The Arbitration–Extension Hypothesis: A Hierarchical Interpretation of the Functional Organization of the Basal Ganglia

Based on known anatomy and physiology, we present a hypothesis where the basal ganglia motor loop is hierarchically organized in two main subsystems: the arbitration system and the extension system. The arbitration system, comprised of the subthalamic nucleus, globus pallidus, and pedunculopontine nucleus, serves the role of selecting one out of several candidate actions as they are ascending from various brain stem motor regions and aggregated in the centromedian thalamus or descending from the extension system or from the cerebral cortex. This system is an action-input/action-output system whose winner-take-all mechanism finds the strongest response among several candidates to execute. This decision is communicated back to the brain stem by facilitating the desired action via cholinergic/glutamatergic projections and suppressing conflicting alternatives via GABAergic connections. The extension system, comprised of the striatum and, again, globus pallidus, can extend the repertoire of responses by learning to associate novel complex states to certain actions. This system is a state-input/action-output system, whose organization enables it to encode arbitrarily complex Boolean logic rules using striatal neurons that only fire given specific constellations of inputs (Boolean AND) and pallidal neurons that are silenced by any striatal input (Boolean OR). We demonstrate the capabilities of this hierarchical system by a computational model where a simulated generic “animal” interacts with an environment by selecting direction of movement based on combinations of sensory stimuli, some being appetitive, others aversive or neutral. While the arbitration system can autonomously handle conflicting actions proposed by brain stem motor nuclei, the extension system is required to execute learned actions not suggested by external motor centers. Being precise in the functional role of each component of the system, this hypothesis generates several readily testable predictions

Oculomotor Deficits in Diseases of the Basal Ganglia: Parkinson\u27s and Huntington\u27s Diseases

Oculomotor deficits are now recognized as being present in several neurological diseases of the basal ganglia. The present report will focus primarily on those observed in Huntington\u27s and Parkinson\u27s diseases. Neuronal cell loss in the pars compacta of the substantia nigra, degeneration of the nigrostriatal pathway, and consequent depletion of the neurotransmitter dopamine is the most obvious etiological abnormality in Parkinson\u27s disease. Huntington\u27s disease, on the other hand, involves the selective genetically-driven atrophy of the striatum (caudate and putamen). In order to attempt to understand oculomotor dysfunction, as a component of basal ganglia disease, it is necessary to first establish a definition of the basal ganglia, its relevant connections, and their associated neurotransmitters and functions

Confirmation of functional zones within the human subthalamic nucleus: Patterns of connectivity and sub-parcellation using diffusion weighted imaging

The subthalamic nucleus (STN) is a small, glutamatergic nucleus situated in the diencephalon. A critical component of normal motor function, it has become a key target for deep brain stimulation in the treatment of Parkinson's disease. Animal studies have demonstrated the existence of three functional sub-zones but these have never been shown conclusively in humans. In this work, a data driven method with diffusion weighted imaging demonstrated that three distinct clusters exist within the human STN based on brain connectivity profiles. The STN was successfully sub-parcellated into these regions, demonstrating good correspondence with that described in the animal literature. The local connectivity of each sub-region supported the hypothesis of bilateral limbic, associative and motor regions occupying the anterior, mid and posterior portions of the nucleus respectively. This study is the first to achieve in-vivo, non-invasive anatomical parcellation of the human STN into three anatomical zones within normal diagnostic scan times, which has important future implications for deep brain stimulation surgery

Simulating Idiopathic Parkinson\u27s Disease by In Vitro and Computational Models

In general there is a wide gap between experimental animal results, especially with respect to neuroanatomical data, and computational modeling. In order to be able to investigate the anatomical and functional properties of afferent and efferent connections between the different nuclei of the basal ganglia, similar studies need to be performed as described in this review for the Substantia Nigra. These studies, though very time-consuming, are essential to decide which pathways play important roles in normal functioning and therefore need to be included in modeling studies. In addition, it should be known what neuroanatomical changes take place resulting from the neurodegeneration associated with Parkinson’s disease and how they affect network behavior. For instance, the direct effects of DBS on motor control are of interest, but since DBS has a low threshold to side effects, additional non-motor pathways are expected to be involved. Including these pathways in network models may shed light on the extent and effect of stimulation. Similarly, as PPN stimulation may have a beneficial influence on gait and balance, different pathways are important regarding the different motor symptoms of Parkinson’s disease

