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Abstract: The hyperdirect pathway of the basal ganglia bypasses the striatum, and delivers cortical information directly to the subthalamic nucleus (STN). In rodents, the STN excites the two output nuclei of the basal ganglia, the entopeduncular nucleus (EP) and the substantia nigra reticulata (SNr). Thus, during hyperdirect pathway activation, the STN drives EP firing inhibiting the thalamus. We hypothesized that STN activity could induce long‐term changes to the STN‐>EP synapse. To test this hypothesis, we recorded in the whole‐cell mode from neurons in the EP in acute brain slices from rats while electrically stimulating the STN. Repetitive pre‐synaptic stimulation generated modest long‐term depression (LTD) in the STN‐>EP synapse. However, pairing EP firing with STN stimulation generated robust LTD that manifested for pre‐before post‐as well as for post‐ before pre‐synaptic pairing. This LTD was highly sensitive to the time difference and was not detected at a time delay of 10 ms. To investigate whether post‐synaptic calcium levels were important for LTD induction, we made dendritic recordings from EP neurons that revealed action potential back‐propagation and dendritic calcium transients. Buffering the dendritic calcium concentration in the EP neurons with EGTA generated long term potentiation instead of LTD. Finally, mild LTD could be induced by post‐synaptic activity alone that was blocked by an endocannabinoid 1 (CB1) receptor blocker. These results thus suggest there may be an adaptive mechanism for buffering the impact of the hyperdirect pathway on basal ganglia output which could contribute to the de‐correlation of STN and EP firing. [ABSTRACT FROM AUTHOR]

The article examines the adverse effect of metoclopramide on the central nervous system (CNS) of the horse. Topics discussed include toxicity of Lidocaine CNS and cardiovascular system; health issues associated with drug overdose; and use of antihistaminic drugs as alternative treatments for metoclopramide-induced extrapyramidal effects.

Key points The excitatory afferents to the striatum from the cortex and thalamus are critical in the expression of basal ganglia function., Thalamostriatal afferents are markedly heterogeneous and arise in different subnuclei of the intralaminar thalamus., We used an optogenetic approach, to isolate and selectively activate thalamostriatal afferents arising in the central lateral or parafascicular thalamic nuclei, and to study the properties of their synapses with principal striatal neurons, the medium-spiny neurons., Thalamostriatal synapses differ in many aspects and our data suggest that inputs from the central lateral nucleus are efficient drivers of medium-spiny neuron action potential firing, whereas inputs from the parafascicular nucleus are likely to be modulatory., These results suggest distinct roles for thalamostriatal inputs from different subnuclei of the thalamus and will help us understand how the striatal circuit operates in health and disease., Abstract To understand the principles of operation of the striatum it is critical to elucidate the properties of the main excitatory inputs from cortex and thalamus, as well as their ability to activate the main neurons of the striatum, the medium spiny neurons (MSNs). As the thalamostriatal projection is heterogeneous, we set out to isolate and study the thalamic afferent inputs to MSNs using small localized injections of adeno-associated virus carrying fusion genes for channelrhodopsin-2 and YFP, in either the rostral or caudal regions of the intralaminar thalamic nuclei (i.e. the central lateral or parafascicular nucleus). This enabled optical activation of specific thalamic afferents combined with whole-cell, patch-clamp recordings of MSNs and electrical stimulation of cortical afferents, in adult mice. We found that thalamostriatal synapses differ significantly in their peak amplitude responses, short-term dynamics and expression of ionotropic glutamate receptor subtypes. Our results suggest that central lateral synapses are most efficient in driving MSNs to depolarization, particularly those of the direct pathway, as they exhibit large amplitude responses, short-term facilitation and predominantly express postsynaptic AMPA receptors. In contrast, parafascicular synapses exhibit small amplitude responses, short-term depression and predominantly express postsynaptic NMDA receptors, suggesting a modulatory role, e.g. facilitating Ca2+-dependent processes. Indeed, pairing parafascicular, but not central lateral, presynaptic stimulation with action potentials in MSNs, leads to NMDA receptor- and Ca2+-dependent long-term depression at these synapses. We conclude that the main excitatory thalamostriatal afferents differ in many of their characteristics and suggest that they each contribute differentially to striatal information processing. [ABSTRACT FROM AUTHOR]

J. Neurochem. (2010) 114, 150–159. A previous study from our laboratory demonstrated the presence within the rat striatum of dopaminergic terminals in different dynamical states, determined at least in part by the extent to which terminals are subject to autoinhibition. The present study is designed to test the hypothesis that heterogeneity in the basal tonic extracellular dopamine concentration contributes to the variable extent of autoinhibition. We probed basal extracellular dopamine concentrations using a previously demonstrated strategy that utilizes intrastriatal microinfusion of kynurenate, a substance that according to voltammetric measurements decreases extracellular dopamine from its basal concentration. In the striatum, however, we find that the response to kynurenate infusion is itself heterogeneous, allowing a broad classification of sites within the striatum as kynurenate-insensitive and kynurenate-sensitive, respectively. These newly identified kynurenate-insensitive and sensitive sites yield substantially and significantly different evoked dopamine release as measured by voltammetry during electrical stimulation of the medial forebrain bundle. Our findings confirm the hypothesis that heterogeneity in the local basal concentration of dopamine is responsible for the variable extent of autoinhibition within the striatum and support the conclusion that the steady state and dynamical components of extracellular dopamine in this brain region are coupled. [ABSTRACT FROM AUTHOR]

Perception of musical rhythms is culturally universal. Despite this special status, relatively little is known about the neurobiology of rhythm perception, particularly with respect to beat processing. Findings are presented here from a series of studies that have specifically examined the neural basis of beat perception, using functional magnetic resonance imaging (fMRI) and studying patients with Parkinson's disease. fMRI data indicate that novel beat-based sequences robustly activate the basal ganglia when compared to irregular, nonbeat sequences. Furthermore, although most healthy participants find it much easier to discriminate changes in beat-based sequences compared to irregular sequences, Parkinson's disease patients fail to show the same degree of benefit. Taken together, these data suggest that the basal ganglia are performing a crucial function in beat processing. The results of an additional fMRI study indicate that the role of the basal ganglia is strongly linked to internal generation of the beat. Basal ganglia activity is greater when participants listen to rhythms in which internal generation of the beat is required, as opposed to rhythms with strongly externally cued beats. Functional connectivity between part of the basal ganglia (the putamen) and cortical motor areas (premotor and supplementary motor areas) is also higher during perception of beat rhythms compared to nonbeat rhythms. Increased connectivity between cortical motor and auditory areas is found in those with musical training. The findings from these converging methods strongly implicate the basal ganglia in processing a regular beat, particularly when internal generation of the beat is required. [ABSTRACT FROM AUTHOR]

