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MRI evaluation of basal ganglia ferritin iron and neurotoxicity in Alzheimer's and Huntingon's disease.

BACKGROUND: The basal ganglia contain the highest levels of iron in the brain and post-mortem studies indicate a disruption of iron metabolism in the basal ganglia of patients with neurodegenerative disorders such as Alzheimer's disease (AD) and Huntington's disease (HD). Iron can catalyze free radical reactions and may contribute to oxidative damage observed in AD and HD brain. Magnetic resonance imaging (MRI) can quantify transverse relaxation rates, which can be used to quantify tissue iron stores as well as evaluate increases in MR-visible water (an indicator of tissue damage). METHODS: A magnetic resonance imaging (MRI) method termed the field dependent relaxation rate increase (FDRI) was employed which quantifies the iron content of ferritin molecules (ferritin iron) with specificity through the combined use of high and low field-strength MRI instruments. Three basal ganglia structures (caudate, putamen and globus pallidus) and one comparison region (frontal lobe white matter) were evaluated. Thirty-one patients with AD and a group of 68 older control subjects, and 11 patients with HD and a group of 27 adult controls participated (4 subjects overlap between AD and HD controls). RESULTS: Compared to their respective normal control groups, increases in basal ganglia FDRI levels were seen in both AD and HD. FDRI levels were significantly increased in the caudate (p = 0.007) and putamen (p = 0.008) of patients with AD with a trend toward an increase in the globus pallidus (p = 0.13). In the patients with HD, all three basal ganglia regions showed highly significant FDRI increases (p<0.001) and the magnitude of the increases were 2 to 3 times larger than those observed in AD versus control group comparison. For both HD andAD subjects, the basal ganglia FDRI increase was not a generalized phenomenon, as frontal lobe white matter FDRI levels were decreased in HD (p = 0.015) and remained unchanged in AD. Significant low field relaxation rate decreases (suggestive of increased MR-visible water and indicative of tissue damage) were seen in the frontal lobe white matter of both HD and AD but only the HD basal ganglia showed such decreases. CONCLUSIONS: The data suggest that basal ganglia ferritin iron is increased in HD and AD. Furthermore, the increased iron levels do not appear to be a byproduct of the illness itself since they seem to be present at the onset of the diseases, and thus may be considered a putative risk factor. Published post-mortem studies suggest that the increase in basal ganglia ferritin iron may occur through different mechanisms in HD and AD. Consistent with the known severe basal ganglia damage, only HD basal ganglia demonstrated significant decreases in low field relaxation rates. MRI can be used to dissect differences in tissue characteristics, such as ferritin iron and MR-visible water, and thus could help clarify neuropathologic processes in vivo. Interventions aimed at decreasing brain iron levels, as well as reducing the oxidative stress associated with increased iron levels, may offer novel ways to delay the rate of progression and possibly defer the onset of AD and HD.

Adult↗

Toward an understanding of the role of glutamate in experimental parkinsonism: agonist-sensitive sites in the basal ganglia.

Increased glutamatergic transmission in the basal ganglia is implicated in the pathophysiology of Parkinson's disease. However, the mechanisms by which activation of glutamate receptors produce parkinsonism are unknown. Therefore, we examined whether the glutamate agonists N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA), kainate, and trans-(+/-)-1-amino-1,3-cyclopentanedicarboxylate produce parkinsonism in rats after microapplication into different subregions of the basal ganglia. Electromyographic activity was used as a measure of parkinsonian rigidity. We found that in the rostral striatum, excitation mediated by NMDA but not by non-NMDA receptors led to parkinsonism. In the substantia nigra pars reticulata, internal pallidal segment/entopeduncular nucleus, and subthalamic nucleus, activation of AMPA/kainate and metabotropic receptors but not of NMDA receptors led to parkinsonian rigidity. Rigidity occurred also in animals bearing ibotenate-induced lesions of the posterior part of the striatum and of the external pallidal segment, but not in animals with lesions of the anterior striatum, subthalamic nucleus, internal pallidal segment/entopeduncular nucleus, or substantia nigra pars reticulata. These observations suggest that the activation of glutamate receptor subtypes in the basal ganglia may be differentially involved in the expression of parkinsonian symptoms.