Pedunculopontine tegmental nucleus. Part I: cytoarchitecture, transmitters, development and connections

The present review compiles data on the cytoarchitecture, transmitters, development, afferent and efferent connections of the pedunculopontine tegmental nucleus (PPN). PPN is a reticular formation nucleus, located in the pontomesencephalic tegmentum, closely associated with the ascending limb of the superior cerebellar peduncle. Its most typical cells are cholinergic and comprise the Ch5 neuronal group of Mesulam. It contains also glutamatergic neurons that may contain glutamate as a sole transmitter or as a co-transmitter of acetylcholine. The cholinergic neurons use also the gaseous transmitter nitric oxide, being the most prominent nitrergic neurons in the central nervous system (CNS). In aged animals, there is practically no cell loss but there are certain drastic changes in the somatodendritic morphology. PPN has an extremely rich afferent input. All basal ganglia send axons to PPN, the strongest connection being from the substantia nigra (SN), followed by pathways arising from the subthalamic nucleus (STN) and from both pallidal segments (PAL). PPN receives afferents also from the cerebral cortex, from areas of the limbic system and hypothalamus, from the cerebellum, from the brainstem - particularly serotoninergic axons from the raphe nuclei and noradrenergic axons from the locus ceruleus - as well as from the spinal cord. The efferent connections of PPN are extremely diverse, and some of them are carried out by axons that emit divergent collaterals to two different structures. The heaviest efferent pathway of PPN is destined to the thalamus, innervating virtually all thalamic nuclei, and especially the "nonspecific" intralaminar nuclei, that innervate broad ares of the cerebral cortex. All basal ganglia are innervated and in most cases the connection is bilateral. The most significant pathway innervates the dopaminergic neurons of SN, followed by a connection to STN and PAL. Other PPN efferent connections reach the cerebellum, the superior colliculus, nuclei of cranial nerves, the reticular formation, and the spinal cord. The reviewed connections of PPN suggest that it is involved significantly in the arousal systems, and is implicated in the disturbances of sleep and wakefulness. PPN is also involved in the motor functions of CNS, as well as in the movement disorders.Biomedical Reviews 2003; 14: 95-120

Topographical Organization of the Pedunculopontine Nucleus

Neurons in the pedunculopontine nucleus (PPN) exhibit a wide heterogeneity in terms of their neurochemical nature, their discharge properties, and their connectivity. Such characteristics are reflected in their functional properties and the behaviors in which they are involved, ranging from motor to cognitive functions, and the regulation of brain states. A clue to understand this functional versatility arises from the internal organization of the PPN. Thus, two main areas of the PPN have been described, the rostral and the caudal, which display remarkable differences in terms of the distribution of neurons with similar phenotype and the projections that originate from them. Here we review these differences with the premise that in order to understand the function of the PPN it is necessary to understand its intricate connectivity. We support the case that the PPN should not be considered as a homogeneous structure and conclude that the differences between rostral and caudal PPN, along with their intrinsic connectivity, may underlie the basis of its complexity

Cholinergic system changes in Parkinson's disease: emerging therapeutic approaches

In patients with Parkinson's disease, heterogeneous cholinergic system changes can occur in different brain regions. These changes correlate with a range of clinical features, both motor and non-motor, that are refractory to dopaminergic therapy, and can be conceptualised within a systems-level framework in which nodal deficits can produce circuit dysfunctions. The topographies of cholinergic changes overlap with neural circuitries involved in sleep and cognitive, motor, visuo-auditory perceptual, and autonomic functions. Cholinergic deficits within cognition network hubs predict cognitive deficits better than do total brain cholinergic changes. Postural instability and gait difficulties are associated with cholinergic system changes in thalamic, caudate, limbic, neocortical, and cerebellar nodes. Cholinergic system deficits can involve also peripheral organs. Hypercholinergic activity of mesopontine cholinergic neurons in people with isolated rapid eye movement (REM) sleep behaviour disorder, as well as in the hippocampi of cognitively normal patients with Parkinson's disease, suggests early compensation during the prodromal and early stages of Parkinson's disease. Novel pharmacological and neurostimulation approaches could target the cholinergic system to treat motor and non-motor features of Parkinson's disease