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.

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.

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.

Mu-rhythm changes during the planning of motor and motor imagery actions.

Motor imagery is a mental representation of motor behavior which has been widely used to study the cognitive basis of movement. The assumption that real movements and motor imagery (virtual movements) use the same neurobiological basis has been questioned by functional magnetic resonance data. The functional similarity in the planning of real and virtual movements was studied here by analyzing event-related EEG recordings of the Mu-activity in the sensitive-motor cortex, pre-motor cortex and supplementary motor cortex. A visual stimulus (an arrow) which displayed the information needed for planning a motion (which can be executed or imaged later after the display of a second stimulus) induced a short-lasting phase-locked Mu-response (PLr) which was wider and more widespread when it was used for the motor planning of real or virtual movements than when it was passively watched. The phase-locked Mu-response was accompanied by a persistent decrease of the Mu-rhythms which were not phase-locked to stimuli (NPLr), a response which also was more marked and generalized when stimuli were used for motor planning than when they were passively observed. PLr and NPLr were similar during motor testing and imagery testing, suggesting that both tasks activated the Mu rhythms to a similar degree. This congruency between real and virtual movements was observed in the three cortical areas studied, where the amplitude, latency and duration of the phase-locked and non-phase-locked Mu response was similar in both cases. These noticeable similarities support the idea that the same cortical mechanisms are recruited during the planning of real and virtual movements, a fact that can be analyzed better when an event-related paradigm and a high time-resolution method are used.

The role of non-synaptic extracellular glutamate.

Although there are some mechanisms which allow the direct crossing of substances between the cytoplasm of adjacent cells (gap junctions), most substances use the extracellular space to diffuse between brain cells. The present work reviews the behavior and functions of extracellular glutamate (GLU). There are two extracellular pools of glutamate (GLU) in the brain, a synaptic pool whose functions in the excitatory neurotransmission has been widely studied and an extrasynaptic GLU pool although less known nonetheless is gaining attention among a growing number of researchers. Evidence accumulated over the last years shows a number of mechanisms capable of releasing glial GLU to the extracellular medium, thus modulating neurons, microglia and oligodendrocytes, and regulating the immune response, cerebral blood flow, neuronal synchronization and other brain functions. This new scenario is expanding present knowledge regarding the role of GLU in the brain under different physiological and pathological conditions. This article is part of a Special Issue entitled 'Extrasynaptic ionotropic receptors'.

Mu rhythm, visual processing and motor control.

OBJECTIVE: The Mu-rhythm has been proposed as both an inhibitor ("idling hypothesis") and as a promoter ("processing hypothesis") of information processing in the primary sensory-motor cortex (SM-C). We tested these possibilities by analyzing the phase-locked and non-phase-locked Mu response during the execution of a visual-motor task. METHODS: EEG was recorded in 13 subjects during the visual presentation of an arrow which indicated the direction of the finger motion to be executed after the presentation of a second stimulus. The EEG activity in the α-range (Mu-α) and ß-range was evaluated by a method which segregated the phase-locked and the non-phase-locked response. The event-related Mu-response observed during this task was compared with that computed when the subjects saw the same arrow-stimuli but did not perform any task (passive test). RESULTS: Visual stimuli induced a phase-locked α-oscillation which began ≈50ms after the stimulus onset and persisted for about 150-200ms. This response was much higher when stimuli were used for motion planning than when they were passively observed, and was more marked in the α-range than in the ß-range. The phase-locked response was followed by a persistent decrease of the non-phase-locked Mu-activity similar to that previously reported with the event-related desynchronization/synchronization method. CONCLUSIONS: The Mu-wave is not a single phenomenon. It was segregated here into two components, one with an early and short-lasting phase locked-response to visual stimuli, which increased during the task execution, and the other without phase-locked responses which persistently decreased during the task execution. SIGNIFICANCE: Present data suggest that Mu-activity performs a double action, increasing the information processing of one task (according to the "processing hypothesis") and decreasing the computation of other potentially interfering tasks (according to the "idling hypothesis"), with task selection being achieved by choosing their phase-association to the Mu-wave.

