Functional Organization of the Basal Ganglia: Therapeutic Implications for Parkinson s Disease

Transcription

1 Movement Disorders Vol. 23, Suppl. 3, 2008, pp. S548 S559 Ó 2008 Movement Disorder Society Functional Organization of the Basal Ganglia: Therapeutic Implications for Parkinson s Disease Jose A. Obeso, MD, 1,2 * MariaCruzRodríguez-Oroz, MD, 1,2 Beatriz Benitez-Temino, PhD, 1 Franscisco J. Blesa, PhD, 1,2 Jorge Guridi, MD, 1,2 Concepció Marin, MD, PhD, 2,3 and Manuel Rodriguez, MD 2,4 1 Department of Neurology and Neurosurgery, Clinica Universitaria and Medical School and Neuroscience Centre, CIMA, University of Navarra, Pamplona, Spain 2 Centro de Investigación Biomédica en Red Enfermedades Neurodegenerativas (CIBERNED) 3 Laboratori de Neurologia Experimental, A`rea de Neurociències, Institut d Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona 4 Neurobiology and Experimental Neurology Laboratory, Department of Physiology, Medical School, University of La Laguna, Tenerife, Spain Abstract: 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 Parkinson s 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 preand 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 Parkinson s 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. Ó 2008 Movement Disorder Society Key words: basal ganglia; striatum; medium spiny neurons; globus pallidus; subthalamic nucleus; parkinson s disease *Correspondence to: José A. Obeso, Clinica Universitaria, Avenida Pio XII 36, Pamplona, 31008, Spain; jobeso@unav.es Potential conflict of interest: Nothing to report. Received 28 January 2008; Revised 30 January 2008; Accepted 4 March 2008 Published online in Wiley InterScience ( com). DOI: /mds Anatomically speaking, the term basal ganglia (BG) refers to any gray matter structure located at the base of the cerebral hemispheres (i.e., the amygdala) but is currently applied to a group of interconnected subcortical nuclei including the striatum (caudate and putamen), the globus pallidus pars externa (GPe) and pars S548

2 THERAPEUTIC IMPLICATIONS FOR PARKINSON S DISEASE S549 interna (GPi), the subthalamic nucleus (STN) and the substantia nigra pars compacta (SNc), and pars reticulata (SNr). The dopaminergic system innervates all BG structures as well as its projection targets like the thalamus and brainstem motor centers (see Fig. 1). Clinicopathological correlations made by pioneer investigators early in the 20th century established that lesions of the lenticular nucleus, STN, substantia nigra, and red nucleus in humans and monkeys are associated with severe motor disturbances 1 4 such as slowness of movement and rigidity and also with uncontrollable movements such as tremor, dystonia, and choreaballism. The series of striking discoveries between 1957 and 1961 describing a high concentration of dopamine (DA) in the striatum, the profound pro-akinetic effect of DA depletion (by reserpine) in the rat, the marked loss of striatal DA in the brain of patients with Parkinson s disease (PD) and the striking therapeutic benefit conveyed by levodopa in PD, strongly reinforced the view that the BG are concerned with movement control. 5 8 This was later elaborated to suggest that the BG are particularly involved in the running of automatic movements. 9 Currently, the BG are functionally sub-divided as motor, oculo-motor, associative, limbic, and orbitofrontal according to the main cortical projection areas (see Fig. 2). This anatomical organization sustains functions such as attention, explicit and implicit learnings, reward-related behavior, habit formation, and time estimation, which depend on the activation of cortical loops through the caudate nucleus, anterior, and ventral putamen This complex anatomo-functional organization has changed the traditional view that the BG are mainly motor centers. Nevertheless, the principles underlying the role of the BG in motor control are the best defined and understood, and movement disorders represent the major clinical expression of the faulty BG. We shall, therefore, concentrate on the organization features of the motor circuit. FIG. 1. Main connections of the basal ganglia within the motor circuit. The striatum receives glutamatergic afferents (green) from the cortex and thalamus and dopaminergic innervation from the substantia nigra (SN). The striatum (putamen) projects inhibitory (red) GABAergic axons to both pallidal segments, the globus pallidus pars externa (GPe) and globus pallidus pars interna (GPi), which also receives glutamatergic fibers from the subthalamic nucleus (STN). The centromedian/parafascicular complex of the thalamus projects to the striatum and STN and the dopaminergic fibers also reach the GP, STN, thalamus, and brainstem motor centers. Reproduced with permission from Obeso et al., Neurology, 62 (Suppl. 