Manganese is an essential nutrient, integral to proper metabolism of amino acids, proteins and lipids. Excessive environmental exposure to manganese can produce extrapyramidal symptoms similar to those observed in Parkinson’s disease (PD). We used in vivo and in vitro models to examine cellular and circuitry alterations induced by manganese exposure. Primary mesencephalic cultures were treated with 10–800 μM manganese chloride which resulted in dramatic changes in the neuronal cytoskeleton even at subtoxic concentrations. Using cultures from mice with red fluorescent protein driven by the tyrosine hydroxylase (TH) promoter, we found that dopaminergic neurons were more susceptible to manganese toxicity. To understand the vulnerability of dopaminergic cells to chronic manganese exposure, mice were given i.p. injections of MnCl2 for 30 days. We observed a 20% reduction in TH-positive neurons in the substantia nigra pars compacta (SNpc) following manganese treatment. Quantification of Nissl bodies revealed a widespread reduction in SNpc cell numbers. Other areas of the basal ganglia were also altered by manganese as evidenced by the loss of glutamic acid decarboxylase 67 in the striatum. These studies suggest that acute manganese exposure induces cytoskeletal dysfunction prior to degeneration and that chronic manganese exposure results in neurochemical dysfunction with overlapping features to PD. [ABSTRACT FROM AUTHOR]

The ability to perform an appropriate response in the presence of competing alternatives is a critical facet of human behavioral control. This is especially important if a response is prepared for execution but then has to be changed suddenly. A popular hypothesis of basal ganglia (BG) function suggests that its direct and indirect pathways could provide a neural mechanism to rapidly switch from one planned response to an alternative. However, if one response is more dominant or ‘automatic’ than the other, the BG might have a different role depending on switch direction. We built upon the pro- and antisaccade tasks, two models of automatic and voluntary behavior, respectively, and investigated whether the BG are important for switching any planned response in general, or if they are more important for switching from a more automatic response to a response that is more difficult to perform. Subjects prepared either a pro- or antisaccade but then had to switch it unexpectedly on a subset of trials. The results revealed increased striatal activation for switching from a pro- to an antisaccade but this did not occur for switching from an anti- to a prosaccade. This activation pattern depended on the relative difficulty in switching, and it was distinct from frontal eye fields, an area shown to be more active for antisaccade trials than for prosaccade trials. This suggests that the BG are important for compensating for differences in response difficulty, facilitating the rapid switching of one response for another. [ABSTRACT FROM AUTHOR]

Regional differences in human brain development during infancy have been studied for many years, but little is known about how regionalization of the brain proceeds during intrauterine life. We investigated the regionalization of cerebral volume and cortical convolutions based on the volumetric magnetic resonance images (MRIs) of 43 fetuses, ranging from 21 to 37 weeks of gestation. Two plausible parcellations of MRI are proposed, and curvature index together with gyrification index are used to quantify the regional cortical convolutions. Our results elucidate that the cortical foldings among different brain regions develop at comparable rates, suggesting a similar uniformity of changes in size of the cortical sheet in these regions over time. On the contrary, the growth of the cerebral volume presents regional difference, with the frontal and parieto-temporal regions growing significantly faster than other regions due to the contribution from expansion of basal ganglia. This quantitative regional information suggests that cerebral volume is not a relevant parameter to measure in relation to gyrification, and that the size of the cortical sheet is more likely to be directly related to cortical folding. The availability of quantitative regional information on normal fetal brains in utero will allow clinical application of this information when probing neurodevelopmental disorders in the future. [ABSTRACT FROM AUTHOR]

Parkinson’s disease (PD) is a neurodegenerative basal ganglia disorder accompanied by deficits in cognitive functions. One important executive function is the inhibition of responses. Due to basal ganglia damage, processes related to the selection of response are also dysfunctional. However, the relevance of deficits in response selection to processes related to response inhibition in PD is not clear. In this study we examined these processes by means of event-related potentials (ERPs) in two Go/Nogo tasks. In one task the stimulus–response mapping was compatible and in the other task it was incompatible with the meaning of the stimuli. The behavioural results show that PD patients were unaffected in the compatible response inhibition task but encountered problems in the incompatible one. In the ERPs the N2, generally reflecting response selection, was delayed for the PD compared to the control group. This suggests that response selection is delayed in PD. Moreover, the N2 was specifically enhanced in Nogo trials. This indicates that premotor inhibition, which is probably reflected by the Nogo-N2, is intensified in PD. The P3 was specifically attenuated and delayed after Nogo stimuli in the incompatible condition for PDs. Assuming that the Nogo-P3 reflects the evaluation of successful motor inhibition, our data show that this process is attenuated and delayed in PD but mainly in the incompatible task. The results suggest that inhibitory deficits in PD are only evident in complex (incompatible) stimulus–response mappings. These effects are probably due to an overstrain of striatal processes. [ABSTRACT FROM AUTHOR]