Animals↗

Computational models of the basal ganglia.

Computer simulation studies and mathematical analysis of models of the basal ganglia are being used increasingly to explore theories of basal ganglia function. We review the implications of these new models for a general understanding of basal ganglia function in normal as well as in diseased brains. The focus is on their functional similarities rather than on the details of mathematical methodologies and simulation techniques. Most of the models suggest a vital role for the basal ganglia in learning. Although this interest in learning is partly driven by experimental results associating the acute firing of dopamine cells with reward prediction in monkeys, some of the models have preceded the electrophysiological results. Another common theme of the models is selection. In this case, the striatum is seen as detecting and selecting cortical contexts for access to basal ganglia output. Although the behavioral consequences of this selection are hard to define, the models provide frameworks within which to explore these ideas empirically. This provides a means of refining our understanding of basal ganglia function and to consider dysfunction within the new logical frameworks.

Animals↗

The basal ganglia: anatomy, physiology, and pharmacology.

The basal ganglia are perceived as important nodes in cortico-subcortical networks involved in the transfer, convergence, and processing of information in motor, cognitive, and limbic domains. How this integration might occur remains a matter of some debate, particularly given the consistent finding in anatomic and physiologic studies of functional segregation in cortico-subcortical loops. More recent theories, however, have raised the notion that modality-specific information might be integrated not spatially, but rather temporally, by coincident processing in discrete neuronal populations. Basal ganglia neurotransmitters, given their diverse roles in motor performance, learning, working memory, and reward-related activity are also likely to play an important role in the integration of cerebral activity. Further work will elucidate this to a greater extent, but for now, it is clear that the basal ganglia form an important nexus in the binding of cognitive, limbic, and motor information into thought and action.

Acetylcholine↗

Embolization of basal ganglia and thalamic arteriovenous malformations.

OBJECTIVE: Basal ganglia and thalamic arteriovenous malformations (AVMs) show a poor natural history and have proven difficult to treat. We report the safety and efficacy of presurgical and preradiosurgical embolization of these deep central lesions and describe the contribution of embolization to multimodality treatment. METHODS: Thirty-eight patients with basal ganglia and/or thalamic AVMs underwent embolization in a total of 69 sessions. Seven of the 38 patients (18.4%) presented with hemorrhage, and 23 of 38 (60.5%) exhibited neurological deficits before therapy. Thirty patients (78.9%) underwent embolization with a liquid adhesive (cyanoacrylate), and five of these patients also underwent embolization with polyvinyl alcohol. Five patients (13.2%) were treated with polyvinyl alcohol or polyvinyl alcohol and silk. One patient (2.6%) underwent embolization alone, 19 (50.0%) underwent embolization followed by radiosurgery, 5 (13.2%) underwent embolization plus microsurgical resection, and 13 (34.2%) patients were treated using all three modalities. RESULTS: Three patients did not undergo embolization because of the morphological features of the AVMs and poor endovascular access. The patients who underwent embolization achieved AVM volume reductions of 10 to 100% (mean, 49.7%). Fifteen patients (39.5%) achieved complete obliteration of their AVMs, one with embolization alone, three with embolization followed by radiosurgery, five with embolization plus microsurgical resection, and six with a combination of all three modalities. At the time of the last follow-up imaging session, embolization combined with radiosurgery (19 patients) yielded a mean volume reduction of 81.1%, and all three modalities (13 patients) yielded a mean reduction of 84.6%. Four permanent neurological deficits resulted from embolization (5.8% of procedures, 10.5% of patients). The embolization-related complication rate was higher in the earlier years (1984-1989) of this series. CONCLUSION: Endovascular embolization plays an important role in multimodality treatment of AVMs involving the basal ganglia and/or thalamus. Embolization can result in obliteration of a significant volume of the AVM and may allow complete obliteration of the AVM when combined with microsurgical resection and/or stereotactic radiosurgery.

Adolescent↗

[A neuroanatomic view of the basal ganglia with some physiopathological implications].

The basal ganglia nuclei are a set of subcortical structures including principally the corpus striatum (caudate and lenticular nuclei), associated with other allied nuclei, namely, the subthalamic nucleus and the substantia nigra. A very remarkable neuroanatomical feature of these structures is their heterogeneity, which can be clearly illustrated from the hodological, histochemical as well as cytoarchitectonical point of view. This report is an attempt to correlate this heterogeneity present in the basal ganglia with the physiopathology of profound alterations of these structures displayed in diseases as hemibalism and Parkinson's and Huntington's diseases.

