Functional neuroanatomy of the nigrostriatal and striatonigral pathways as studied with dual probe microdialysis in the awake rat--I. Effects of perfusion with tetrodotoxin and low-calcium medium

Family studies using thresholds showed that PROP (6-n-propylthiouracil) tasting is produced by a dominant allele, T. Nontasters have two recessive alleles and tasters have one or two dominant alleles. The bitterness of suprathreshold PROP and anatomical criteria subdivide tasters into medium and supertasters. Supertasters may be TT tasters, but this has yet to be demonstrated. Supertasters preceive the greatest bitterness and sweetness from many stimuli as well as the greatest oral burn from alcohol and capsaicin. Women are more likely than men to be supertasters. Otitis media and head trauma can alter taste and thus PROP classifications, complicating studies on PROP genetics. Some subjects with a history of otitis media show taste reductions, but others show enhanced tastes and appear to have more taste buds per fungiform papilla. Subjects with head trauma show reduced tastes on some oral loci, but there is evidence that severe reductions on the front of the tongue ameliorate reductions at the circumvallate papillae on the back of the tongue by a release of inhibition mechanism.     

Pigeon basal ganglia: insights into the neuroanatomy underlying telencephalic sensorimotor processes in birds

This paper reviews the organization of the avian and mammalian striatum. The striatum receives input from virtually the entire rostrocaudal and mediolateral expanse of the cerebral cortex. The corticostriatal projections appear to be glutamatergic, forming excitatory synapses in the striatum. Another major projection to the avian striatum that also appears to be glutamatergic stems from a set of nuclei in the dorsal zone of the avian thalamus that are comparable to the mammalian intralaminar, mediodorsal, and midline nuclei. Furthermore, the striatum receives a massive projection from dopaminergic neurons of the ventral tegmental area and substantia nigra in the midbrain tegmentum. In return, the midbrain tegmentum receives a direct GABAergic/substance P-ergic/ dynorphinergic projection from the striatum, as well as an indirect one formed by GABAergic/substance P-ergic/ dynorphinergic and GABA-ergic/enkephalinergic striatal neurons projecting to the pallidum in the first step, and pallidal GABAergic/LANT6/parvalbumin neurons projecting to the midbrain tegmentum in the second step. In addition to its projection neurons, the striatum possesses GABAergic and cholinergic interneurons. One motor output pathway of the striatum runs via the pallidum and dorsal thalamic ventral tier nulei to the motor cortex. In addition to this pathway, birds possess a major descending pathway from the basal ganglia to the tectum via the GABAergic nucleus spiriformis lateralis in the pretectum. On hodological and topological grounds, similar nuclei, although not GABAergic, can be found in mammals. Finally, an other striatal motor output is formed by a sequential GABAergic pathway from the basal ganglia via the substantia nigra to the tectum. In conclusion, it appears that the organization of the avian and mammalian basal ganglia is similar rather than different.     

Functional coupling between substantia nigra and basal ganglia homologues in amphibians.

Neuroanatomical and pharmacological experiments support the existence of a homologue of the mammalian substantia nigra-basal ganglia circuit in the amphibian brain. Demarcation of borders between the striatum and pallidum in frogs, however, has been contentious, and direct evidence of functional coupling between the putative nigral and striatal homologues is lacking. To clarify basal ganglia function in anurans, the authors used expression of immediate-early gene egr-1 as a marker of neural activation in the basal ganglia of túngara frogs (Physalaemus pustulosus). Regional variation in egr-1 mRNA levels distinguished striatal and pallidal portions of the basal ganglia and supported the grouping of the striatopallidal transition zone with the dorsal pallidum. As further evidence for a functional coupling between the dopaminergic cells in the posterior tuberculum (the putative substantia nigra homologue) and the basal ganglia, a positive relationship was demonstrated between the size of the dopaminergic cell population and the neural activation levels within the dorsal pallidum. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

HIV dementia and the basal ganglia

Infection with the human immunodeficiency virus frequently results in a dementing illness which manifests predominantly as a subcortical dementia. Parkinsonian features may be prominent in these patients and may on occasion be the presenting manifestation. These patients are exquisitely sensitive to dopaminergic blocking agents. Radiological studies, metabolic uptake studies and pathological examination of the brain suggest that the basal ganglia are the major target of this infection. Although further studies are necessary to determine appropriate treatment for this condition and to develop an understanding of the underlying pathophysiological mechanisms, available evidence suggests that the response to dopamine agonists may be variable and that viral strains and viral products may specifically target cells within the basal ganglia.     