PURPOSE The characterization and differentiation of central nervous system (CNS) lymphoma has important diagnostic, therapeutic, and prognostic significance. The purpose of this study is to characterize the diffusion-weighted imaging (DWI) and MR spectroscopic (MRS) findings in CNS lymphoma. MATERIALS AND METHODS Twenty consecutive patients (male [ n= 12], female [ n= 8]) with histopathologically proven CNS lymphoma were retrospectively evaluated during this study from July 2005 to April 2007. Patients included immunocompromised ( n= 9) and immunocompetent ( n= 11) individuals. MR Imaging (pretreatment n= 13), pre- and post-treatment ( n= 7) included DWI ( n= 20) (b = 1000s/mm2) and ADC (apparent diffusion coefficient) maps of all patients. MRS was performed ( n= 10) with PRESS (point-resolved spectroscopy) sequence (multivoxel n= 8, single voxel n= 2) with a TE of 144 msec. All patients were histopathologically confirmed to have lymphoma by biopsy. RESULTS Areas of restricted diffusion were observed in 90 % ( n= 18/20) on pretreatment scans. The diffusion restriction was variable on post-treatment scans. Median metabolite ratios in 10 patients were Cho/Cr- 2.12, NAA/Cho - .49, and NAA/Cr - 1.64. Presence of lactate or lipid was noted in 90 % ( n= 9/10). Sites of lesion location were subcortical white matter ( n= 6), basal ganglia ( n= 4), corpus callosum ( n= 3), extra-axial space including cavernous sinus ( n= 5), cerebellum ( n= 1), and lateral ventricle ( n= 1). CONCLUSION Restricted diffusion is a consistent imaging finding in CNS lymphoma in immunocompetent patients. Spectroscopy is helpful in initial imaging diagnosis and post-treatment surveillance. These lesions are usually paraventricular in location. MR imaging appearances differ among immunocompetent and immunosuppressed individuals in most cases. [ABSTRACT FROM AUTHOR]

Objective – To measure the prevalence of computed tomography (CT)-detected cerebral lesions in a population-based sample of elderly persons living in Göteborg, Sweden. Methods – Cerebral CT-scans were performed in the case of 466 women (mean age 74.3 ± 5.1 years) and 191 70-year-old men. A single rater assessed white matter lesions (WML) using four different scales, lacunar lesions, large infarcts, cortical atrophy, and basal ganglia calcifications. Results – White matter lesions frequency assessed by different scales ranged between 54.5% and 68.5%. Lacunar lesions were detected in 46.7% (30.1% had lacunes >5 mm) and cerebral infarcts in 3.0% of participants. Overall, 72.8% of participants evidenced cerebral vascular abnormalities. Severe cortical atrophy was more common in temporal (6.4%) and frontal (6.7%) lobes, than in parietal (1.7%) and occipital (1.1%) lobes. Basal ganglia calcifications were found in 38.7% of participants. WML, lacunar lesions, large infarcts, and degree of cortical atrophy correlated positively with age. More lacunes, basal ganglia calcifications, and occipital lobe atrophy were associated with male gender. Conclusions – Vascular and other brain lesions are very common on CT-scan in an elderly population, but large vascular lesions are rare. This study provides the first reference for the prevalence of CT-detected abnormalities in an elderly Swedish population. [ABSTRACT FROM AUTHOR]

Background and purpose: We investigated whether patients with a lacunar infarct (LI) syndrome exhibiting unique LI or multiple LI on magnetic resonance imaging (MRI) examinations differed in terms of topography and severity of white matter hyperintensities (WMH) ratings. Methods: Forty consecutive patients with a first-ever acute LI, who presented a lacunar syndrome according to Miller–Fisher’s classification were recruited and were classified into a group presenting isolated LI on MRI ( n = 17) or multiple LI ( n = 23). Results: Despite equivalent demographic, clinical and cognitive characteristics, patients with multiple LI had increased ratings of WMH in frontal, occipital and subcortical regions. No significant correlations could be evidenced between the number of LI and WMH ratings. Conclusions: Present findings provide support to previous hypothesis considering single and multiple LI MRI presentations of lacunar infarct patients as distinct entities. [ABSTRACT FROM AUTHOR]

This paper reviews the main neurological complications of psychiatric drugs, in particular antipsychotics and antidepressants. Extrapyramidal syndromes include acute dystonia, parkinsonism, akathisia, tardive dyskinesia and tardive dystonia. Extrapyramidal symptoms (EPS) are less frequent with atypical than with conventional antipsychotics but remain common in clinical practice partly due to lack of screening by health professionals. Neuroleptic malignant syndrome (NMS) consists of severe muscle rigidity, pyrexia, change in conscious level and autonomic disturbance but partial forms also occur. NMS is particularly associated with the initiation and rapid increase in dose of high-potency antipsychotics but it has been reported with all the atypical antipsychotics and rarely with other drugs including antidepressants. Serotonin toxicity comprises altered mental state (agitation, excitement, confusion), neuromuscular hyperactivity (tremor, clonus, myoclonus, hyper-reflexia) and autonomic hyperactivity and occurs on a spectrum. Severe cases, termed serotonin syndrome, usually follow the co-prescription of drugs that increase serotonergic transmission by different pathways, for example a monoamine oxidase inhibitor (MAOI) and a selective serotonin reuptake inhibitor (SSRI). Most antipsychotics and antidepressants lower the seizure threshold and can cause seizures; the risk is greater with clozapine than with other atypical antipsychotics and greater with tricyclic antidepressants (TCAs) than with SSRIs. In randomised controlled trials in elderly patients with dementia atypical antipsychotics are associated with a higher risk of stroke and death than placebo. Cohort studies suggest that conventional drugs carry at least the same risk. Cessation of treatment with antipsychotics and antidepressants can lead to a wide range of discontinuation symptoms which include movement disorders and other neurological symptoms. Clinicians need to be familiar with strategies to reduce the risk of these adverse events and to manage them when they arise. Their occurrence needs to be balanced against the benefits of psychiatric drugs in terms of efficacy and improved quality of life in a range of disorders. Copyright © 2007 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Manganese neurotoxicity in humans is recognized as a form of parkinsonism with lesions occurring predominantly within the globus pallidus, subthalamic nucleus, putamen, and caudate nucleus.This study evaluated dopamine, 3,4‐dihydroxyphenylacetic acid, homovanillic acid, serotonin, norepinephrine, 5‐hydroxyindoleacetic acid, γ‐aminobutyric acid (GABA), and glutamate concentrations in the globus pallidus, caudate, and putamen of male rhesus monkeys exposed subchronically to either air or manganese sulfate (MnSO4) at 0.06, 0.3, or 1.5 mg Mn/m3.An approximate 1.5–6‐fold increase (vs. air‐exposed controls) in mean brain manganese concentration was observed following subchronic MnSO4 exposure. A marginally significant (P < 0.1) decrease in pallidal GABA and 5‐hydroxyindoleacetic acid concentration and caudate norepinephrine concentration occurred in monkeys exposed to MnSO4 at 1.5 mg Mn/m3.Despite the presence of increased tissue manganese concentrations, high‐dose exposure to MnSO4 was associated with relatively few changes in basal ganglial neurotransmitter concentrations. Am. J. Ind. Med. 50:772–778, 2007. © 2007 Wiley‐Liss, Inc. [ABSTRACT FROM AUTHOR]

