Elsevier

Progress in Neurobiology

Volume 76, Issue 6, August 2005, Pages 393-413
Progress in Neurobiology

The functional role of the subthalamic nucleus in cognitive and limbic circuits

https://doi.org/10.1016/j.pneurobio.2005.09.005Get rights and content

Abstract

Once it was believed that the subthalamic nucleus (STN) was no more than a relay station serving as a “gate” for ascending basal ganglia-thalamocortical circuits. Nowadays, the STN is considered to be one of the main regulators of motor function related to the basal ganglia. The role of the STN in the regulation of associative and limbic functions related to the basal ganglia has generally received little attention. In the present review, the functional role of the STN in the control of cortico-basal ganglia-thalamocortical associative and limbic circuits is discussed. In the past 20 years the concepts about the functional role of the STN have changed dramatically: from being an inhibitory nucleus to a potent excitatory nucleus, and from being involved in hyperkinesias to hypokinesias. However, it has been demonstrated only recently, mainly by reports on the behavioral (side-) effects of STN deep brain stimulation (DBS), which is a popular surgical technique in the treatment of patients suffering from advanced Parkinson Disease (PD), that the STN is clinically involved in associative and limbic functions. These findings were confirmed by results from animal studies. Experimental studies applying STN DBS or STN lesions to investigate the neuronal mechanisms involved in these procedures found profound effects on cognitive and motivational parameters. The anatomical, electrophysiological and behavioral data presented in this review point towards a potent regulatory function of the STN in the processing of associative and limbic information towards cortical and subcortical regions. In conclusion, it can be stated that the STN has anatomically a central position within the basal ganglia thalamocortical associative and limbic circuits and is functionally a potent regulator of these pathways.

Introduction

Once it was believed that the subthalamic nucleus (STN), a relatively small nucleus in the midbrain, was no more than a relay station serving as a “gate” for cortico-basal ganglia-thalamocortical circuits. Nowadays, the STN is considered to be one of the main regulators of motor function related to the basal ganglia, through its fundamental role within the basal ganglia-thalamocortical motor circuit (Albin et al., 1989b, Alexander and Crutcher, 1990). Clinically, this is evidenced by its involvement in movement disorders such as Parkinson disease (PD) (Benabid, 2003, Houeto et al., 2000, Visser-Vandewalle et al., 2004). In PD, which is histopathologically characterized by selective, chronic and progressive nigrostriatal degeneration, the STN displays a continuous abnormal “bursting” mode of activity whereas in physiological conditions it exhibits more or less a regular pattern of discharge with intervals of burst activity (Dostrovsky and Lozano, 2002, Magill et al., 2000, Urbain et al., 2002). This so-called STN hyperactivity, reflecting the increase in firing rate, has been implicated in increasing the activity of basal ganglia output nuclei and, consequently, excessive inhibition of their targets (Bevan et al., 2002, Liu et al., 2002). This mechanism is held responsible for at least part of the cardinal PD symptoms such as hypokinesia/bradykinesia and rigidity (Benazzouz and Hallett, 2000). In order to surgically “silence” the hyperactive STN, chronic stereotactic deep brain stimulation (DBS) has been applied since the past decade. It has now largely been established that STN DBS is an effective treatment in advanced PD (Benabid et al., 1994, Capus et al., 2001, Krack et al., 1998a, Krack et al., 1998b, Kumar et al., 1998b, Kumar et al., 1999b, Levesque et al., 1999, Limousin et al., 1998, Lopiano et al., 2001, Volkmann et al., 2001b) and more recently, 4- (Rodriguez-Oroz et al., 2004, Visser-Vandewalle et al., 2005) and 5-year followup (Krack et al., 2003) effects were reported. Bilateral STN DBS induced a marked long-term improvement in motor function and activities of daily living (ADL).

DBS has generally the same clinical effects as a lesion with respect to the improvement of motor disability in movement disorders, but has more advantages such as its adjustability and reversibility (Benabid, 2003, Temel et al., 2004a). Nevertheless, the cellular effects of DBS and lesions are considerably different: a lesion destroys and DBS modulates the (electro)physiological activity of neuronal elements (Dostrovsky and Lozano, 2002, Grill and McIntyre, 2001, Grill et al., 2004, McIntyre et al., 2004a). To this day, fundamental knowledge regarding the application of electrical currents to deep brain structures is far from complete. A number of possible mechanisms have, however, been proposed (Dostrovsky and Lozano, 2002). One of the more popular hypotheses is that DBS causes a reduction of neuronal activity by means of a depolarization block. This proposed mechanism involves the suppression of voltage-gated sodium, and T-type calcium currents leading to an interruption of spontaneous activity within the neurons (Beurrier et al., 2001). It has also been proposed that the silencing of target nuclei by DBS is achieved by the stimulation of GABAergic afferents to the target cells and the consequent hyperpolarization of postsynaptic terminals by release of the inhibitory neurotransmitter GABA (Moser et al., 2003). The situation becomes even more complex when it is stated that DBS can have opposing effects on structures being stimulated depending on the cellular architecture of the target area. The similarity in clinical outcomes between DBS and lesion led to the proposition that DBS inhibits the target being stimulated. Recordings made in the stimulated nucleus show inhibition or decreased activity during and after the stimulus train (Benazzouz et al., 2004, Filali et al., 2004, Tai et al., 2003). However, electrical recordings from the efferent nuclei from the stimulated nucleus indicate that DBS increases the output of the stimulated nucleus (Hashimoto et al., 2003, Windels et al., 2003). Quantitative models have revealed that DBS inhibits the cell bodies of neurons around the electrode by activation of presynaptic terminals, while stimulating the output of local neurons by initiation of action potentials in the axon remote from the cell body (Grill and McIntyre, 2001, McIntyre et al., 2004a). Furthermore, this dual effect appeared with high frequencies only (Grill et al., 2004). Further studies are warranted to determine precisely how DBS works.

