Manuel Rodriguez

Pathophysiology of the basal ganglia in Parkinson's disease

Insight into the organization of the basal ganglia in the normal, parkinsonian and L-dopa-induced dyskinesia states is critical for the development of newer and more effective therapies for Parkinsons disease. We believe that the basal ganglia can no longer be thought of as a unidirectional linear system that transfers information based solely on a firing-rate code. Rather, we propose that the basal ganglia is a highly organized network, with operational characteristics that simulate a non-linear dynamic system.

Goal-directed and habitual control in the basal ganglia: implications for Parkinson's disease

Progressive loss of the ascending dopaminergic projection in the basal ganglia is a fundamental pathological feature of Parkinsons disease. Studies in animals and humans have identified spatially segregated functional territories in the basal ganglia for the control of goal-directed and habitual actions. In patients with Parkinsons disease the loss of dopamine is predominantly in the posterior putamen, a region of the basal ganglia associated with the control of habitual behaviour. These patients may therefore be forced into a progressive reliance on the goal-directed mode of action control that is mediated by comparatively preserved processing in the rostromedial striatum. Thus, many of their behavioural difficulties may reflect a loss of normal automatic control owing to distorting output signals from habitual control circuits, which impede the expression of goal-directed action.

Missing pieces in the Parkinson's disease puzzle

Parkinsons disease is a neurodegenerative process characterized by numerous motor and nonmotor clinical manifestations for which effective, mechanism-based treatments remain elusive. Here we discuss a series of critical issues that we think researchers need to address to stand a better chance of solving the different challenges posed by this pathology.

Functional organization of the basal ganglia: Therapeutic implications for Parkinson's disease

The basal ganglia (BG) are a highly organized network, where different parts are activated for specific functions and circumstances. The BG are involved in movement control, as well as associative learning, planning, working memory, and emotion. We concentrate on the “motor circuit” because it is the best understood anatomically and physiologically, and because Parkinsons disease is mainly thought to be a movement disorder. Normal function of the BG requires fine tuning of neuronal excitability within each nucleus to determine the exact degree of movement facilitation or inhibition at any given moment. This is mediated by the complex organization of the striatum, where the excitability of medium spiny neurons is controlled by several pre‐ and postsynaptic mechanisms as well as interneuron activity, and secured by several recurrent or internal BG circuits. The motor circuit of the BG has two entry points, the striatum and the subthalamic nucleus (STN), and an output, the globus pallidus pars interna (GPi), which connects to the cortex via the motor thalamus. Neuronal afferents coding for a given movement or task project to the BG by two different systems: (1) Direct disynaptic projections to the GPi via the striatum and STN. (2) Indirect trisynaptic projections to the GPi via the globus pallidus pars externa (GPe). Corticostriatal afferents primarily act to inhibit medium spiny neurons in the “indirect circuit” and facilitate neurons in the “direct circuit.” The GPe is in a pivotal position to regulate the motor output of the BG. Dopamine finely tunes striatal input as well as neuronal striatal activity, and modulates GPe, GPi, and STN activity. Dopaminergic depletion in Parkinsons disease disrupts the corticostriatal balance leading to increased activity the indirect circuit and reduced activity in the direct circuit. The precise chain of events leading to increased STN activity is not completely understood, but impaired dopaminergic regulation of the GPe, GPi, and STN may be involved. The parkinsonian state is characterized by disruption of the internal balance of the BG leading to hyperactivity in the two main entry points of the network (striatum and STN) and excessive inhibitory output from the GPi. Replacement therapy with standard levodopa creates a further imbalance, producing an abnormal pattern of neuronal discharge and synchronization of neuronal firing that sustain the “off” and “on with dyskinesia” states. The effect of levodopa is robust but short‐lasting and converts the parkinsonian BG into a highly unstable system, where pharmacological and compensatory effects act in opposing directions. This creates a scenario that substantially departs from the normal physiological state of the BG.

Chronic dopaminergic stimulation in Parkinson's disease: from dyskinesias to impulse control disorders

Dopamine is an essential neurotransmitter for many brain functions, and its dysfunction has been implicated in both neurological and psychiatric disorders. Parkinsons disease is an archetypal disorder of dopamine dysfunction characterised by motor, cognitive, behavioural, and autonomic symptoms. While effective for motor symptoms, dopamine replacement therapy is associated not only with motor side-effects, such as levodopa-induced dyskinesia, but also behavioural side-effects such as impulse control disorders (eg, pathological gambling and shopping, binge eating, and hypersexuality), punding (ie, abnormal repetitive non-goal oriented behaviours), and compulsive medication use. We review clinical features, overlapping molecular mechanisms, and a specific cognitive mechanism of habit learning that might underlie these behaviours. We integrate these mechanisms with the emerging view of the basal ganglia as a distributive system involved in the selection and facilitation of movements, acts, and emotions.

