Complementary ‘bottom-up’ and ‘top-down’ approaches to basal ganglia function

Recently, two quite different approaches exemplifying ‘bottom-up’ and ‘top-down’ philosophies have shed new light on basal ganglia function. In vitro work using organotypic co-cultures has implicated the subthalamic nucleus (STN) and the external segment of the globus pallidus (GP_e) as pacemakers for low-frequency bursting that is reminiscent of the activity produced in Parkinsonian tremor. A circuit essential for avian song learning has been identified as part of the basal ganglia with surprisingly well conserved cellular details; investigation of this system may help to address general issues of basal ganglia function.     

The basal ganglia-circa 1982. A review and commentary

Our review has shown that recent studies with the new anterograde and retrograde axon transport methods have confirmed and extended our knowledge of the projection of the basal ganglia and clarified their sites of origin. They have thrown new light on certain topographic connectional relationships and revealed several new reciprocal connections between constituent nuclei of the basal ganglia. Similarly, attention has been drawn to the fact that there have also been many new histochemical techniques introduced in recent years that are now providing regional biochemical overlays for connectional maps of the central nervous system, especially regions in, or interconnecting with, the basal ganglia. However, although these new morphological biochemical maps are very complex and technically highly advanced, our understanding of the function controlled by the basal ganglia still remains primitive. The reader who is interested in some new ideas of the functional aspects of the basal ganglia is directed to Nauta's [88] proposed conceptual reorganization of the basal ganglia telencephalon and to Marsden's [72] more clinically orientated appraisal of the unsolved mysteries of the basal ganglia participation in the control of movement.     

Considerations on the thalamostriatal system with some functional implications

The thalamostriatal projections are largely neglected in current reviews dealing with basal ganglia function. In the past few years, however, several studies have re-evaluated these projections and have postulated their implication in more complex tasks within the basal ganglia organization. In this review, we try to focus on the morphological and functional importance of this system in the basal ganglia of the rat, cat and monkey. Special attention is paid to the thalamus as an important place for interaction between the input and the output systems of the basal ganglia through the thalamostriatal projections. Thus, we stress on the overlapping thalamic territories between the thalamic projection of the output nuclei of the basal ganglia and the thalamostriatal neurons. Our experimental data support the existence of several thalamic feedback circuits within the basal ganglia functional design. Finally, some considerations are provided upon the functional significance of these thalamic feedback circuits in the overall organization of the basal ganglia in health and disease.     

The role of medial temporal lobe structures in implicit learning: an event-related FMRI study

The medial temporal lobe (MTL) has been associated with declarative learning of flexible relational rules and the basal ganglia with implicit learning of stimulus-response mappings. It remains an open question of whether MTL or basal ganglia are involved when learning flexible relational contingencies without awareness. We studied learning of an explicit stimulus-response association with fMRI. Embedded in this explicit task was a hidden structure that was learnt implicitly. Implicit learning of the sequential regularities of the "hidden rule" activated the ventral perirhinal cortex, within the MTL, whereas learning the fixed stimulus-response associations activated the basal ganglia, indicating that the function of the MTL and the basal ganglia depends on the learned material and not necessarily on the participants' awareness.     

Striatal information signaling and integration in globus pallidus: timing matters

Advances in research on globus pallidus (GP) suggest that this 'long thought to be' relay in the 'indirect pathway' plays a unique and critical role in basal ganglia function. The traditional idea of parallel processing within the basal ganglia is also challenged by recent findings. It is now clear that axons of GP neurons form large, perisomatic baskets around target neurons in all major basal ganglia nuclei, thereby exerting a profound influence on the output of the entire basal ganglia. GP neurons are autonomously active both in vivo and in vitro. It is believed that temporal information carried along the corticostriatopallidal pathway is critical for proper motor execution. The importance of appropriately controlled discharge of GP neurons is highlighted by psychomotor disorders such as Parkinson's disease, in which alterations in the pattern and synchrony of discharge in GP neurons are thought to contribute to motor symptoms. Several lines of evidence suggest that the aberrant activity of GP neurons following dopamine depletion is caused by alteration in the synaptic input from both striatum and subthalamic nucleus. In normal subjects, the capability of striatal input in translating cortical input into precisely timed responses in GP neurons is mediated by (1) the expression of postsynaptic GABA(A) receptor composed of subunits with fast kinetic properties; (2) an effective GABA reuptake system in terminating the action of synaptically released GABA, and (3) the existence of dendritic HCN channels that actively abbreviate the time course of the inhibitory postsynaptic potentials and reset rhythmic discharge. Despite the rapid pace in uncovering the elements that shape the activity along the striatopallidosubthalamic pathway, the origin of rhythmic, synchronized bursting of GP neurons seen in parkinsonism has not been fully established experimentally. Further elucidation of the factors that control the information transfer in the striatopallidal synapses is thus critical to our understanding of basal ganglia function and establishing treatment for Parkinson's disease and other basal ganglia disorders.     