1), Ó Lippincott Williams & Wilkins. [Color figure can be viewed in the online issue, which is available at THE BG AND MOVEMENT: BASIC CONCEPTS The pathophysiological model developed in the late 1980s made great impact on the understanding of BG and their pathological deviations. The limitations and pitfalls of the model have also been discussed extensively on several occasions Accordingly, in this section we shall only summarize the basic principles underlying BG organization. Anatomo-Functional Organization of the Basal Ganglia The original model of the BG was concerned with motor control and based on three main findings: Somatotopic Arrangement The cortical motor areas (Area 4, Area 6, and supplementary motor area) and the primary somatosensory FIG. 2. Main functional division of the cortico-basal ganglia connections. A, The motor loop, which involves the cortical motor areas (Areas 4 and 6 and supplementary motor area), the posterolateral putamen, posterolateral globus pallidus pars externa and pars interna, the dorsolateral subthalamic nucleus and the ventrolateral thalamus. B, The associative loop. C, The limbic loop. [Color figure can be viewed in the online issue, which is available at wiley.com.]

3 S550 J.A. OBESO ET AL. FIG. 3. The basal ganglia are somatotopically arranged in a fashion that mimics by and large the cortical representation of the body (homunculus). For all nuclei, the motor region lies posterolaterally with the leg dorsally, the face ventrally, and the arm in between. [Color figure can be viewed in the online issue, which is available at cortex project in a somatotopically organized fashion to the striatum (see Fig. 3). 23 The motor zone is situated in the dorsolateral region throughout the BG. 24 The leg is represented in the dorsal region, the face ventrally, and the arm in-between the coronal plane. 24 In recent years, recording of neuronal activity from the STN and GPi during surgery for PD have also disclosed a similar somatotopic organization (Fig. 4). More recently, some degree of topographic differentiation has been encountered for cortical projections from Area 4 and SMA into the putamen, STN, and GPi Conversely, no definite somatotopic arrangement has been found for the SNc and its nigrostriatal DAergic projection. 31 Striato-Pallidal Pathways Striatal efferent neurons, the medium spiny neurons (MSN), are GABAergic and connect with the GPe and GPi by two different projections systems, the indirect and direct pathways. Neurons in the direct pathway project directly from putamen to GPi/SNr. They bear DA D-1 receptors, co-express the peptides substance-p, and dynorphin and establish a monosynaptic inhibitory connection with GPi/SNr neurons. Neurons in the indirect pathway contain DA D-2 receptors and co-express enkephalin. They project to the GPe which in turn influence the GPi/SNr by a monosynaptic inhibitory connection and indirectly through the GPe STN GPi projection (see Fig. 1). DA modulates glutamatergic effects on corticostriatal inputs by exerting a dual effect on striatal neurons, exciting D1 neurons in the direct pathway and inhibiting D2 neurons in the indirect circuit The direct and indirect circuits were conceived as having opposite functional effects on BG output (i.e., inhibition and excitation by the direct and indirect circuits), which in turn exert a tonic inhibition of the thalamic ventralis anterior and lateralis nuclei Output of the BG Neuronal recordings in the SNr in monkeys trained to generate saccadic eye movements, showed that a cease or pause in neuronal firing was associated with movement facilitation. 32 The same observation was subsequently made for movements of the arm and neuronal firing in the GPi. 33 This sustained the concept that reduced BG output leads to movement facilitation and increased activity to movement inhibition. Pathological Deviations: The Parkinsonian and Dyskinetic States DA depletion in the parkinsonian state leads to a series of functional changes that mediates the cardinal