There is lack of clarity in the literature over whether patients with Parkinson's disease (PD) show the same post-exercise depression of corticospinal excitability as is usually observed in healthy control. This study set out to resolve the problem. Ten patients with idiopathic PD and 10 age-matched controls were included in this study. Each subject performed a submaximal sustained voluntary contraction of the right first dorsal interosseous muscle (FDI) for 10 min or until force could no longer be sustained. Resting motor threshold, motor-evoked potential (MEP), input–output curve, cortical silent period duration, interference pattern (IP) and M/F ratio were recorded at baseline, immediately after fatigue and after 20 min rest. Immediately after exercise, decreased MEP amplitude and increased cortical SP duration were observed in the control group whilst no such changes were observed in PD patients. The input–output curve was also significantly suppressed only in controls, but not in patients. The amplitude of IP was significantly reduced immediately after exercise in both PD patients and controls. Almost all these changes returned nearly to baseline values after 20 min rest. The amount of exercise was approximately equal in both groups because the effect on M-waves and EMG amplitude was similar. However, the expected decline in corticospinal excitability was absent in PD patients. The absence of this effect in PD patients may reflect reorganization of motor commands in response to basal ganglia deficit. [ABSTRACT FROM AUTHOR]

Psychostimulants and other dopamine agonists produce molecular changes in neurons of cortico–basal ganglia–cortical circuits, and such neuronal changes are implicated in behavioural disorders. Methylphenidate, a psychostimulant that causes dopamine overflow (among other effects), alters gene regulation in neurons of the striatum. The present study compared the effects of acute and repeated methylphenidate treatment on cortical and striatal gene regulation in adolescent rats. Changes in the expression of the immediate–early genes zif 268 and homer 1a were mapped in 23 striatal sectors and 22 cortical areas that provide input to these striatal sectors, in order to determine whether specific corticostriatal circuits were affected by these treatments. Acute administration of methylphenidate (5 mg/kg, i.p.) produced modest zif 268 induction in cortical areas. These cortical zif 268 responses were correlated in magnitude with zif 268 induction in functionally related striatal sectors. In contrast, after repeated methylphenidate treatment (10 mg/kg, 7 days), cortical and striatal gene induction were dissociated. In these animals, the methylphenidate challenge (5 mg/kg) produced significantly greater gene induction ( zif 268 and homer 1a) in the cortex. This enhanced response was widespread but regionally selective, as it occurred predominantly in premotor, motor and somatosensory cortical areas. At the same time, striatal gene induction was partly suppressed ( zif 268) or unchanged ( homer 1a). Thus, repeated methylphenidate treatment disrupted the normally coordinated gene activation patterns in cortical and striatal nodes of corticostriatal circuits. This drug-induced dissociation in cortical and striatal functioning was associated with enhanced levels of behavioural stereotypies, suggesting disrupted motor switching function. [ABSTRACT FROM AUTHOR]

The molecular mechanisms that regulate basal ganglia development are largely unknown. Eph receptor tyrosine kinases are potential participants in this process as they regulate development of other CNS regions and are expressed in basal ganglia nuclei, such as the substantia nigra (SN) and striatum. To address the role of Eph receptors in the development of these nuclei, we analysed anatomical changes in the SN and striatum of mice with null mutations for EphB1. These mice express β-galactosidase as a marker for cells normally expressing EphB1. In situ hybridization data and a direct comparison of SN neurons expressing tyrosine hydroxylase (TH) and/or the β-gal marker for EphB1 revealed that EphB1 is not expressed in TH+ neurons of pars compacta (SNc), but is restricted to neurons in pars reticulata (SNr). Consistent with this, we find that EphB1 null mice exhibit a significant decrease in the volume and number of neurons (40% decrease) in SNr, whereas the volume and number of TH+ neurons in SNc is not significantly affected nor are there changes in the distribution of nigrostriatal dopamine neurons. Although EphB1 is expressed in the striatum, EphB1–/– mice exhibit no significant changes in striatal volume and TH fiber density, and have no obvious alterations in striatal patch/matrix organization. Behavioral evaluation of EphB1 null mice in an open-field environment revealed that these mice exhibited spontaneous locomotor hyperactivity. These results suggest that EphB1 is necessary for the proper formation of SNr, and that neuronal loss in SNr is associated with altered locomotor functions. [ABSTRACT FROM AUTHOR]

The objective of this study was to investigate the possible existence of gender-related neurophysiological differences in the oscillatory activity of the human subthalamic area. To this end, we recorded local field potentials (LFPs) after neurosurgical procedures for deep brain stimulation (DBS) in 24 patients (12 males and 12 females) with Parkinson's disease. LFP recordings at rest before levodopa medication (19 nuclei from 11 female patients and 16 nuclei from ten male patients) showed significantly higher power in the alpha/low-beta band (8–12 Hz, P < 0.01; 13–20 Hz, P = 0.03) in females than in males. After levodopa medication (ten nuclei from six female patients and 11 nuclei from seven male patients), the power in the high-gamma band (60–90 Hz) and of the 300 Hz rhythm was significantly higher in females than in males (high-gamma, P = 0.007; 300 Hz, P = 0.002). These findings show that functional gender-related differences in the central nervous system involve the human subthalamic area (STN) and its response to levodopa in Parkinson's disease. Gender-related neurophysiological differences may be important for understanding gender-specific features of neurodegenerative disorders and should be considered when interpreting LFP data from the human basal ganglia. [ABSTRACT FROM AUTHOR]