Comprehensive in vivo mapping of the human basal ganglia and thalamic connectome in individuals using 7T MRI

Basal ganglia circuits are affected in neurological disorders such as Parkinson's disease (PD), essential tremor, dystonia and Tourette syndrome. Understanding the structural and functional connectivity of these circuits is critical for elucidating the mechanisms of the movement and neuropsychiatric disorders, and is vital for developing new therapeutic strategies such as deep brain stimulation (DBS). Knowledge about the connectivity of the human basal ganglia and thalamus has rapidly evolved over recent years through non-invasive imaging techniques, but has remained incomplete because of insufficient resolution and sensitivity of these techniques. Here, we present an imaging and computational protocol designed to generate a comprehensive in vivo and subject-specific, three-dimensional model of the structure and connections of the human basal ganglia. High-resolution structural and functional magnetic resonance images were acquired with a 7-Tesla magnet. Capitalizing on the enhanced signal-to-noise ratio (SNR) and enriched contrast obtained at high-field MRI, detailed structural and connectivity representations of the human basal ganglia and thalamus were achieved. This unique combination of multiple imaging modalities enabled the in-vivo visualization of the individual human basal ganglia and thalamic nuclei, the reconstruction of seven white-matter pathways and their connectivity probability that, to date, have only been reported in animal studies, histologically, or group-averaged MRI population studies. Also described are subject-specific parcellations of the basal ganglia and thalamus into sub-territories based on their distinct connectivity patterns. These anatomical connectivity findings are supported by functional connectivity data derived from resting-state functional MRI (R-fMRI). This work demonstrates new capabilities for studying basal ganglia circuitry, and opens new avenues of investigation into the movement and neuropsychiatric disorders, in individual human subjects.     

Do Basal Ganglia Amplify Willed Action by Stochastic Resonance? A Model

Basal ganglia are usually attributed a role in facilitating willed action, which is found to be impaired in Parkinson''s disease, a pathology of basal ganglia. We hypothesize that basal ganglia possess the machinery to amplify will signals, presumably weak, by stochastic resonance. Recently we proposed a computational model of Parkinsonian reaching, in which the contributions from basal ganglia aid the motor cortex in learning to reach. The model was cast in reinforcement learning framework. We now show that the above basal ganglia computational model has all the ingredients of stochastic resonance process. In the proposed computational model, we consider the problem of moving an arm from a rest position to a target position: the two positions correspond to two extrema of the value function. A single kick (a half-wave of sinusoid, of sufficiently low amplitude) given to the system in resting position, succeeds in taking the system to the target position, with high probability, only at a critical noise level. But for suboptimal noise levels, the model arm''s movements resemble Parkinsonian movement symptoms like akinetic rigidity (low noise) and dyskinesias (high noise).     

Input to the lateral habenula from the basal ganglia is excitatory, aversive, and suppressed by serotonin

The lateral habenula (LHb) has recently been identified as a key regulator of the reward system by driving inhibition onto dopaminergic neurons. However, the nature and potential modulation of the major input to the LHb originating from the basal ganglia are poorly understood. Although the output of the basal ganglia is thought to be primarily inhibitory, here we show that transmission from the basal ganglia to the LHb is excitatory, glutamatergic, and suppressed by serotonin. Behaviorally, activation of this pathway is aversive, consistent with its role as an "antireward" signal. Our demonstration of an excitatory projection from the basal ganglia to the LHb explains how LHb-projecting basal ganglia neurons can have similar encoding properties as LHb neurons themselves. Our results also provide a link between antireward excitatory synapses and serotonin,?a neuromodulator implicated in depression.     

Loss of Nkx2.1 homeobox gene function results in a ventral to dorsal molecular respecification within the basal telencephalon: evidence for a transformation of the pallidum into the striatum.

The telencephalon is organized into distinct longitudinal domains: the cerebral cortex and the basal ganglia. The basal ganglia primarily consists of a dorsal region (striatum) and a ventral region (pallidum). Within the telencephalon, the anlage of the pallidum expresses the Nkx2.1 homeobox gene. A mouse deficient in Nkx2.1 function does not form pallidal structures, lacks basal forebrain TrkA-positive neurons (probable cholinergic neurons) and has reduced numbers of cortical cells expressing GABA, DLX2 and calbindin that migrate from the pallidum through the striatum and into the cortex. We present evidence that these phenotypes result from a ventral-to-dorsal transformation of the pallidal primordium into a striatal-like anlage.     