The kinematics of motor imagery: comparing the dynamics of real and virtual movements.

Motor imagery (MI) is a key tool for studying the cognitive functions of movement. These studies assume that movements and their MI (virtual movements) involve the same cognitive functions. The real-virtual isochrony and isometry of movements of different complexity and accuracy, and the kinematics of real and virtual movements (real-virtual spatial homology and partial isometry) were studied to test this hypothesis. Isochrony was high in complex attention-demanding tasks but not in simple or inaccurate tasks, with isometry and spatial homology also being different for different motor patterns. These data suggest that movements and their MI do not always involve the same cognitive functions, and are particularly different in simple motor tasks requiring low attention levels.

How similar are motor imagery and movement?

It has been suggested that motor imagery (MI) has the basic components of real motion. This possibility was tested here in 17 healthy volunteers studied while performing or imaging a fast sequence of finger movements of progressive complexity, a fast and precise extension of the arm to touch a small circle with the tip of a pencil, a periodic repetitive flexion-extension of the index finger at a specified rate, and a velocity-regulated continuous rotary movement of the right hand. Motor sequences of 4 to 5 fingers showed a real-virtual congruency similar to that previously reported with other equivalent tests, but it decreased in the simplest sequences performed with 1 to 2 fingers. A more marked decrease of real-virtual congruency was found in the experimental paradigm aimed at producing movements with a pre-specified velocity, which was low for rhythmic movements of the index finger and practically absent in the continuous rotary movements of the hand. Present data show that the ability of MI to produce "realistic" simulations of motion is not the same for all motor tasks.

Integration of auditory and kinesthetic information in motion: alterations in Parkinson's disease.

The main aim in this work was to study the interaction between auditory and kinesthetic stimuli and its influence on motion control. The study was performed on healthy subjects and patients with Parkinson's disease (PD). Thirty-five right-handed volunteers (young, PD, and age-matched healthy participants, and PD-patients) were studied with three different motor tasks (slow cyclic movements, fast cyclic movements, and slow continuous movements) and under the action of kinesthetic stimuli and sounds at different beat rates. The action of kinesthesia was evaluated by comparing real movements with virtual movements (movements imaged but not executed). The fast cyclic task was accelerated by kinesthetic but not by auditory stimuli. The slow cyclic task changed with the beat rate of sounds but not with kinesthetic stimuli. The slow continuous task showed an integrated response to both sensorial modalities. These data show that the influence of the multisensory integration on motion changes with the motor task and that some motor patterns are modulated by the simultaneous action of auditory and kinesthetic information, a cross-modal integration that was different in PD-patients.

Nigrostriatal cell firing action on the dopamine transporter.

The influence of nigrostriatal cell firing on the dopamine transporter (DAT) activity of the rat striatum was studied in vivo with amperometric methods. Data were obtained after preventing dopamine (DA) release with alpha-methyl-L-tyrosine and replenishing extracellular DA with local injections. The DA cell stimulation, which under basal conditions increased extracellular DA, decreased DA after this pre-treatment, suggesting that firing activity facilitates the DA cell uptake of DA under these circumstances (drain response). Cocaine and GBR13069 markedly decreased the drain response, suggesting that it is dependent on DAT activation. Data obtained after haloperidol and apomorphine administration showed that the drain response was facilitated by pre-synaptic DA receptor stimulation but that receptors are not a necessary requirement. Two components in the drain response were observed, one with a short latency and duration that needed high-frequency stimuli, and the other with a long latency and duration that was even induced by low-frequency stimuli. This is the first evidence showing that DAT can be activated by the firing activity in nigrostriatal cells in a direct way and without the participation of pre-synaptic DA receptors.