Several animal studies have shown that striatal dopamine can be released under direct control of glutamatergic corticostriatal efferents. In Parkinson's disease (PD), abnormalities in corticostriatal interactions are believed to play an important role in the pathophysiology of the disease. Previously, we have reported that, in healthy subjects, repetitive transcranial magnetic stimulation (rTMS) of motor cortex (MC) induces focal dopamine release in the ipsilateral putamen. In the present study, using [11C]raclopride PET, we sought to investigate early PD patients with evidence of unilateral motor symptoms. We measured in the putamen changes in extracellular dopamine concentration following rTMS (intensity, 90% of the resting motor threshold; frequency, 10 Hz) of the left and right MC. The main objective was to identify potential differences in corticostriatal dopamine release between the hemisphere associated with clear contralateral motor symptoms (symptomatic hemisphere) and the presymptomatic stage of the other hemisphere (asymptomatic hemisphere). Repetitive TMS of MC caused a binding reduction in the ipsilateral putamen of both hemispheres. In the symptomatic hemisphere, while the amount of TMS-induced dopamine release was, as expected, smaller, the size of the significant cluster of change in [11C]raclopride binding was, instead, 61.4% greater than in the asymptomatic hemisphere. This finding of a spatially enlarged area of dopamine release, following cortical stimulation, may represent a possible in vivo expression of a loss of functional segregation of cortical information to the striatum and an indirect evidence of abnormal corticostriatal transmission in early PD. This has potential implications for models of basal ganglia function in PD. [ABSTRACT FROM AUTHOR]

Severe chronic dopamine (DA) depletion increases the proportion of neurons in the basal ganglia that fire rhythmic bursts of action potential (LFO units) synchronously with the cortical oscillations. Here we report on how different levels of mesencephalic DA denervation affect substantia nigra pars reticulata (SNpr) neuronal activity in the rat and its relationship to akinesia (stepping test). Chronic nigrostriatal lesion induced with 0 (control group), 4, 6 or 8 µg of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle resulted in a dose-dependent decrease of tyrosine hydroxylase positive (TH+) neurons in the SN and ventral tegmental area (VTA). Although 4 µg of 6-OHDA reduced the number of TH+ neurons in the SN by ∼60%, both stepping test performance and SNpr neuronal activity remained indistinguishable from control animals. By contrast, animals that received 6 µg of 6-OHDA showed a marked reduction of TH+ cells in the SN (∼75%) and VTA (∼55%), a significant stepping test deficit and an increased proportion of LFO units. These changes were not dramatically enhanced with 8 µg 6-OHDA, a dose that induced an extensive DA lesion (> 95%) in the SN and ∼70% reduction of DA neurons in the VTA. These results suggest a threshold level of DA denervation for both the appearance of motor deficits and LFO units. Thus, the presence of LFO activity in the SNpr is not related to a complete nigrostriatal DA neuron depletion (ultimate stage parkinsonism); instead, it may reflect a functional disruption of cortico-basal ganglia dynamics associated with clinically relevant stages of the disease. [ABSTRACT FROM AUTHOR]

The basal ganglia are widely regarded as structures involved in sensorimotor co-ordination, but little is known about the sensory background of their function. We publish here descriptions of the excitatory sensory responses and receptive field properties of the visual, auditory, somatosensory and multisensory caudate nucleus and substantia nigra pars reticulata neurons. Altogether 111 caudate nucleus and 124 substantia nigra sensory neurons were recorded in halothane-anaesthetized, immobilized, artificially ventilated cats. The sensory properties of the caudate and nigral neurons were found to be quite similar. A majority of the units were unimodal while a significant proportion of them were multisensory. The visual and the somatosensory modalities predominated for both nuclei. The sensory receptive fields were extremely large. The visual and auditory receptive fields covered the whole physically approachable sensory field and the somatosensory receptive fields covered the whole body surface of the animal. The receptive field properties of the multisensory caudate and nigral units were similar to those of the unimodal neurons. We observed no signs of retinotopical or somatotopical organization within the basal ganglia. The particular sensory receptive field properties, together with the significant number of multisensory neurons in the basal ganglia, suggest the existence of a multisensory pathway of presumably tectal origin involving the caudate nucleus and the substantia nigra that may serve for the sensory feedback of motor actions co-ordinated by the basal ganglia. [ABSTRACT FROM AUTHOR]

Nuclei within the basal ganglia (BG), in particular the substantia nigra pars reticulata (SNr), subthalamic nucleus (STN) and caudate nucleus, are known to be involved in the generation of rapid or saccadic eye movements. Neurons in the SNr are active tonically and generally show a pause, but also increase, in discharge rate, for the appearance of visual stimuli and the generation of saccades. Recent experimental results in oculomotor regions of the brainstem reveal overlap in the neuronal pathways used for saccades and smooth pursuit, or slow tracking, eye movements. Whether the overlap of processing for saccades and pursuit extends to the oculomotor BG is unknown. In the present report, we were interested in whether the overlap between the pursuit and saccadic systems extends into the oculomotor BG. Using single-neuron recording and electrical stimulation techniques, we tested whether neurons within the saccade portion of the BG, the SNr, could be involved in smooth pursuit eye movements. Monkeys were required to follow visual targets with either a smooth eye movement or a saccade while we recorded from SNr neurons. We report here on SNr neuronal activity that was modulated during the performance of visually guided saccades and also during the initiation and the maintenance of smooth pursuit eye movements. Importantly, the modulation of neuronal activity during pursuit was present even when catch-up saccades were absent. The majority of SNr neurons was active tonically and their discharge ceased during pursuit, although some neurons also increased their discharge rate during smooth pursuit, similar to the behaviour reported for saccades. We also found that electrical stimulation of the SNr during the initiation of pursuit suppressed ipsiversive and, in some cases, enhanced contraversive pursuit. Our combined recording and stimulation results are consistent with the hypothesis that the overlap between the pursuit and saccadic systems extends, at least somewhat, into the BG and that the signal conveyed by the SNr can be used by the pursuit system. Like the signal for saccades, the SNr may provide a permissive disinhibition for pursuit eye movements. We hypothesize that alterations in this signal in BG diseased states such as Parkinson's may explain in part the deficits observed in smooth pursuit eye movements of these patients. [ABSTRACT FROM AUTHOR]