4 THERAPEUTIC IMPLICATIONS FOR PARKINSON S DISEASE S551 FIG. 4. Somatotopic organization of the globus pallidus pars interna and subthalamic nucleus in humans. Data obtained by recording the response of single neurons to passive and active movements of the limbs and face. Reproduced from Guridi et al., Neurosurgery 1999;45: Ó Lippincott Williams & Wilkins and Rodriguez-Oroz et al., Brain 2001;124: Ó Oxford University Press. motor features of PD. The most important characteristic is increased neuronal activity in the STN and GPi/ SNr leading to excessive inhibition of thalamocortical and brainstem motor nuclei. 18,34,35 There is a bulk of experimental and clinical evidence supporting this main pathophysiological feature. For example, in the monkey 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model in situ hybridization of cytochrome oxidase-i mrna, as a measure of cellular mitochondrial activity, and neuronal firing rate are increased in the STN and GPi/SNr. 35,36 Importantly, lesions of the STN and GPi induce marked motor improvement in MPTP monkeys 37,38 and reduced hyperactivity in GPi/ SNr neurons. 37,39 Moreover, it has been convincingly demonstrated in recent years that blockade or lesion of the STN or GPi induced marked clinical improvement and functional restoration of thalamocortical activity in PD patients. 40,41 Chorea-ballism as well as levodopa-induced dyskinesias (LID) in PD are associated with reduced neuronal

5 S552 J.A. OBESO ET AL. activity in BG output. 17,22 Neuronal activity in the STN and GPi shifts from increased neuronal firing in the parkinsonian state to marked hypoactivity during levodopa or apomorphine-induced dyskinesia in MPTP monkeys, 42 in patients with chorea-ballism, 43,44 and in PD patients exhibiting LID. 45 This is the most direct evidence supporting the concept of reduced BG output activity in the dyskinetic state. Limitations of Classic Concepts The original pathophysiological model was based on the notion of parallel cortico-bg-cortical loops, the direct and indirect circuit and the concept that the neuronal firing rate in the output of the BG governs and predicts the motor state. During the last decade, a larger complexity for BG organization has been recognized and evidence has been gathered for some marked limitations of the model. In this section, we highlight here some of the more relevant findings leading to revisit the functional organization of the BG. Striato-Pallidal Pathways Striatal neurons projecting to the GPe and GPi are not so distinctly separated. Thus, the same striato-fugal neurons frequently establish connections with GPi, GPe, and SNr neurons 46 and a large proportion of MSN (50%) co-expressed D-2 and D-1 receptors as well as the enkephalin, dynorphin A, and leu-enkephalin. 47 Accordingly, the anatomical and chemical separation between neurons giving rise to the direct and indirect circuits is less accurate than previously thought. Neuronal Firing Patterns and Motor States In addition to the rate of discharge, it is now known that the motor state in PD correlates with changes in the degree of neuronal synchronization. Recording local field potentials (Fig. 5) through macroelectrodes implanted in the STN or GPi for deep brain stimulation has brought to light the following associations: (a) the off parkinsonian state is characterized by a peak in the Hz (beta band) and a 4 6 Hz peak in patients with tremor. 48 (b) In the On pharmacological state there is a predominant Hz g band peak while the beta rhythm is drastically attenuated. 48 (c) In patients with LID there is predominant 4 10 Hz activity These findings indicate that the degree of neuronal synchronization and discharge pattern in PD change drastically within the BG in direct relation with the degree of DAergic replacement. Such oscillatory FIG. 5. Oscillatory activity assessed after recording local field potentials from the subthalamic nucleus in a patient with Parkinson s disease treated with deep brain stimulation. The power or amount of activity (lv 2 ) for each main oscillatory band is shown in the Y-axis and the different motor states in the X-axis. In the off medication state power is maximum and predominantly in the beta band range(11 30 Hz). After administering 250/25 mg of levodopa/carbidopa there is a marked reduction of activity in the beta band and an increment in the gamma (>60 Hz) and theta (4 10 Hz) bands. The latter coincides with the presence of dyskinesias. Reproduced with permission from Alonso et al., Brain 2006;129: Ó BMJ Publishing Group. activity could be generated internally within the BG but also, and perhaps more likely, as part of a larger network involving the cortex and thalamus. Thus, the parkinsonian and dyskinetic states cannot be understood only as the result of changes in neuronal firing rate in the output of the BG. Effect of Surgery Lesion of the GPi (i.e., pallidotomy) induces motor improvement but it is particularly effective against dyskinesias. Pallidotomy induces a drastic reduction in GPi efferent activity to the motor thalamus, which should facilitate rather than abate dyskinesias. Moreover, lesion of the pallidal receiving area within the motor thalamus (i.e., thalamotomy) should lead to reduced thalamocortical drive and, therefore, enhanced bradykinesia. However, thalamotomy is not associated with a permanent and noticeable worsening of PD motor features. 51,52 These two well-established