Substantia nigra osmoregulation: taurine and ATP involvement.

An extracellular nonsynaptic taurine pool of glial origin was recently reported in the substantia nigra (SN). There is previous evidence showing taurine as an inhibitory neurotransmitter in the SN, but the physiological role of this nonsynaptic pool of taurine has not been explored. By using microdialysis methods, we studied the action of local osmolarity on the nonsynaptic taurine pool in the SN of the rat. Hypoosmolar pulses (285-80 mosM) administered in the SN by the microdialysis probe increased extrasynaptic taurine in a dose-dependent way, a response that was counteracted by compensating osmolarity with choline. The opposite effect (taurine decrease) was observed when osmolarity was increased. Under basal conditions, the blockade of either the AMPA-kainate glutamate receptors with 6-cyano-7-nitroquinoxaline-2,3-dionine disodium or the purinergic receptors with pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid modified the taurine concentration, suggesting that both receptors modulate the extrasynaptic pool of taurine. In addition, these drugs decreased the taurine response to hypoosmolar pulses, suggesting roles for glutamatergic and purinergic receptors in the taurine response to osmolarity. The participation of purinergic receptors was also supported by the fact that ATP (which, under basal conditions, increased the extrasynaptic taurine in a dose-dependent way) administered in doses saturating purinergic receptors also decreased the taurine response to hypoosmolarity. Taken together, present data suggest osmoregulation as a role of the nonsynaptic taurine pool of the SN, a function that also involves glutamate and ATP and that could influence the nigral cell vulnerability in Parkinson's disease.

Adapting movement planning to motor impairments: the motor-scanning system.

Previous studies have reported a similar duration for movement execution (real movement) and its internal simulation with motor imagery (virtual movement). The present work has studied the real movement-virtual movement relationship for complex sequences of finger movements after different acute and chronic brain lesions and after a long-lasting restriction of right-hand movements. Age, hand-movement restriction and lesions of pyramidal system, basal ganglia and cerebellum did not prevent the high real movement-virtual movement correlation. The data suggest that movement execution and its internal simulation share the same neuronal basis. However, the calculation of virtual delay (a useful procedure for detecting small real movement-virtual movement differences) showed significant real movement-virtual movement mismatches, suggesting the existence of a separate and selective system that, continuously scanning the competence of the different elements participating in motor behavior, adjusts the planning of future movements to the real capability of the motor system.

Disturbance of motor imagery after cerebellar stroke.

The authors studied the possible involvement of the cerebellum in nonexecutive motor functions needed for a normal performance of complex motor patterns by analyzing (using chronometric evaluation) finger movement sequences and their respective motor imagery (a mental simulation of motor patterns). Patients suffering from a cerebellar stroke (n=11) were compared with aged-matched control volunteers (n=11). Patients that had apparently recovered from a unilateral cerebellar stroke showed a marked slowing of motor performance in both hands (ipsi- and contralateral to lesion). This effect was accompanied by a similar slowing of motor imagery, suggesting that the cerebellum, traditionally implicated in the control of motor execution, is also involved in nonexecutive motor functions such as the planning and internal simulation of movements.

Glial regulation of nonsynaptic extracellular glutamate in the substantia nigra.

GLU is the main neurotransmitter in the brain, where it induces a synaptic excitatory action. There is recent evidence for an extracellular nonsynaptic GLU (EnS-GLU) pool in different brain nuclei that, released from glial cells, may act on extrasynaptic GLU receptors of cells located far from the position in which it was released. In the present work, the EnS-GLU pool was studied with microdialysis in the rat substantia nigra (SN). We observed an EnS-GLU pool that increased in a Ca2+-dependent manner during cell depolarization. The selective alteration of with methionine sulfoximide (MSO) and fluorocitrate induced marked modifications in EnS-GLU suggesting that EnS-GLU is dependent on glial cells. Glutamine administration increased GLU, suggesting that neurons are also involved in EnS-GLU modulation. GLU administered in the rostral SN showed a long-distance diffusion to the caudal SN. The ionotropic GLU receptors agonist N-methyl-D-aspartate and kainate and the metabotropic GLU receptors agonist ACPD increased EnS-GLU and decreased extracellular glutamine. Taken together, these data indicate that nigral glia releases GLU, which probably performs a volume transmitter role.