Brain–computer interfaces (BCIs) enable humans or animals to communicate or control external devices without muscle activity using electric brain signals. The BCI used here is based on self-regulation of slow cortical potentials (SCPs), a skill that most people and paralyzed patients can acquire with training periods of several hours up to months. The neurophysiological mechanisms and anatomical sources of SCPs and other event-related brain potentials have been described but the neural mechanisms underlying the self-regulation skill for the use of a BCI are unknown. To uncover the relevant areas of brain activation during regulation of SCPs, the BCI was combined with functional magnetic resonance imaging. The electroencephalogram was recorded inside the magnetic resonance imaging scanner in 12 healthy participants who learned to regulate their SCP with feedback and reinforcement. The results demonstrate activation of specific brain areas during execution of the brain regulation skill allowing a person to activate an external device; a successful positive SCP shift compared with a negative shift was closely related to an increase of the blood oxygen level-dependent response in the basal ganglia. Successful negativity was related to an increased blood oxygen level-dependent response in the thalamus compared with successful positivity. These results may indicate learned regulation of a cortico-striatal-thalamic loop modulating local excitation thresholds of cortical assemblies. The data support the assumption that human subjects learn the regulation of cortical excitation thresholds of large neuronal assemblies as a prerequisite for direct brain communication using an SCP-driven BCI. This skill depends critically on an intact and flexible interaction between the cortico-basal ganglia-thalamic circuits. [ABSTRACT FROM AUTHOR]

Although the subthalamic nucleus (STN) is involved in regulating motor function, and inactivation of this structure relieves the motor symptoms in Parkinsonian patients, recent data indicate that corticosubthalamic connections are involved in both the regulation of attention and the ability to withhold from responding. Considerable evidence suggests that the neural circuitry underlying such behavioural disinhibition or impulsive action can be at least partially dissociated from that implicated in impulsive decision-making and it has been suggested that the tendency to choose impulsively is related to the ability to form and use Pavlovian associations. To explore these hypotheses further, STN-lesioned rats were tested on the delay-discounting model of impulsive choice, where impulsivity is defined as the selection of a small immediate over a larger delayed reward, as well as in a rodent autoshaping paradigm. In contrast to previous reports of increased impulsive action, STN lesions decreased impulsive choice but dramatically impaired the acquisition of the autoshaping response. When the STN was lesioned after the establishment of autoshaping behaviour, lesioned subjects were more sensitive to the omission of reward, indicative of a reduction in the use of Pavlovian associations to control autoshaping performance. These results emphasize the importance of the STN in permitting conditioned stimulus–unconditioned stimulus associations to regulate goal-seeking, a function which may relate to the alterations in impulsive choice observed in the delay-discounting task. These data bear a striking similarity to those observed after lesions of the orbitofrontal cortex and are suggestive of an important role for corticosubthalamic connections in complex cognitive behaviour. [ABSTRACT FROM AUTHOR]

The immunoarchitectonics of the macaque motor thalamus was analysed to look for a possible neurochemical characterization of thalamic territories, which were not definable cytoarchitectonically, associated with different functional pathways. Thalamic sections from 15 macaque monkeys were processed for visualization of calbindin (CB), parvalbumin (PV), calretinin (CR) and SMI-32 immunoreactivity (ir). PV-, CR- and SMI-32ir distributions did not show any clear correlation with known functional subdivisions. In contrast, CBir distribution reliably defined two markedly distinct motor thalamic territories, one characterized by high cell and neuropil CBir (CB-positive territory), the other by very low cell and neuropil CBir (CB-negative territory). These two neurochemically distinct compartments, the CB-negative and the CB-positive territories, appear to correspond to the cerebellar- and basal ganglia-recipient territories, respectively. To verify the possible correspondence of the CB-negative territory with the cerebellar-recipient sector of the motor thalamus, we compared the distribution of cerebello-thalamic projections with the distribution of CBir in two monkeys. The distribution of cerebellar afferent terminals was similar to that reported from previous reports and in line with the notion that in the motor thalamus the cerebellar-recipient territory does not respect cytoarchitectonic boundaries. Comparison with CB immunoarchitecture showed very close correspondence in the motor thalamus between the distribution of the anterograde labeling and the CB-negative territory, suggesting that the CB-negative territory represents the architectonic counterpart of the cerebellar-recipient territory. CB immunostaining may therefore represent a helpful tool for describing the association between thalamocortical projections and the basal ganglia or the cerebellar loops and for establishing possible homologies between the motor thalamus of non-human primates and humans. [ABSTRACT FROM AUTHOR]

Treatment of schizophrenia with antipsychotics is often associated with extrapyramidal symptoms (EPS), a disorder involving involuntary muscle movement. Because EPS are often associated with the use of antipsychotics, anticholinergic agents are often indicated.In this observational, retrospective study, we examined whether the initiation of olanzapine or risperidone, the two most widely prescribed atypical antipsychotics, is related to the adjunctive use of anticholinergic agents.We identified patients with schizophrenia from outpatient clinics in the Veterans Health Administration (VA) and defined initiation of olanzapine or risperidone as patients who were not on any antipsychotics for 6 months and subsequently initiated on the target drug between 1/4/1999 and 31/3/2000. The data were analysed using tests of means or chi-square tests.The study yielded two major findings. First, compared with risperidone initiators, there were significantly fewer olanzapine initiators who used at least one anticholinergic agent adjunctively. Secondly, among olanzapine or risperidone initiators, patients who used at least one anticholinergic agent adjunctively tended to stay on the target drug significantly longer than those who did not use any anticholinergic agent adjunctively with the target drug.As the use of anticholinergics is a proxy for the presence of EPS, these findings suggest that risperidone may be more associated with EPS than olanzapine. However, to assess the benefits and side effects associated with olanzapine or risperidone, future research needs to examine various patient outcomes resulting from the initiation of each drug. [ABSTRACT FROM AUTHOR]