6 THERAPEUTIC IMPLICATIONS FOR PARKINSON S DISEASE S553 sets of clinical observations clearly indicate that the BG does not control movement simply by modifying the neuronal firing rate of its output nuclei. CURRENT CONCEPTS OF THE BG The BG are currently seen as a highly organized network, where different parts are activated depending on specific functions and circumstances. 52,53 As noted earlier, present evidence suggests that the BG are not only involved in movement control, but also in functions such as learning, planning, working memory, and emotions ,54 Interestingly, most if not all of these domains frequently become abnormal in PD, but detailed studies are still in progress. Corticobasal Ganglia Projections The motor circuit has two entry points, 55 the striatum and STN and an efferent point, the GPi, to the cortex via the motor thalamus (see Fig. 6). Neuronal activity coding for a given movement or task arrives the BG by two different projection systems: (1) direct disynaptic projections to the GPi via the striatum and STN. (2) Indirect trisynaptic projections to the GPi via the GPe. Thanks to this organization, a cortical volley associated with movement initiation can excite simultaneously MSN and STN neurons. Striatal output is conditioned by the distribution of cortical afferents. In the rat 56 cortical, pyramidal neurons from Layer V, with thick axons (mean 0.82 lm diameter) that form the pyramidal tract, connect with MSN giving rise to the striatopallidal projection (indirect circuit). Cortical neurons projecting to MSN in the direct striatonigral circuit are smaller, arise from Layer III and upper Layer V neurons and have thinner (mean 0.41 lm) axons that do not project outside the striatum and cortex. 56 Both in the rat and monkey, STN neurons are rapidly and robustly excited by somatotopically organized cortical afferents (Layer V) from the motor and premotor cortex As a consequence, cortical stimulation induces a short duration of excitation of the GPi and GPe via the STN. 60 Accord with this organization, GPe and GPi neurons are under dual disynaptic control. The GPe is submitted to two fast acting disynaptic transmission systems: (1) inhibition through the cortex- GABAergic-enkephalin projection and (2) excitation from the cortex-stn projection. GPi is also regulated by two slower and brief disynaptic effects consisting of: (1) excitation from the cortico-stn projection and (2) inhibition from the corticostriatal direct projection. FIG. 6. Functional organization of the basal ganglia (BG). Cortical input accesses the BG through the corticostriatal projection to medium spiny neurons projecting to the globus pallidus pars externa (GPe) and to the subthalamic nucleus (STN). The cortical projection exerts an opposite (inhibitory/excitatory) disynaptic effect onto the GPe and globus pallidus pars interna (GPi). Activity of the GPe modulates back the excitability of the striatum and STN by means of the reciprocal inhibitory connections. Thus, the GPe seems as a critically important nucleus controlling BG output. Reproduced from Obeso et al., Exp Neurol 2006;202:1 7. Ó Academic Press. [Color figure can be viewed in the online issue, which is available at www. interscience.wiley.com.] It is noteworthy that according to this newer understanding of the organization of the BG, the GPe appears in a key position to regulate BG neuronal output toward the thalamocortical projection within the motor loop. 61,62 Finally, one should consider the classic corticostriato-gpe-stn-gpi giving rise to the indirect circuit. Despite the enormous popularity of this as an explanation of normal and pathological BG functioning, the precise physiological significance of this circuit has not been unraveled. This is related first to the poly-synaptic nature of these connections, and importantly to the fact that STN activity is directly influenced by excitatory cortical and thalamic inputs and the powerful reciprocal excitatory/inhibitory connection with the GPe. The Modulatory Role of DA DAergic mesencephalic neurons modulate BG excitability by two main systems: (1) the dense and wellknown DAergic nigrostriatal projection (see article by A. Grace in this supplement). (2) Extra-striatal fibers (see article by Y. Smith in this supplement) to the GPe, GPi, and STN. (3) The striatum in turn can modify SNc excitability by a striatonigral projection.