Cellular principles underlying normal and pathological activity in the subthalamic nucleus

The motor symptoms of Parkinson's disease are associated with abnormal, correlated, low frequency, rhythmic burst activity in the subthalamic nucleus and connected nuclei. Research into the mechanisms controlling the pattern of subthalamic activity has intensified because therapies that manipulate the pattern of subthalamic activity, such as deep brain stimulation and levodopa administration, improve motor function in Parkinson's disease. Recent findings suggest that dopamine denervation of the striatum and extrastriatal basal ganglia profoundly alters the transmission and integration of glutamatergic cortical and GABAergic pallidal inputs to subthalamic neurons, leading to pathological activity that resonates throughout the basal ganglia and wider motor system.     

基底节区脑梗塞的神经心理学和听觉事件相关诱发电位的研究

目的：了解基底节区脑梗塞（BGRI）患者发病后记忆力和视空间能力的状况,分析BGRI是否对认知功能产生影响及其特点。方法：通过对21名初发的单侧单灶BGRI及21位年龄、性别、受教育程度相匹配的基本健康志愿者分别进行Rey复杂图形检查（Rey）,临床记忆量表（CMS）、Hospital Anxiety-Depression Scale（HAD）,美国国立卫生研究院卒中量表（NIHSS）、牛津残障量表（OHS）、Barthel指数（BI）及听觉事件相关诱发电位（AERP）的检查。结果：病例组的焦虑及抑郁分值,具有极显著的统计学意义;AERP检查反应时较对照组长,具有显著的统计学意义;在临床记忆量表中,病例组图像自由回忆分测验的量表分和记忆商（MQ）较差,与对照组相比有显著统计学意义。病例组Rey检查中临摹得分、即刻回忆得分和延迟回忆得分与对照组比较无显著性差异。结论：单侧单灶的基底节区脑梗塞可以对执行功能、记忆能力以及情绪造成影响：对视空间功能的影响不大.     

Decreased Basal Ganglia Activation in Subjects with Chronic Fatigue Syndrome: Association with Symptoms of Fatigue

Reduced basal ganglia function has been associated with fatigue in neurologic disorders, as well as in patients exposed to chronic immune stimulation. Patients with chronic fatigue syndrome (CFS) have been shown to exhibit symptoms suggestive of decreased basal ganglia function including psychomotor slowing, which in turn was correlated with fatigue. In addition, CFS patients have been found to exhibit increased markers of immune activation. In order to directly test the hypothesis of decreased basal ganglia function in CFS, we used functional magnetic resonance imaging to examine neural activation in the basal ganglia to a reward-processing (monetary gambling) task in a community sample of 59 male and female subjects, including 18 patients diagnosed with CFS according to 1994 CDC criteria and 41 non-fatigued healthy controls. For each subject, the average effect of winning vs. losing during the gambling task in regions of interest (ROI) corresponding to the caudate nucleus, putamen, and globus pallidus was extracted for group comparisons and correlational analyses. Compared to non-fatigued controls, patients with CFS exhibited significantly decreased activation in the right caudate (p = 0.01) and right globus pallidus (p = 0.02). Decreased activation in the right globus pallidus was significantly correlated with increased mental fatigue (r² = 0.49, p = 0.001), general fatigue (r² = 0.34, p = 0.01) and reduced activity (r² = 0.29, p = 0.02) as measured by the Multidimensional Fatigue Inventory. No such relationships were found in control subjects. These data suggest that symptoms of fatigue in CFS subjects were associated with reduced responsivity of the basal ganglia, possibly involving the disruption of projections from the globus pallidus to thalamic and cortical networks.     

A neural model of basal ganglia-thalamocortical relations in normal and parkinsonian movement

 Anatomical, neurophysiological, and neurochemical evidence supports the notion of parallel basal ganglia–thalamocortical motor systems. We developed a neural network model for the functioning of these systems during normal and parkinsonian movement. Parkinson’s disease (PD), which results predominantly from nigrostriatal pathway damage, is used as a window to examine basal ganglia function. Simulations of dopamine depletion produce motor impairments consistent with motor deficits observed in PD that suggest the basal ganglia play a role in motor initiation and execution, and sequencing of motor programs. Stereotaxic lesions in the model’s globus pallidus and subthalamic nucleus suggest that these lesions, although reducing some PD symptoms, may constrain the repertoire of available movements. It is proposed that paradoxical observations of basal ganglia responses reported in the literature may result from regional functional neuronal specialization, and the non-uniform distributions of neurochemicals in the basal ganglia. It is hypothesized that dopamine depletion produces smaller-than-normal pallidothalamic gating signals that prevent rescalability of these signals to control variable movement speed, and that in PD can produce smaller-than-normal movement amplitudes. Received: 1 September 1994/Accepted in revised form: 16 May 1995     