Animals↗

Basal ganglia and cerebellar loops: motor and cognitive circuits.

The traditional view that the basal ganglia and cerebellum are simply involved in the control of movement has been challenged in recent years. One of the pivotal reasons for this reappraisal has been new information about basal ganglia and cerebellar connections with the cerebral cortex. In essence, recent anatomical studies have revealed that these connections are organized into discrete circuits or 'loops'. Rather than serving as a means for widespread cortical areas to gain access to the motor system, these loops reciprocally interconnect a large and diverse set of cerebral cortical areas with the basal ganglia and cerebellum. The properties of neurons within the basal ganglia or cerebellar components of these circuits resembles the properties of neurons within the cortical areas subserved by these loops. For example, neuronal activity within basal ganglia and cerebellar loops with motor areas of the cerebral cortex is highly correlated with parameters of movement, while neuronal activity within basal ganglia and cerebellar loops with areas of the prefrontal cortex is more related to aspects of cognitive function. Thus, individual loops appear to be involved in distinct behavioral functions. Studies of basal ganglia and cerebellar pathology support this conclusion. Damage to the basal ganglia or cerebellar components of circuits with motor areas of cortex leads to motor symptoms, whereas damage of the subcortical components of circuits with non-motor areas of cortex causes higher-order deficits. In this report, we review some of the new anatomical, physiological and behavioral findings that have contributed to a reappraisal of function concerning the basal ganglia and cerebellar loops with the cerebral cortex.

Animals↗

Relationship between oscillations in the basal ganglia and synchronization of cortical activity.

The functions of oscillations within the basal ganglia are poorly understood. We discuss in the present paper, the possible physiological or pathological roles of oscillatory activities within the basal ganglia, and their relationship to cortical oscillations. Three aspects are presented: 1. What do we know from animal studies? 2. What do we know from neurophysiological studies in parkinsonian patients? 3. What is the effect of L-dopa treatment and electrical stimulation within basal ganglia circuits on cortical oscillations? Animal studies suggest that neuronal oscillations are spontaneously generated within the basal ganglia system, especially from the GPE and the subthalamic nucleus (STN), but are mainly synchronized by cortical activity via the striatal inputs. Dopamine depletion results in a global increase of oscillations within the whole basal ganglia system, particularly in the GP-NST network. Oscillations within the basal ganglia may, in part, be related to tremor since they are enhanced, especially in the globus pallidus internus (GPI) and the STN, in human and animal dopaminergic depletion. However, they also play a role in the physiology of movement as revealed by coherence analysis between cortex, muscles and GPI/STN in parkinsonian patients undergoing deep brain stimulation. It is known that the basal ganglia may influence cortico-muscular oscillations such as the Piper rhythm and other rhythms in the beta band. In off-drug parkinsonian patients, low frequency oscillations (4-10 Hz) are favoured, presumably resulting in bradykinesia and low force. When medically (Ldopa) or surgically (deep brain stimulation) treated, these low frequency oscillations are replaced by high frequency (70 Hz) oscillations that are important for motor programs to be correctly executed. Studies of cortical reactivity related to planning of voluntary movement in parkinsonian patients provide evidence that it is possible to influence cortical reactivity through the basal ganglia system.

Animals↗

Neuronal activity in the substantia nigra in the anaesthetized rat has fractal characteristics. Evidence for firing-code patterns in the basal ganglia.

Current models of the basal ganglia assume a firing-rate code for information processing. We have applied five complementary computing methods to assess firing patterns in 188 cells of the substantia nigra in the anaesthetized rat. Fractal firing activity was found in 100% of nigral cells projecting to the superior colliculus, in 51% of cells projecting to the thalamus and in 33% of cells projecting to the pedunculopontine nucleus, but was practically absent in dopaminergic nigrostriatal neurons (3%). The finding of fractal firing patterns may lead to a better understanding of the normal operational mode and pathological manifestations of the basal ganglia.

Anesthesia↗

Disruption of automatic speech following a right basal ganglia lesion.