BTS 74 398 (1-[1-(3,4-dichlorophenyl)cyclobutyl]−2-(3-diaminethylaminopropylthio)ethanone monocitrate) is a monoamine reuptake inhibitor that reverses motor deficits in MPTP-treated (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) common marmosets without provoking established dyskinesia. However, it is not known whether BTS 74 398 primes the basal ganglia for dyskinesia induction. In this study, the ability of BTS 74 398 to sensitize 6-hydroxydopamine (6-OHDA)-lesioned rats for the production of abnormal motor behaviours and the induction of striatalΔFosB were determined in comparison withl-3,4-dihydroxyphenylalanine methyl ester (l-dopa). Acute administration of BTS 74 398 induced a dose-dependent ipsilateral circling response in unilaterally 6-OHDA-lesioned rats whereasl-dopa produced dose-dependent contraversive rotation. The ipsilateral circling response to BTS 74 398 did not alter during 21 days of administration. In contrast,l-dopa treatment for 21 days caused a marked increase in rotational response. Repeated administration of bothl-dopa and BTS 74 398 increased general motor activity and stereotypic behaviour. Inl-dopa-treated rats, orolingual, locomotive, forelimb and axial abnormal movements developed whereas BTS 74 398 produced only locomotion with a side bias but no other abnormal movements. Sensitization of circling responses and the development of abnormal movements in 6-OHDA-lesioned rats have been associated with the potential of dopaminergic drugs to induce dyskinesia. Furthermore, striatalΔFosB immunoreactivity, shown to correlate with dyskinesia induction, was increased byl-dopa but was unaffected by repeated BTS 74 398 administration. The lack of such changes following repeated BTS 74 398 treatment suggests that it may be an effective antiparkinsonian therapy that is unlikely to produce involuntary movements. [ABSTRACT FROM AUTHOR]

The basal ganglia are a group of subcortical nuclei classically thought to be involved in the control of movement, and they have reciprocal connections with the cortex, thalamus and structures in the brainstem. Recent findings suggest that the basal ganglia interact with structures involved in the control of the sleep–waking cycle. The pedunculopontine tegmental nucleus (PPN) maintains a close relationship with the basal ganglia and is intimately involved in the regulation of wakefulness and REM sleep. This study evaluated changes in activity of PPN neurons following striatal kainic acid-induced lesions. Rats were injected in the anterodorsal striatum with either kainic acid or vehicle and allowed to recover for 7 or 30 days. The results showed an increase in the number of c-Fos+ cells in the PPN 30 days but not 7 days after the striatal lesion, when motor hyperactivity was no longer detected. In addition, we found a significant correlation between the ventricular brain ratio, as an indicator of lesion size, and the number of c-Fos+ cells in the PPN. Furthermore, the spatial distribution of cell types suggested that most c-Fos+ cells in the PPN were not cholinergic. These results provide new insights into the functional relationship between the basal ganglia and the PPN and suggest that the striatum, through its indirect influence on the PPN, may contribute to the regulation of wakefulness and cortical activation. [ABSTRACT FROM AUTHOR]

Fractalkine is a unique chemokine reported to be constitutively expressed by neurons. Its only receptor, CX3CR1, is expressed by microglia. Lithe is known about the expression of fractalkine and CX3CR1 in spinal cord. Given that peripheral nerve inflammation and/or injury gives rise to neuropathic pain, and neuropathic pain may be partially mediated by spinal cord glial activation and consequent glial proinflammatory cytokine release, there must be a signal released by affected neurons that triggers the activation of glia. We sought to determine whether there is anatomical evidence implicating spinal fractalkine as such a neuron-to-glia signal. We mapped the regional and cellular localization of fractalkine and CX3CR1 in the rat spinal cord and dorsal root ganglion, under basal conditions and following induction of neuropathic pain, employing both an inflammatory (sciatic inflammatory neuropathy; SIN) as well as a traumatic (chronic constriction injury; CCI) model. Fractalkine immunoreactivity and mRNA were observed in neurons, but not glia, in the rat spinal cord and dorsal root ganglia, and levels did not change following either CCI or SIN. By contrast, CX3CR1 was expressed by microglia in the basal state, and the microglial cellular concentration was up-regulated in a regionally specific manner in response to neuropathy. CX3CR1-expressing cells were identified as microglia by their cellular morphology and positive OX-42 and CD4 immunostaining. The cellular distribution of fractalkine and CX3CR1 in the spinal circuit associated with nociceptive transmission supports a potential role in the mechanisms that contribute to the exaggerated pain state in these models of neuropathy. [ABSTRACT FROM AUTHOR]

There is growing experimental evidence for the implication of glutamate-mediated mechanisms both in the pathophysiology of Parkinson's disease and in the development of dyskinesias with long-term administration of L-3,4-dihydroxyphenylalanine (L-DOPA). However, the impact of this treatment on glutamate transmission in the basal ganglia has been poorly investigated. In this study, we examined the effects of 6-hydroxydopamine-induced lesion of nigral dopamine neurons with or without subsequent chronic L-DOPA treatment on several parameters of glutamate system function in the rat striatum and substantia nigra pars reticulata. All the lesioned animals treated with L-DOPA developed severe dyskinesias. Extracellular glutamate levels, measured by microdialysis in freely moving conditions, and gene expression of the glial glutamate transporter GLT1, assessed by in situ hybridization, were unaffected by dopamine lesion or L-DOPA treatment alone, but were both markedly increased on the lesion side of rats with subsequent L-DOPA treatment. No change in the expression of the vesicular glutamate transporters vGluT1 and vGluT2 was measured in striatum. These data show that chronic L-DOPA treatment leading to dyskinesias increases basal levels of glutamate function in basal ganglia. The L-DOPA-induced overexpression of GLT1 may represent a compensatory mechanism involving astrocytes to limit glutamate overactivity and subsequent toxic processes. [ABSTRACT FROM AUTHOR]

The anterior forebrain pathway (AFP) is a basal ganglia-dorsal forebrain circuit that is prominent specifically in birds that learn to sing. This circuit is interconnected with the song motor pathway, is active during song production, and contains neurons that are selective for the sound of the bird's own song, suggesting an important role for the AFP in vocal behavior. However, interruption of the AFP by lesions in adult birds has little overt effect on the production of learned song. In contrast, lesions in juvenile birds prevent the normal progression of song learning. Moreover, lesions in adults, while not disrupting production, can prevent experience-dependent plasticity of song. Such data implicate the AFP specifically in song learning and vocal plasticity. This chapter reviews some of the experimental evidence supporting a role for the AFP in these processes and discusses potential instructive and permissive functions of the AFP in vocal plasticity. [ABSTRACT FROM AUTHOR]