7 S554 J.A. OBESO ET AL. 1. The ascending DAergic projections from ventral midbrain neurons are the only source of DA in the BG. These cells are located in the substantia nigra (A9 cell group), ventral tegmental area (A10), and retrorubral area (A8). The mesostriatal (or nigrostriatal) system, mainly composed by A9 cells, has some 100,000 neurons in humans, each of which exhibits some 300,000 synaptic buttons, which densely innervate the striatum. 31 DAergic axons are thin ( lm) and varicose, traveling over long distances throughout the striatum to innervate differentially the patch (less densely innervated) and matrix compartments. 63,64 SNc neurons in the normal and awake monkey discharge tonically at a low frequency, but exhibit robust and highly synchronous burst firing under special circumstances such as reward or anticipation of movement. 65 Stable firing of SNc neurons probably plays a key role in maintaining continuous delivery of DA in the striatum. More than 90% of DA-terminals form conventional synapses with spines and dendrites of striatal projection neurons. 66 In addition, axons of meso-striatal DA-neurons also form large varicosities near to soma and dendrites of striatal cells that do not establish classical synapses 67 and release DA molecules that diffuse away from the synaptic cleft, exerting parasynaptic actions on DA-receptors located at a distance from the synapse. Thus, DA may act in the striatum both as a neurotransmitter and as a neuromodulator or volume transmitter. 65,66 As a neurotransmitter, DA is released by action potentials, inducing a fast and short-lasting action restricted within the perisynaptic region. 67 As a volume transmitter, DA is released in the nonsynaptic extracellular space inducing, after a lengthy diffusion, a slow, long-lasting, and wide-spread action that affects large striatal regions Accordingly, phasic DA release activates intrasynaptic D-1 and D-2 receptors whereas tonic release preferentially excites extra-synaptically located D-1 receptors. 31,68 Synaptic and extrasynaptic homeostasis is exquisitely and specifically regulated by powerful mechanisms modulating SNc cell firing and DA re-uptake and metabolism These secure a fairly continuous, albeit neither constant nor homogenous, DAergic striatal activity. DA regulates the excitability of MSN by pre- and postsynaptic mechanisms. Glutamatergic striatal afferents from the cortex and thalamus make dendritic synaptic contacts onto MSN with a ratio of about 1000:1. This massive excitatory input requires some type of filtering or modulation, a function mainly mediated by DA. Thus, presynaptically, DA depresses striatal glutamatergic release by activation of D-2 receptors. 75 On the other hand, postsynaptic activation of D-1 receptors increases MSN excitability triggering a cascade of intracellular events that enhanced the expression of glutamate receptors mediated by L-type calcium channels. 76 According to a recent report, D-1 receptor activation leads to enhanced surface expression of AMPA and NMDA receptors 77 However, D-2 receptor activation is associated with reduced cell excitability through AMPA receptor translocation outside the synaptic membrane. 78 MSN excitability is also strongly modulated by striatal interneurons. Among these, the large, aspiny cholinergic neurons and the small, fast spiking GABA neurons are the best characterized. Cholinergic striatal activity has been associated with several functional effects under different experimental conditions. The most prominent effects are a presynaptic reduction of glutamate release 79 and the excitation of MSN. 80 Fast-spiking GABA interneurons mediate a powerful feed-forward inhibition of MSN. 81 Both interneuron types are controlled by DA. 82 D-2 activation leads to inhibition of acetyl-choline release in the striatum, 83 resulting in reduced facilitation of MSN. On the other hand, fast-spiking GABA interneurons are facilitated by D-1 direct activation but inhibited by presynaptic D-2 receptors 84 ; the latter would lead to facilitation of MSN activity. DA also plays a fundamental role in the mediation of plastic synaptic changes in the striatum. Thus, striatal long-term potentiation (LTP) and depression (LTD) are critically dependent on D-1 and D-2 receptor activation respectively, and therefore mediated by MSN in the direct and indirect circuits. 