The Basal Ganglia in Parkinson's Disease: Current Concepts and Unexplained Observations

The pathophysiology of Parkinsons disease is reviewed in light of recent advances in the understanding of the functional organization of the basal ganglia (BG). Current emphasis is placed on the parallel interactions between corticostriatal and corticosubthalamic afferents on the one hand, and internal feedback circuits modulating BG output through the globus pallidus pars interna and substantia nigra pars reticulata on the other. In the normal BG network, the globus pallidus pars externa emerges as a main regulatory station of output activity. In the parkinsonian state, dopamine depletion shifts the BG toward inhibiting cortically generated movements by increasing the gain in the globus pallidus pars externa‐subthalamic nucleus‐globus pallidus pars interna network and reducing activity in “direct” cortico‐putaminal‐globus pallidus pars interna projections. Standard pharmacological treatments do not mimic the normal physiology of the dopaminergic system and, therefore, fail to restore a functional balance between corticostriatal afferents in the so‐called direct and indirect pathways, leading to the development of motor complications. This review emphasizes the concept that the BG can no longer be understood as a “go‐through” station in the control of movement, behavior, and emotions. The growing understanding of the complexity of the normal BG and the changes induced by DA depletion should guide the development of more efficacious therapies for Parkinsons disease. Ann Neurol 2008;64 (suppl):S30–S46

Compartmental organization and chemical profile of dopaminergic and GABAergic neurons in the substantia nigra of the rat.

The substantia nigra (SN) is a midbrain center composed of dopaminergic (DA‐) and gamma aminobutyric acid (GABA)ergic (GABA‐) neurons. In this study, we investigated the topographical relationship between both cell populations and their chemical profile by using single and double immunostaining for tyrosine hydroxylase (TH), glutamic acid decarboxylase (GAD), cholecystokinin (CCK), calretinin (CR), calbindin (CB), parvalbumin (PV), and nitric oxide synthase (NOS). Our results showed that DA‐cells are arranged in two bands, one rostrodorsal that corresponds to the SN pars compacta (SNC), and another caudoventral that corresponds to the SN pars reticulata (SNR) and emits cell bridges that make contact with the rostrodorsal one. In the SNR, GABA‐cells are arranged in dorsoventrally elongated clusters that occupy DA‐cell free regions. According to cytoarchitectural, topographical, and chemical criteria, we identified ten different cell groups: five dopaminergic ones, and five GABAergic ones. Within DA‐cells, we found a cell group in the dorsomedial portion of the SNC which contains CCK, CR, and CB (dmSNC); DA‐cells in the SN pars lateralis (SNL) which also contain CCK, CR and CB; DA‐cells in the rostral half of the SNC containing CCK and CR (rSNC); DA‐cells in the SNR and the caudal half of the SNC which only express CR (cSNC‐SNR), and a DA‐cell group in the lateral part of the SNC that contains none of the markers studied (lSNC). Within GABA‐cells, we distinguished: large GABA‐cells in the SNL that contain PV; large GABA‐cells in the rostrolateral part of the SNR containing PV and NOS (rlSNR), small GABA‐cells in the caudomedial part of the SNR containing PV (cmSNR), and two groups of small GABA‐cells in the rostromedial portion of the SNR, one of them containing CR (rmcSNR), and the other containing NOS (rmnSNR). These data suggest that over a compartmental and complementary organization, DA‐ and GABA‐nigral cells form a mosaic of neurochemically different subnuclei which probably differ in their physiological and pharmacological properties and vulnerability to aggression. J. Comp. Neurol. 421:107–135, 2000.

Sex differences in behavioral despair: Relationships between behavioral despair and open field activity

Many studies have reported sex differences in the rates of depression in humans. Due to experimental problems, the nature of these sexual differences is still unknown. In the present study, we quantify the sex differences in depression using two animal models. Both the Porsolt et al. test and the Hilakivi and Hilakivi forced swimming test have shown that the duration of immobility is higher in the male than in the female. Sexual differences in the animal models of depression are probably unrelated to general activity differences because there is no significant correlation between activity in both tests. However, the correlation between the two models of depression used reached statistical significance. Finally, the immobility levels in the Porsolt test were similar in the different stages of the estrous cycle.

Effects of maternal stress during pregnancy on forced swimming test behavior of the offspring

It has been reported that gonadal steroids modulate brain and behavioral sex differentiation during development. Prenatal maternal restraint also alters development by affecting gonadal steroid levels in the fetus. Prenatal maternal restraint of animals decreases sex differences for sexual behavior, locomotion, aggression, etc. In recent work on animal models, we reported that, like humans, laboratory rats show sex differences in depression. From the present study, performed on Sprague-Dawley rats, we conclude that: 1) there are sex differences for depression in two different animal models (swimming-induced immobility and natatory tests); 2) there are also sex differences in open-field behavior; 3) prenatal maternal restraint decreases sex differences for depression but does not affect sex differences in open-field behavior; 4) prenatal maternal restraint affects female but not male behavior in the two depression tests used. These results suggest that: 1) sex differences reported in animal models of depression are under the control of gonadal steroids during prenatal brain development; 2) stress during early phases of development increases the risk for depression in adulthood.

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.