Hand movement distribution in the motor cortex: the influence of a concurrent task and motor imagery.

The aim of this work was to study the relevance of the primary motor cortex (M1) for motor functions different to the simple execution of motor orders. The M1 activity during the performance with individual fingers of a simple motor task (tonic flexion), a motor task that includes a complex motor computation but not motor execution (motor imagery), and a motor task that involves both the computation and execution of movements (phasic movement) was evaluated by functional magnetic resonance imaging (fMRI). The possible influence of other cortical tasks on the M1 activation induced by finger movements was assessed by evaluating the effect of a distracting concurrent task (numeric calculation). Data show that both the dimension of the area activated and the intensity of response were higher during motor planning than during motor execution. There is a mosaic-like distribution for motor-planning M1 functions, with the movement of individual fingers being controlled from several M1 loci. The concurrent mental-task induces a rapid functional reconfiguration of M1, adding M1 subsets to motor programming but excluding others. Present data support the involvement of the M1 in more than just simple motor execution, showing broader and more intense modifications during motor tasks not accompanied by movements (motor imagery) than during the execution of simple motor acts (tonic flexion).

Brain lateralization of motor imagery: motor planning asymmetry as a cause of movement lateralization.

Movement asymmetry in humans and animals is often considered as being induced by the brain lateralization of the motor system. In the present work, the hemispheric asymmetry for motor planning as a cause of behavioral lateralization was examined. This study was carried out on normal volunteers and patients suffering unilateral brain damage caused by a stroke. Motor planning was evaluated by using the motor imagery of hand movement, a mental representation of a motor pattern that includes its internal simulation but not its real execution. The present study shows marked similarities between virtual movement executed during motor imagery and real movements. Thus, performance time showed a high correlation between real and virtual movements in the following conditions: (1) during dominant and non-dominant hand movements; (2) in simple and complex motor tasks; (3) in young control subjects; (4) in stroke patients; and (5) control subjects aged-matched to stroke patients. Brain strokes increased the performance time in both real and virtual movements. Left-brain strokes decreased the velocity of the real movements in both hands, whereas right-brain strokes mainly disturbed movements in the left hand. A similar effect was observed for virtual movements, suggesting a left-brain dominance for motor planning in humans. However, two-handed movement tasks suggest a complex interaction during motor planning, an interaction that facilitates motor performance during mirror movements and delays motor execution during non-mirror movements.

Firing regulation in dopaminergic cells: effect of the partial degeneration of nigrostriatal system in surviving neurons.

Two mechanisms for firing rate regulation were identified in dopaminergic nigrostriatal cells (DA cells), one of a renewal nature which prevents short and long interspike intervals (ISIs) and the other of a no-renewal nature which compensates long ISIs with short ISIs and vice versa. Renewal regulation was found in 96% of DA cells and less frequently in nigrocollicular (63%), nigrothalamic (61%) and nigropeduncular (50%) nigral GABA cells. No-renewal regulation was found in 77% of DA cells, and was only observed in 8% of GABA cells. Thus, most DA cells showed both regulatory mechanisms, which justifies the low variability in their firing rate and the low oscillation of extracellular striatal dopamine previously reported. DA cells surviving a partial degeneration of the nigrostriatal system did not show alterations in their firing rate and burst firing but presented a marked disturbance for no-renewal regulation. Under these conditions, small fluctuations in firing rate are not compensated for in time, which could be one of the factors responsible for the motor fluctuations often observed in advanced Parkinson's disease.