80,85 However, whether or not such distinct separation is effective and what the precise mechanisms mediating striatal LTD and LTP remain a subject of intense scrutiny and discussion currently 80 and lie beyond the scope of this article. We must be aware that the complexity of striatal functional organization makes it very difficult to envisage the final consequence, in functional terms, of DA on striatal output activity. Nevertheless, the available data suggest that the DAergic system is capable of selectively inhibiting and exciting different MSN pools. Such differential effect of DA on D-1 and D-2 expressing MSN, and its effects on interneurons, seem designed to facilitate a particular signal while inhibiting all others, and therefore increasing the signal to noise ratio. 86 When striatal DA is depleted, cortical input on direct MSN is reduced 87 but those of the indirect circuit are unchanged. 87 This results in a functional imbalance 88 with increased activity in MSN projecting to the GPe, which added to the direct effect of DA on D-1 and D-2 receptors, lead to overactivity in the indirect circuit and hypoactivity in the direct cir-

8 THERAPEUTIC IMPLICATIONS FOR PARKINSON S DISEASE S555 cuit. In addition, loss of striatal DA provokes a derangement of LTP and LDP, which could potentially contribute to reinforce abnormal striatal output. 80,85 Advances in defining the fine organization of the striatum and the changes taking place in the parkinsonian state, albeit still imperfectly defined, may be very relevant and useful to understand common practical problems in patients with PD. For example, in the 6- OHDA rat model, treatment with levodopa induces dyskinesias that are associated with an extra-synaptic displacement of the NR2-b fraction of the NMDA striatal receptor. 89 Similarly, in rats with LID, LTD becomes established and not subjected to desensitization (i.e., disappearance after a period without stimulation), a feature present in control rats. 90 Such abnormalities may well be revealing the intimate molecular basis of clinical problems. 2. DAergic neurons also innervate and modulate neuronal activity of other key BG nuclei such as the GPe, STN, GPi (see Y Smith in this supplement) and also various thalamic nuclei, including the ventrolateral nuclei (motor region). 91 Morphological, physiological, and behavioral evidence indicates that DA exerts a direct modulatory effect on neuronal activity in the STN or GP. 92,93 A recent study in rodents has shown common DAergic innervation for the GP and the reticularis nucleus of the thalamus. 94 This may be important, as there is a direct projection from the GPe to the reticularis, 95 a structure supposed to modify the excitability of specific thalamic nuclei serving as a gating mechanism for afferent signals. Through this connection, DA and the GPe could further modulate and sharpen the impact of BG output to the thalamocortical projection. Accordingly, the importance of extra-striatal DA in the control of BG activity and movement and the effects of DAergic drugs should not be underestimated; on the contrary further work is needed in this area. 3. Finally, the striatonigral projection may act as a feedback system to control DA cell activity. Thus, DA is also released by dendrites and somata of DA-cell in the substantia nigra, 96 a release affecting both the vesicular and non-vesicular DA-pools. Acting on D1 receptors, nigral DA facilitates the GABA release from the strionigral cells, thus modulating the activity of this inhibitory feedback loop that regulates firing activity of DA-cells. Thalamic and Pedunculopontine Nucleus Connections with the Basal Ganglia The role of projections from outside the BG in the control of neuronal afferent and efferent activity is not well defined. Two of the best known projections are those stemming from the centro-median/parafascicular(cm/pf) thalamic complex and from the pedunculopontine nucleus (PPN). The intralaminar thalamic nuclei project to the BG and establish two well organized circuits 97 : (1) the CM/Pf-striatum-GPi-CM/Pf circuit, which is probably a positive feedback loop. (2) The CM/Pf-STN-GPi- CM/Pf circuit, which may be a negative feedback loop. (3) In addition, the CM is reciprocally connected with the motor cortex. The CM sends glutamatergic projections to the striatum, particularly to the postcommissural putamen, to establish asymmetric synapse with medium spiny neurons projecting to both GPe and GPi, and also with cholinergic and gabaergic interneurons. 