Following a right basal ganglia lesion, a right-handed man, age 75, was unable to recite familiar verses. Serial automatic speech, singing, recitation of rhymes, and swearing were impaired, and only idioms and social greetings were preserved. Speech no longer contained overused phrases and he could comprehend automatic speech. In contrast, propositional speech was preserved in both French and Hebrew. Right basal ganglia lesions may impair production but not comprehension of automatic speech.

Aged↗

What do the basal ganglia do?

We propose that the basal ganglia support a basic attentional mechanism operating to bind input to output in the executive forebrain. Such focused attention provides the automatic link between voluntary effort, sensory input, and the calling up and operation of a sequence of motor programmes or thoughts. The physiological basis for this attentional mechanism may lie in the tendency of distributed, but related, cortical activities to synchronise in the gamma (30 to 50 Hz) band, as occurs in the visual cortex. Coherent and synchronised elements are more effective when convergence occurs during successive stages of processing, and in this way may come together to give the one gestalt or action. We suggest that the basal ganglia have a major role in facilitating this aspect of neuronal processing in the forebrain, and that loss of this function contributes to parkinsonism and abulia.

Animals↗

Neuropsychiatric disorders, myoclonus, and dystonia in calcification of basal ganglia pathways.

Two cases of basal ganglia calcification involving the globus pallidus are presented. Both patients had cognitive dysfunction, temporal lobe-like symptoms (including amnestic state, perceptual distortions, or complex visual hallucinations), and myoclonus. Patient 1 manifested depression, auditory hallucinations, anxiety, paranoia, and postural tremor; patient 2 manifested multifocal dystonia with dystonic tremor. These cases supplement other reports of psychotic features and dementia associated with pallidal pathology. Additionally, the phenomena encountered in these cases are considered in light of recent advances in our understanding of basal ganglia functional pathways. These cases afford a potential pathophysiological window to the possible role of the globus pallidus in these neuropsychiatric conditions. In concert with other recent findings, these cases suggest specific pathway involvement in hallucinations, paranoia, depression, myoclonus, and dystonia. Further research will indicate if these pathways play a role in schizophrenia, mood disorders, and anxiety disorders.

Adult↗

Circuits and circuit disorders of the basal ganglia.

Views of the anatomy and function of the basal ganglia and their role in motor and nonmotor disorders have undergone major revisions during the past decades. The basal ganglia are now appreciated as components of parallel, reentrant cortico-subcortical circuits, which originate from individual cortical areas, traverse the basal ganglia and thalamus, and terminate in their respective areas of origin in the frontal lobe. Further research and clinical experience have resulted in new insights and perspectives on the details of the circuitry and on the role of these structures in Parkinson disease and other basal ganglia disorders. On the basis of anatomical and physiological studies and the striking success of focused surgical interventions, it seems appropriate to view these varied clinical disorders as circuit disorders, resulting from pathologic disturbances in neuronal activity throughout specific cortico-subcortical loops.

Animals↗

[History of the basal ganglia system. Slow development of a major cerebral system].

Initially, basal ganglia was a descriptive term for onto- and phylogenetic or topographic classifications. A variable list of structures were included as basal ganglia. A major step was made when the thalamus was separated from the "striated bodies" (Vic d'Azyr, 1786) which was sometimes taken into account in the French description of the noyaux gris centraux. Even if the term is not perfect, it is preferable to "the system of basal ganglia". The subdivisions of the putamen, the distinction between the striatum and the pallidum were not really made until the beginning of the twentieth century. Modern tracing methods were needed to demonstrate the main connections. It was not until the end of the 1960s that the importance of the striato-pallido-nigral network within the basal ganglia and the cortico-striatal connections, the main afferent system, were recognized. With the description of the cortico-striatal connections, the sub-cortical system with multiple complex "loops" was questioned. The term "extra-pyramidal system" had an exaggerated success. Initially, it designated descending non-pyramidal afferents (some which do not exist) and their source. In 1992, Spatz based his separation of this heterogeneous group on the iron content. The terms of extra-pyramidal "system" and "syndrome" should be abandoned by clinicians. Physiological interpretations have varied. The role of automatic "habitual" motricity, derived from a concept of hierarchic, Jacksonian cerebral organization, was questioned when the pyramidal network was described. Clinico-pathological analysis (hemiballism, Parkinson's disease ...) has placed new emphasis on the motor role, for a time the only role accepted as real. More recently, debate has centred on other roles, particularly in cognition and motivation. An illustration of functions other than purely motor functions of the basal ganglia is given by the syndromes of loss of psychic auto-activation secondary to bilateral lesions.