Dopamine-glutamate interactions in the basal ganglia

In an attempt to formulate a working hypothesis of basal-ganglia functions, arguments are considered suggesting that the basal ganglia are involved in a process of response selection i.e. in the facilitation of "wanted" and in the suppression of "unwanted" behaviour. The meso-accumbal dopamine-system is considered to mediate natural and drug-induced reward and sensitization. The meso-striatal dopamine-system seems to fulfill similar functions: It may mediate reinforcement which strengthens a given behaviour when elicited subsequently, but which is not experienced as reward or hedonia. Glutamate as the transmitter of the corticofugal projections to the basal ganglia nuclei and of the subthalamic neurons is critically involved in basal ganglia functions and dysfunctions; for example Parkinson's disease can be considered to be a secondary hyperglutamatergic disease. Additionally, glutamate is an essential factor in the plasticity response of the basal-ganglia. However, opposite to previous suggestions, the NMDA-receptor blocker MK-801 does not prevent psychostimulant- nor morphine-induced day to day increase (sensitization) of locomotion. Also the day to day increase of haloperidol-induced catalepsy was not prevented by MK-801.     

Calcinosis of the basal ganglia and hypoparathyroidism

In most patients with basal ganglia calcification no disturbance of calcium metabolism is present. We present four patients with basal ganglia calcification. Two suffered from a secondary hypoparathyroidism following a complicated strumectomy years ago, one had an Alport-Syndrome and hypoparathyroidism. Her mother showed basal ganglia calcification and an abortive Alport-Syndrome as well, but no hypoparathyroidism.     

Temporal processing in the basal ganglia.

This study investigated the role of the basal ganglia in timing operations. Nondemented, medicated Parkinson's disease (PD) patients and controls were tested on 2 motor-timing tasks (paced finger tapping at a 300- or 600-ms target interval), 2 time perception tasks (duration perception wherein the interval between the standard tone pair was 300 or 600 ms), and 2 tasks that controlled for the auditory processing (frequency perception) demands of the time perception task and the movement rate (rapid tapping) in the motor-timing task. Using A. M. Wing and A. B. Kristofferson's (1973) model, the total variability in motor timing was partitioned into a clock component, which reflects central timekeeping operations, and a motor delay component, which estimates random variability due to response implementation processes. The PD group was impaired at both target intervals of the time perception and motor-timing tasks. Impaired motor timing was due to elevated clock but not motor delay variability. The findings implicate the basal ganglia and its thalamocortical connections in timing operations. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

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.     

Functional neuroanatomy of auditory pathways in the sound-producing fish Pollimyrus

We have described the acoustic pathway from the ear to the diencephalon in a sound-producing fish (Pollimyrus) based on simultaneous neurophysiological recordings from single neurons and injections of biotin pathway tracers at the recording sites. Fundamental transformations of auditory information from highly phase-locked and entrained responses in primary eighth nerve afferents and first-order medullary neurons to more weakly phase-locked responses in the auditory midbrain were revealed by physiological recordings. Anatomical pathway tracing uncovered a bilateral array of both first- and second-order medullary nuclei and a perilemniscal nucleus. Interconnections within the medullary auditory areas were extensive. Medullary nuclei projected to the auditory midbrain by means of the lateral lemniscus. Midbrain auditory areas projected to both ipsilateral and contralateral optic tecta and to an array of three nuclei in the auditory thalamus. The significance of these findings to the elucidation of mechanisms for the analysis of communication sounds and spatial hearing in this vertebrate animal is discussed.     

Schizophrenia, psychosis, and the basal ganglia

Schizophrenia is one of the most common and perhaps the most disabling of mental disorders, for which effective forms of treatment have not yet been established definitively. The findings reviewed in this article strongly suggest that basal ganglia abnormalities are involved in the pathophysiology of psychotic syndromes in general, and schizophrenia in particular.     