Dichotomous organization of the external globus pallidus

Different striatal projection neurons are the origin of?a?dual organization essential for basal ganglia function. We have defined an analogous division of labor in the external globus pallidus (GPe) of Parkinsonian rats, showing that the distinct temporal activities of two populations of GPe neuron in?vivo are?underpinned by distinct molecular profiles and axonal connectivities. A first population of prototypic GABAergic GPe neurons fire antiphase to subthalamic nucleus (STN) neurons, often express parvalbumin, and target downstream basal ganglia nuclei, including STN. In contrast, a second population (arkypallidal neurons) fire in-phase with STN neurons, express preproenkephalin, and only innervate the striatum. This novel cell type provides the largest extrinsic GABAergic innervation of striatum, targeting both projection neurons and interneurons. We conclude that GPe exhibits several core components of?a dichotomous organization as fundamental as?that in striatum. Thus, two populations of GPe neuron?together orchestrate activities across all basal ganglia nuclei in a cell-type-specific manner.     

Stepping out of the box: information processing in the neural networks of the basal ganglia

The Albin-DeLong 'box and arrow' model has long been the accepted standard model for the basal ganglia network. However, advances in physiological and anatomical research have enabled a more detailed neural network approach. Recent computational models hold that the basal ganglia use reinforcement signals and local competitive learning rules to reduce the dimensionality of sparse cortical information. These models predict a steady-state situation with diminished efficacy of lateral inhibition and low synchronization. In this framework, Parkinson's disease can be characterized as a persistent state of negative reinforcement, inefficient dimensionality reduction, and abnormally synchronized basal ganglia activity.     

Looking at the trees in the central forest: a new pallidal-striatal cell type

The glopus pallidus is a central nucleus of the basal ganglia, pivotal to their function in health and disease. In this issue of Neuron, Mallet et?al. (2012) reveal that this structure is more diverse than previously thought, and identify a novel cell type that projects from pallidum to striatum providing massive GABAergic innervation. These findings invite new views on basal ganglia processing.     

Anatomical funneling, sparse connectivity and redundancy reduction in the neural networks of the basal ganglia

The major anatomical characteristics of the main axis of the basal ganglia are: (1) Numerical reduction in the number of neurons across layers of the feed-forward network, (2) lateral inhibitory connections within the layers, and (3) neuro-modulatory effects of dopamine and acetylcholine, both on the basal ganglia neurons and on the efficacy of information transmission along the basal ganglia axis. We recorded the simultaneous activity of neurons in the output stages of the basal ganglia as well as the activity of dopaminergic and cholinergic neurons during the performance of a probability decision-making task. We found that the functional messages of the cholinergic and dopaminergic neurons differ, and that the cholinergic message is less specific than that of the dopaminergic neurons. The output stage of the basal ganglia showed uncorrelated neuronal activity. We conclude that despite the huge numerical reduction from the cortex to the output nuclei of the basal ganglia, the activity of these nuclei represents an optimally compressed (uncorrelated) version of distinctive features of cortical information.     

Complementary roles of basal ganglia and cerebellum in learning and motor control

The classical notion that the basal ganglia and the cerebellum are dedicated to motor control has been challenged by the accumulation of evidence revealing their involvement in non-motor, cognitive functions. From a computational viewpoint, it has been suggested that the cerebellum, the basal ganglia, and the cerebral cortex are specialized for different types of learning: namely, supervised learning, reinforcement learning and unsupervised learning, respectively. This idea of learning-oriented specialization is helpful in understanding the complementary roles of the basal ganglia and the cerebellum in motor control and cognitive functions.     

Basal ganglia oscillations and pathophysiology of movement disorders

Low frequency rest tremor is one of the cardinal signs of Parkinson's disease and some of its animal models. Current physiological studies and models of the basal ganglia differ as to which aspects of neuronal activity are crucial to the pathophysiology of Parkinson's disease. There is evidence that neural oscillations and synchronization play a central role in the generation of the disease. However, parkinsonian tremor is not strictly correlated with the synchronous oscillations in the basal ganglia networks. Rather, abnormal basal ganglia output enforces abnormal thalamo-cortical processing leading to akinesia, the main negative symptom of Parkinson's disease. Parkinsonian tremor has probably evolved as a downstream compensatory mechanism.