by astrogliosis. Because the experimental manipulations did not induce unspecific damage in the striatal tissue, this method could be particularly suitable to study the basic mechanisms involved in the distal degeneration and regeneration of dopaminergic nigrostriatal neurons, and the possible role of astrocytes and microglia in the dynamics of both processes.

Parkinson's disease as a result of aging.

It is generally considered that Parkinson's disease is induced by specific agents that degenerate a clearly defined population of dopaminergic neurons. Data commented in this review suggest that this assumption is not as clear as is often thought and that aging may be critical for Parkinson's disease. Neurons degenerating in Parkinson's disease also degenerate in normal aging, and the different agents involved in the etiology of this illness are also involved in aging. Senescence is a wider phenomenon affecting cells all over the body, whereas Parkinson's disease seems to be restricted to certain brain centers and cell populations. However, reviewed data suggest that Parkinson's disease may be a local expression of aging on cell populations which, by their characteristics (high number of synaptic terminals and mitochondria, unmyelinated axons, etc.), are highly vulnerable to the agents promoting aging. The development of new knowledge about Parkinson's disease could be accelerated if the research on aging and Parkinson's disease were planned together, and the perspective provided by gerontology gains relevance in this field.

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.

The degeneration and replacement of dopamine cells in Parkinson's disease: the role of aging.

Available data show marked similarities for the degeneration of dopamine cells in Parkinson's disease (PD) and aging. The etio-pathogenic agents involved are very similar in both cases, and include free radicals, different mitochondrial disturbances, alterations of the mitophagy and the ubiquitin-proteasome system. Proteins involved in PD such as α-synuclein, UCH-L1, PINK1 or DJ-1, are also involved in aging. The anomalous behavior of astrocytes, microglia and stem cells of the subventricular zone (SVZ) also changes similarly in aging brains and PD. Present data suggest that PD could be the expression of aging on a cell population with high vulnerability to aging. The future knowledge of mechanisms involved in aging could be critical for both understanding the etiology of PD and developing etiologic treatments to prevent the onset of this neurodegenerative illness and to control its progression.