In contrast to the classic signal transduction of D1 dopamine receptors in striatum or molecular expression systems, it has been reported that D1 receptor agonists do not stimulate adenylate cyclase in homogenates of microdissected nuclei of the amygdaloid complex. This article examines this phenomenon in detail to determine if lack of cAMP signaling in the amygdaloid complex is an experimental artifact, or an indication of a marked difference from the well-studied basal ganglia terminal fields. Thus, whereas dopamine agonists failed to increase cAMP synthesis in the amygdala, forskolin, guanine nucleotides, or Mg2+ were able to stimulate adenylate cyclase activity in the same preparations. Under several different conditions, caudate preparations responded more robustly than amygdaloid preparations, while amygdala homogenates exhibited higher basal production of cAMP. Whereas the β-adrenergic agonist isoproterenol was able to stimulate cAMP efflux in membranes from both the caudate and amygdala under a variety of tested conditions, neither dopamine nor fenoldopam (D1 agonist) could stimulate adenylate cyclase in the amygdala. Additionally, while manipulation of Ca2+ and calmodulin affected the differential actions of dopamine in the caudate, no change in these parameters restored sensitivity to dopamine in the amygdala. Together, these data challenge the commonly accepted notion that cAMP is a mandatory signaling pathway for D1 receptors. Because it is now proven that G protein-coupled receptors can signal promiscuously, elucidation of the non-cAMP-dependent signaling mechanisms resulting from D1 activation is clearly critical in understanding how this important receptor functions in situ. Synapse 50:320–333, 2003. © 2003 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

1 The effect on rat catalepsy induced by δ[sup9]'-tetrahydrocannabinol (δ-THC) in association with haloperidol (HP) or clozapine (CLOZ) administration was investigated. 2 Δ[sup]-THC dose-dependently increased HP (0.05-1 mg kg[sup-1], S.C.)--induced rat catalepsy, while no catalepsy was observed after CLOZ (1 -20 mgkg[sup-1]. i.e.) or δ-THC + CLOZ administration. 3 The CB[sub1] antagonist SR141716A (0.5 5 mgkg[sup-1], i.p.) reversed the increase mediated by δ-9 -THC on HP-induced catalepsy, 4 The D[sup2] agonist quinpirole completely reversed the catalepsy induced by both HP and HP + δ[sup9] THC; however, higher doses of quinpirole were needed in the presence of δ[sup9]-THC. 5 The M[sup1] antagonist scopolamine and α[sup2] antagonist yohimbine were able to reduce the catalepsy induced by HP and HP + δ[sup9]-THC in a similar manner. 6 CLOZ and the 5-HT[sup2a/2c] antagonists ritanserin, RS10222I and SB242084 were more effective in antagonizing HP than HP + Δ[sup9]-THC-induced catalepsy. 7 HP and CLOZ failed to inhibit in vitro [[sup3]H]CP-55,940 binding, while δ[sup9]-THC and SR14I716A did not show an appreciable affinity for the D[sub2] receptor. 8 It was suggested that the different effects on rat catalepsy induced by &delta[sup9]-THC following HP or CLOZ administration may depend on the receptor-binding profiles of the two antipsychotics. 9 The preferential use of CLOZ rather than HP in the treatment of psychotic symptoms in cannabis abusers was discussed. [ABSTRACT FROM AUTHOR]

Objective To evaluate whether the relationship between extrapyramidal signs (EPS) and cognitive disturbances in Alzheimer's disease (AD) is influenced by illness duration. Methods A multivariate regression analysis was used to study the relationships between EPS, illness duration and five cognitive ability areas based on the Mattis Dementia Rating Scale (DRS) in 89 clinically diagnosed AD patients with extrapyramidal motor involvement. Results Severity of EPS was statistically associated with performance on four cognitive ability areas from the DRS including: attention, initiation and perseveration, construction and memory. Age was a significant factor related to severity of EPS. However illness duration did not contribute to the strength of the association between EPS and cognitive disturbances in patients with AD. Conclusions The findings of the present study support the notion that while neuropsychological and motor functions often coexist in patients with AD, their relationship seems to be unrelated to degenerative processes that accumulate throughout the illness. Copyright © 2001 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background and purpose: This study investigated whether incompleteness of the anterior part of the circle of Willis affects the occurrence of lacunes in the basal ganglia. Methods: One thousand and seventy-seven healthy individuals examined by magnetic resonance (MR) imaging and MR angiography were divided into eight subgroups according to our new classification. Results: Logistic regression analysis demonstrated that healthy individuals with incompleteness of the anterior circle of Willis had significantly higher frequency of lacunes [odds ratio (OR): 2.121, 95% confidence interval (CI): 1.477-3.108; or OR: 2.46, 95% CI: 1.377-4.384 in cases without or with fetal type posterior communicating artery, respectively] and higher numbers of lacunes ( P < 0.001 or P < 0.001 in cases without or with fetal type posterior communicating artery, respectively) compared to patients with complete circle of Willis. Conclusions: Incompleteness of the anterior part of the circle of Willis significantly affected the occurrence of lacunes. [ABSTRACT FROM AUTHOR]

Idiopathic basal ganglia calcification (IBGC) is a neuropathological condition known to manifest as motor disturbance, cognitive impairment, and psychiatric symptoms. The pathophysiology of the psychiatric symptoms of IBGC, however, remains controversial. A previous biochemical study suggested that dopaminergic impairment is involved in IBGC. We thus hypothesized that dopaminergic dysfunction might be related with the psychiatric manifestations of IBGC. We used positron emission tomography to measure glucose metabolism and dopaminergic function in the basal ganglia of an IBGC patient with psychiatric symptoms. The results showed that widespread hypometabolism was evident in the frontal, temporal, and parietal cortices while the decline in dopaminergic function was severe in the bilateral striatum. The functional decline of the dopamine system in the calcified area of the bilateral striatum and the disruption of cortico-subcortical circuits may contribute to clinical manifestations of IBGC in our patient. [ABSTRACT FROM AUTHOR]

There are several categories of neurologic dysfunction which have been associated with metal intoxication. Many examples of case histories or animal studies where toxicity by metals has produced clinical manifestations and pathophysiologic changes similar to those found in certain primary neurological disorders have been reported. It is easy to make a diagnosis of metal intoxication in a subject whose work history and circumstances of exposure to specific substances is known. Observation of defined safety standards and time weighted averages for a work day in conjunction with environmental monitoring procedures are intended to reduce risk of undue absorption of known potential intoxicants. However, when a patient is seen by a physician and a probable neurological diagnosis is to be made in the absence of a detailed life-work history, the possible relationship to previous or current intoxication may be overlooked. This communication will review several neurological syndromes which have been found in association with metal accumulation.