97 These same CM/Pf thalamostriatal neurons project to the STN. 98 Accordingly, the CM/Pf excites the afferent knots of the BG and it is well placed to reinforce the efferent, inhibitory, influence of the striato-gpi projection, and the excitatory effect of the subthalamo-pallidal pathway. However, the functional relevance of these two BG loops is not well defined. A recent study (from our laboratory) failed to show any motor improvement in MPTP monkeys in whom a focal lesion of the CM was performed. It may be that the role of the CM/Pf is more related to modulating BG activity related with attention and behavior stimuli than with primary control of movement. The PPN is highly and reciprocally connected with the BG. It receives input from the GPi and SNr and also from the STN, and sends large glutamatergic efferents to the SNc, STN, and GPi. 99 Through the thalamus, the PPN is reciprocally connected with the motor cortex and has important descending projections to the spinal cord. Accordingly, the PPN has attracted much attention as a possible key structure in movement control, and in gait in particular, as a fundamental part of the so-called mesencephalic locomotor center. The functional state of the PPN in PD is complex. 100 Cholinergic PPN neurons are lost by about 50% in the brain of PD patients and the firing rate is reduced in rats with 6-OHDA lesion. On the other hand, the opposite results have been described in the same rat model, where lesion of the STN reduces the PPN hyperactivity. Moreover, lesion of the PPN in monkeys induces akinesia, whereas blockade in MPTP monkeys is associated with improved mobility. This complex functional state of the PPN and the effects of local intervention in the parkinsonian state have been explained in view of the dual afferent projections from the BG. Thus, PPN neurons could be receiving

9 S556 J.A. OBESO ET AL. increased inhibitory input from the GPi (SNr/entopenduncular nucleus in the rat) and excessive excitatory input from the STN. This dual mechanism and the precise PPN neuronal sub-groups receiving BG projections have not been defined precisely and more-detailed assessment, particularly in the primate brain, needs to be done to clarify this issue. Moreover, the emphasis and attention given to the PPN as if it were the most relevant brainstem center for movement control and PD may well be exaggerated and further studies are pending. THE BG AND LEVODOPA IN PD The functional hallmark of the parkinsonian state are striatal DA depletion and increased neuronal activity in the output nuclei of the BG leading to excessive inhibition of the thalamocortical and brainstem motor systems. An ideal replacement therapy should be capable of compensating the deficit caused by the lesion and the functional derangements associated with it. In PD, exogenous administration of levodopa could theoretically lead to normalized DA synthesis and restore DAergic activity. However, this does not seem to be exactly the case. Striatal DA depletion is estimated to be around 70% at the time of diagnosis of PD but even higher for the posterior putamen (the motor circuit), where it may reach a loss of nearly 90% even in early PD. 101 Animal and human studies have shown that DA striatal levels remain very stable following levodopa administration under normal conditions. 67,74 This is primarily due to the powerful re-uptake system 74 that captures and shifts DA into the synaptic pools. However, in the DA depleted state, each dose of levodopa is associated with a large increase in DA striatal concentration lasting for some 2 3 hours. In the normal state, large increments in striatal DA trigger a complex series of events that ensure a rapid and efficacious clearance of DA molecules, so that DAergic levels return to normal and stable concentrations. 