As STN DBS has become a widely applied surgical procedure, more data have appeared on its surgical and target-related side effects (Hariz, 2002, Hariz and Johansson, 2001, Lyons et al., 2001, Oh et al., 2002). Concerning the latter, clinicians observed behavioral effects such as stimulation-dependent cognitive alterations (Saint-Cyr et al., 2000, Temel et al., 2004b) and changes in affective and emotional behavior (Berney et al., 2002, Kulisevsky et al., 2002, Sensi et al., 2004). Basic researchers applying STN DBS and lesions in animal models to study the neuronal mechanisms entailed in these procedures found profound effects on cognitive and limbic functions (Baunez et al., 1995, Baunez et al., 2001, Baunez and Robbins, 1997, Desbonnet et al., 2004, Temel et al., 2005). Anatomical tracing studies in rodents and primates have shown that the STN is composed of parts that project to associative and limbic areas of the pallidal complex and substantia nigra pars reticulata (SNr) and that the basal ganglia associative and limbic circuits are processed through the STN (Alexander and Crutcher, 1990, Alexander et al., 1990a, Parent and Hazrati, 1995a, Parent and Hazrati, 1995b). The functionality of these projections, however, remains as yet elusive. Furthermore, to which extent these projections are influenced by changing STN's neuronal activity by either lesioning or DBS also needs clarification. Although the beneficial effects of STN DBS and lesions on motor function are relatively well described, the consequences of these surgical interventions on the associative and limbic circuits and associated neuropsychological functions have received relatively little attention. In the present review, we aim to provide a synopsis on the functional role of the STN in the control of the cortico-basal ganglia-thalamocortical associative and limbic circuits.

The present review commences with the history of the STN as in the past 20 years the concepts about the functional role of the STN have changed dramatically. We believe that adequate knowledge about these changes and related historical views will contribute to a better understanding of the current functional concepts of the STN. Subsequently, the current data on the anatomical place of the STN in the cortico-basal ganglia-thalamocortical circuits are summarized with emphasis on the associative and limbic circuits. The intrinsic organization of the STN is also discussed in Section 3. After delineating the anatomical position of the STN, original clinical and experimental studies providing data on the involvement of the STN in behavioral processes are systematically discussed. Finally, the role of the STN in the control of cortico-basal ganglia-thalamocortical associative and limbic circuits is outlined.

Section snippets

The history of the STN

The STN was classically regarded as a nucleus exerting a potent inhibitory effect on the cortico-basal ganglia-thalamocortical motor circuit. This theory was substantiated by histopathological findings in patients with hyperkinesias such as hemiballismus, who had mostly hemorrhagic lesions at the level of the STN. Now, we know, for example, that the STN exerts a potent excitatory effect on its efferents. Furthermore, it has been demonstrated that the STN also plays a key role in hypokinetic

The place of the STN in basal ganglia-thalamocortical circuits

The primary elements of the basal ganglia are the striatum, the pallidum, the SN and the STN (Parent and Hazrati, 1995a). In primates, five cortico-basal ganglia-thalamocortical circuits are described consisting of the motor, oculomotor, two prefrontal (dorsolateral and lateral orbitofrontal) and the limbic circuits (Albin et al., 1989b, Alexander and Crutcher, 1990, Alexander et al., 1986, Alexander et al., 1990b, Parent and Hazrati, 1995a).

The cortico-basal ganglia-thalamocortical circuits

Behavioral consequences of STN stimulations and lesions

The anatomical data support the hypothesis that the STN plays an important role in cognitive and limbic functions. In this section, clinical and experimental studies on the effects of STN stimulations and lesions confirming this hypothesis are chronologically and systematically discussed.

Delineating the role of the STN in the basal ganglia-thalamocortical associative and limbic circuits

The clinical and experimental data demonstrated in Sections 4.1 Clinical studies, 4.2 Experimental studies point out that modulating the neuronal activity in STN by ablation or stimulation results in substantial improvement of the pathological motor behavior, but can be accompanied by behavioral changes. In patients, different aspects of behavior were altered (Table 3). Apart from clear changes in motor disability, cognitive impairments were the most commonly observed behavioral consequence of

Acknowledgements

The authors are grateful to Prof. Dr. Emile Beuls for his support. Grant information: YT received grants from the Dutch Medical Research Council (ZonMw), no.: 940-37-027 and the Dutch Brain Foundation (Hersenstichting Nederland) nos. 10F02.13, 10F03.19 and 10F04.17.

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