Basal Ganglia↗

Modulation of the basal ganglia by metabotropic glutamate receptors: potential for novel therapeutics.

The basal ganglia are implicated in a number of disorders including neurodegenerative motor diseases such as Huntington's and Parkinson's disease, as well as psychiatric disorders such as schizophrenia and obsessive compulsive disorder. In recent years, a great deal of effort has been focused on determining the basal ganglia circuitry that underlies normal behavior, as well as many of these syndromes. This has led to a detailed understanding of both the normal and pathophysiological flow of information through the basal ganglia, and has provided the opportunity to begin developing novel pharmacological methods of intervention by targeting neuromodulatory receptors with in the basal ganglia circuit. One group of receptors that holds much promise for several basal ganglia disorders is the metabotropic glutamate receptors. Data from behavioral, neurochemical, neuroanatomical and electrophysiological studies has begun to reveal the functional roles that the metabotropic glutamate receptors play in modulating the basal ganglia circuit, and suggests that compounds selectively targeting these receptors may provide novel therapies for a variety of disorders including Parkinson's disease, addiction, and epilepsy.

Animals↗

Actor-critic models of the basal ganglia: new anatomical and computational perspectives.

A large number of computational models of information processing in the basal ganglia have been developed in recent years. Prominent in these are actor-critic models of basal ganglia functioning, which build on the strong resemblance between dopamine neuron activity and the temporal difference prediction error signal in the critic, and between dopamine-dependent long-term synaptic plasticity in the striatum and learning guided by a prediction error signal in the actor. We selectively review several actor-critic models of the basal ganglia with an emphasis on two important aspects: the way in which models of the critic reproduce the temporal dynamics of dopamine firing, and the extent to which models of the actor take into account known basal ganglia anatomy and physiology. To complement the efforts to relate basal ganglia mechanisms to reinforcement learning (RL), we introduce an alternative approach to modeling a critic network, which uses Evolutionary Computation techniques to 'evolve' an optimal RL mechanism, and relate the evolved mechanism to the basic model of the critic. We conclude our discussion of models of the critic by a critical discussion of the anatomical plausibility of implementations of a critic in basal ganglia circuitry, and conclude that such implementations build on assumptions that are inconsistent with the known anatomy of the basal ganglia. We return to the actor component of the actor-critic model, which is usually modeled at the striatal level with very little detail. We describe an alternative model of the basal ganglia which takes into account several important, and previously neglected, anatomical and physiological characteristics of basal ganglia-thalamocortical connectivity and suggests that the basal ganglia performs reinforcement-biased dimensionality reduction of cortical inputs. We further suggest that since such selective encoding may bias the representation at the level of the frontal cortex towards the selection of rewarded plans and actions, the reinforcement-driven dimensionality reduction framework may serve as a basis for basal ganglia actor models. We conclude with a short discussion of the dual role of the dopamine signal in RL and in behavioral switching.

Animals↗

Calcifications of the basal ganglia in children with brain tumours.

Calcifications in the basal ganglia have been found in nine (5.4%) of all children treated for any kind of brain tumour in our department. This has occurred over a mean period of 2.8 years after diagnosis. The group of patients has been compared with a group of other children, matched for age, sex, histologic diagnosis and tumour treatment, but without calcifications of the basal ganglia. The groups differ from each other with respect to a significantly higher incidence of hypothyroidism and growth hormone deficiency in the group of children with calcifications in the basal ganglia. Moreover the children with calcifications show a larger IQ-loss. Although the pathogenesis of the calcifications of the basal ganglia is not known, an association of damage to the vascular bed of the basal ganglia due to periods of increased intracranial pressure, together with endocrine deficiencies is discussed. We advise an adequate supplementation in cases of endocrine deficiencies in children treated for brain tumours as early as possible.

Basal Ganglia Diseases↗

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.

Animals↗