Reciprocal dopamine-glutamate modulation of release in the basal ganglia

Dopaminergic and glutamatergic transmissions have long been known to interact at multiple levels in the basal ganglia to modulate motor and cognitive functions. One important aspect of their interactions is represented by the reciprocal modulation of release. This topic has been the object of interest since the late 70's, particularly in the striatum and in midbrain dopaminergic areas (substantia nigra and ventral tegmental area). Analysis of glutamate-dopamine interactions in the control of each other's release is complicated by the fact that both glutamate and dopamine act on multiple receptor subtypes which can exert different effects. Therefore, glutamatergic modulation of dopamine release has been reviewed by analyzing the effects of glutamatergic selective receptor agonists and antagonists in the striatum (both motor and limbic portions) and in midbrain dopaminergic areas, as revealed by in vitro (slices, cell cultures, synaptosomes) and in vivo (push-pull, microdialysis and voltammetry techniques) experimental approaches. The same approach has been followed for dopaminergic modulation of glutamate release. The facilitatory nature of glutamate modulating both presynaptic and dendritic dopamine release has clearly emerged from in vitro studies. However, evidence is presented that, at least in the striatum and in the nucleus accumbens of awake rats, glutamate-mediated inhibitory effects may also occur. In vitro and in vivo experiments in the striatum and midbrain dopaminergic areas mainly depict dopamine as an inhibitory modulator of glutamate release. However, in vivo studies reporting dopamine D1 receptor mediated facilitatory effects are also considered. Therefore, the general notion that glutamate and dopamine act oppositely to regulate each other's release, is only partly supported by the available data. Conversely, the nature of the interaction between the two neurotransmitters seems to vary depending on the experimental approach, the brain area considered and the subtype of receptor involved.     

Neuronal circuitry and synaptic connectivity of the basal ganglia

This article reviews the presentation and management of common breast disorders. It focuses on the diagnosis of treatment and management of patients with breast cancer in a multidisciplinary approach.     

Intratumoral differences in methotrexate levels within human osteosarcoma xenografts studied by microdialysis

A central tenet in oncology is the assumed relationship between drug concentration and cytotoxicity. Determinations of drug levels in tumor tissues are, however, generally not undertaken. Microdialysis is a method where continuous drug monitoring may be achieved by sampling of low molecular weight substances from the extracellular space. By employing this technique it is possible to observe variable drug levels within tissues, including tumors, over time. Herein, we present results from a nude rat model where subcutaneous human osteosarcoma xenografts were established prior to the administration of the antifolate methotrexate as an intravenous infusion. Significant differences in drug exposure within single tumors were evident. Generally, peak drug concentrations were lower and drug efflux slower from the center of the tumors as compared to the periphery. The use of microdialysis could be an important tool for optimizing current strategies in anticancer chemotherapy.     

Functional neuroanatomy of spatial working memory in children.

Functional magnetic resonance imaging (fMRI) was used to examine spatial working memory in 8- to 11-year-old children tested under three conditions. In the visual condition, children were asked to examine the location of a dot on a screen. In the motor condition, children were instructed to push a button that corresponded to the location of a dot presented on a screen. In the memory condition, children were asked to remember the location of a dot presented 1 or 2 trials previously. Subtracting the activation of the motor condition from the memory condition revealed activity in the dorsal aspects of the prefrontal cortex and in the posterior parietal and anterior cingulate cortex. These findings were also obtained in the analysis of the memory minus visual conditions except that motor cortex activation was also observed. These findings parallel those reported in comparable studies of adults and suggest that fMRI may be a useful means of examining function–structure relations in developmental populations. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Functional injury of cholinergic, GABAergic and dopaminergic systems in the basal ganglia of adult rat with kaolin-induced hydrocephalus

Our study intended to describe some inflammatory and tumoral lesions associated to pseudoepithelimatous hyperplasia. In our casuistry, pseudoepithelimatous hyperplasia was determined by tuberculosis in two cases, granulomatous ulcerate epuils in 4 cases, myoblastoma in one case. Recognising these lesions is very important, since it helps differentiating between these tumors and some epidermal carcinomas, the two affections involving different therapies.     