74 In the parkinsonian state these homeostatic mechanisms are not available and exogenous levodopa administration exposes the striatum to high levels of DA. The impact of such massive and uncontrolled DA availability onto the striatal mechanism is colossal. There is a marked dis-regulation in genes, peptides and proteins, and MSN excitability is modified and subjected to plastic synaptic changes such as desensitization after induction of longterm potentiation. 90 Abnormal striatal DAergic activity is also associated with marked changes in neuronal firing activity in the output of the BG as revealed by studies comparing normal and parkinsonian monkeys. In the off state STN and GPi discharge rate is increased while GPe activity is reduced. 102 Moreover, bursting activity and synchronous activity between pair neurons is increased in the STN, GPe, and GPi of MPTP treated monkeys 103 and oscillatory activity in the 3 8 and 8 15 Hz bands is also augmented in the parkinsonian state. 102 Most of these abnormalities have been verified by recording neuronal activity during surgery in PD patients. Treatment with levodopa does not normalize the firing pattern of the BG. Thus, the GPe/ GPi ratio for discharge rate is normally 1, decreases to less than 0.5 in the off parkinsonian state and increases to 2.5 in the on dyskinetic state. 103 Interestingly, while the increased correlation for synchronous firing between pair neurons present in the GPe/GPi in the off state is drastically reduced after levodopa in monkeys, 103 in PD patients the on-dyskinetic" state is associated with the appearance of a specific oscillation in the 4 8 Hz band in the STN. 50 The latter has been verified by recording field potentials from the SNr in 6-OHDA lesion rats with LID. 104 Because levodopa is administered 3 times/day in routine clinical practice, cyclical changes in the functional state of the BG are induced. 105 Each levodopa cycle probably triggers compensatory mechanisms aiming to restore the functional balance of the BG. However, functional changes occur over hours or days and are, therefore, out of phase with the stimulation pattern imposed by oscillating levodopa plasma levels and striatal DA availability. As a result, in PD standard levodopa treatment converts the highly stable and autocompensated BG network into an unstable system. 105 Altogether these sets of events probably account, at least partially, for clinical problems associated with levodopa therapy such diphasic dyskinesias, the super-off phenomenon, progressive shortening of the duration of the on response and the appearance of pharmacological tolerance. Considering all the available evidence, it seems unquestionable to us that avoiding the discontinuous or pulsatile DAergic stimulation associated with standard levodopa treatment can only result in a better therapeutic profile and evolution. Clearly, achieving stable levodopa plasma levels cannot be equated with restoration of the nigrostriatal DAergic system nor can this be claimed to be really physiological. Both standards require reinnervation. The point emphasized by some of us in the past is that tonic DAergic activity predominates in the normal striatum under routine conditions and stable levodopa delivery is associated with a pattern of DA stimulation that deviated less deviated from

10 THERAPEUTIC IMPLICATIONS FOR PARKINSON S DISEASE S557 normality than discontinuous or pulsatile levodopa delivery Given the catastrophic derangement of BG physiological mechanisms associated with the latter, providing a more stable DAergic stimulation seems a logical approach, despite obvious theoretical and practical deficiencies. 108 In conclusion, the BG seems to be anatomo-functionally designed to provide stability to the network underlying and operating movement control. DA depletion is compensated for a long period (i.e., years in PD) because the intrinsic BG mechanisms are capable of maintaining neuronal output within normal range. Once striatal DA reaches a threshold deficit, treatment with standard levodopa induces marked variability in DA availability and consequently, drastic changes in BG output activity. This departs significantly from the normal features of the BG. 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