The basal ganglia and chunking of action repertoires

The basal ganglia have been shown to contribute to habit and stimulus-response (S-R) learning. These forms of learning have the property of slow acquisition and, in humans, can occur without conscious awareness. This paper proposes that one aspect of basal ganglia-based learning is the recoding of cortically derived information within the striatum. Modular corticostriatal projection patterns, demonstrated experimentally, are viewed as producing recoded templates suitable for the gradual selection of new input-output relations in cortico-basal ganglia loops. Recordings from striatal projection neurons and interneurons show that activity patterns in the striatum are modified gradually during the course of S-R learning. It is proposed that this recoding within the striatum can chunk the representations of motor and cognitive action sequences so that they can be implemented as performance units. This scheme generalizes Miller's notion of information chunking to action control. The formation and the efficient implementation of action chunks are viewed as being based on predictive signals. It is suggested that information chunking provides a mechanism for the acquisition and the expression of action repertoires that, without such information compression would be biologically unwieldy or difficult to implement. The learning and memory functions of the basal ganglia are thus seen as core features of the basal ganglia's influence on motor and cognitive pattern generators.     

Germinoma of the basal ganglia and thalamus--CT and MRI findings

A case of germinoma originating in the basal ganglia and thalamus is presented. This tumour most commonly originates during childhood and adolescence, at pineal and suprasellar regions. In the early stages, the diagnosis of germinoma in the basal ganglion and thalamus is difficult because of its rarity and non-specific findings. The computed tomography (CT) and magnetic resonance imaging (MRI) findings though non-diagnostic, are discussed here. A few differential diagnoses had been discussed with radiological abnormality. Open biopsy done in this case proved to be two-cell pattern germinoma. Early detection of the tumour is desirable, since this tumour is highly sensitive to radio and chemotherapy and is potentially curable. Our patient was treated with combined chemotherapy and the response was well and no residual tumour or recurrence was seen on the repeated imaging modality, however his neurological deficits remained unchanged.     

Microcircuitry of the direct and indirect pathways of the basal ganglia

Our understanding of the organization of the basal ganglia has advanced markedly over the last 10 years, mainly due to increased knowledge of their anatomical, neurochemical and physiological organization. These developments have led to a unifying model of the functional organization of the basal ganglia in both health and disease. The hypothesis is based on the so-called "direct" and "indirect" pathways of the flow of cortical information through the basal ganglia and has profoundly influenced the field of basal ganglia research, providing a framework for anatomical, physiological and clinical studies. The recent introduction of powerful techniques for the analysis of neuronal networks has led to further developments in our understanding of the basal ganglia. The objective of this commentary is to build upon the established model of the basal ganglia connectivity and review new anatomical findings that lead to the refinement of some aspects of the model. Four issues will be discussed. (1) The existence of several routes for the flow of cortical information along "indirect" pathways. (2) The synaptic convergence of information flowing through the "direct" and "indirect" pathways at the single-cell level in the basal ganglia output structures. (3) The convergence of functionally diverse information from the globus pallidus and the ventral pallidum at different levels of the basal ganglia. (4) The interconnections between the two divisions of the pallidal complex and the subthalamic nucleus and the characterization of the neuronal network underlying the indirect pathways. The findings summarized in this commentary confirm and elaborate the models of the direct and indirect pathways of information flow through the basal ganglia and provide a morphological framework for future studies.     

Modeling the route of administration-based enhancement in the brain delivery of EAB 515, studied by microdialysis

EAB 515 (S-alpha-amino-5-phosphonomethyl[1,1'biphenyl]-3-propanoic acid) is an extremely hydrophilic N-methyl-D-aspartate antagonist. It shows marked CNS activity, in that it is a potent neuroprotector in models of cerebral ischemia, and also demonstrates social and non-social behavioral alteration following systemic administration in animals. Because of its high degree of ionization at physiologic pH, one would not expect appreciable brain uptake of EAB 515 across tight junctions of the blood-brain barrier. This is in contrast to its pharmacologic effect as well as brain/plasma ratios measured during systemic administration in rats. These observations lead us to investigate other transport pathways that might account for its brain uptake. Such mechanistic information is imperative in rational drug delivery and drug design strategies. Upon intracerebroventricular administration, the observed steady-state cortical extracellular fluid concentrations of EAB 515 were over 100-fold higher than those observed following intravenous administration, when normalized for the dosing rate. This increased distribution into the brain, based upon the route of administration, suggests the transport of drug directly between the cerebrospinal fluid and the brain extracellular space. The parameters of the model that adequately describes the data obtained from the two routes of administration in individual animals were estimated. The clinical significance of these results is in the use of intracerebroventricular administration for enhanced brain delivery of hydrophilic drugs that poorly cross the blood-brain barrier.