Dynamics of tremor-related oscillations in the human globus pallidus: a single case study

Physiological evidence indicates that the resting tremor of Parkinson's disease originates in oscillatory neural activity in the forebrain, but it is unknown whether that activity is globally synchronized or consists of parallel, independently oscillating circuits. In the present study, we used dual microelectrodes to record tremor-related neuronal activity from eight sites in the internal segment of the globus pallidus (GPi) from an awake Parkinson's disease patient undergoing stereotaxic pallidotomy. We utilized spectral analysis to evaluate the temporal correlations between multiunit activity at spatially separated sites and between neural and limb electromyographic activity. We observed that some GPi neural pairs oscillated synchronously at the tremor frequency, whereas other neural pairs oscillated independently. Additionally, we found that GPi tremor-related activity at a given site could fluctuate between states of synchronization and independence with respect to upper limb tremor. Consistent with this finding, some paired recording sites within GPi showed periods of transient synchronization. These observations support the hypothesis of independent tremor-generating circuits whose coupling can fluctuate over time.     

The behavioural effects of manipulating GABA function in the globus pallidus

Effects of drugs on precapillary vessels and oxygen uptake may differ from effects on resistance vessels and total flow in skeletal muscle. This study was performed to compare effects of phentolamine and isoproterenol, two drugs which are used to treat shock, on oxygen uptake in skeletal muscle. Oxygen uptake of gracilis muscle (GVO2) was measured in muscles perfused at constant flow or constant pressure in normotensive dogs. We compared effects of the drugs on oxygen uptake at doses chosen so that both drugs produced comparable effects on vascular resistance. With flow constant, phentolamine increased but isoproterenol decreased or did not alter GVO2. With constant pressure, phentolamine produced significantly greater increases in GVO2. For example, increases in GVO2 occurred with all three doses of phentolamine, but only with the high dose of isoproterenol. Neither drug altered oxygen-hemoglobin affinity of red blood cells or oxygen consumption of skeletal muscle in vitro. The results suggest that phentolamine produces more favorable effects than isoproterenol on oxygen uptake in skeletal muscle, presumably because of greater dilator action on precapillary sphincters.     

Left-right differences in motor thresholds after stimulation of the globus pallidus before pallidotomy

A family is presented in whom hereditary angioedema (HAE) and hereditary breast cancer were coexistent, an association not previously reported. A potential for genetic and treatment-related interactions between the two conditions exists. The use of the hormonal agent danazol to suppress HAE is unlikely to adversely affect the development or outcome of breast cancer. Surgery, chemotherapy, and radiotherapy were received by affected family members, without triggering edema. Whether hormonal breast cancer treatment affects the suppression of HAE by danazol remains unknown.     

A defective control of small-amplitude movements in monkeys with globus pallidus lesions: an experimental study on one component of pallidal bradykinesia

The effects of globus pallidus (GP) lesion were examined in two monkeys trained to perform a visually guided pointing movement in simple and choice reaction time tasks involving small and large amplitude movements. The reaction time (RT) and the movement time (MT) were measured. The Y-axis error (EY) was also analyzed in order to assess the movement accuracy. Unilateral GP lesion was made by locally injecting an excitatory amino acid, quisqualic acid. GP lesion led to little change in the RTs (simple and choice RTs) and in the EY, whereas a large increase in the MT occurred. The MT impairments seem to have been correlated with the movement amplitude, since they were larger in the case of small-amplitude than large-amplitude movements. These results suggest that the GP may be involved in the control of small-amplitude rather than large-amplitude movements. As various studies have shown that proprioceptive cues are more strongly involved in the control of discrete than large-amplitude movements, the MT deficit, i.e., the bradykinesia observed here, may reflect a defective integration of proprioceptive information occurring after GP lesion.     

Emotional and motivational changes after bilateral lesions of the globus pallidus.

This study investigated motivational changes in a 44 year-old man (PJ) who developed considerable reduction in spontaneous activity and speech, flat affect, social withdrawal, loss of interest, inability to "feel," and lack of concern regarding his medical condition after bilateral, focal, anoxic lesions of the globus pallidus. PJ and 30 male controls performed a task designed to parse hedonic evaluation, or liking, from incentive motivation, or wanting. Affective stimuli were presented on a computer screen and subjects controlled viewing time by pressing keys. PJ's liking and wanting of unpleasant stimuli was similar to that of controls. In response to pleasant stimuli, PJ showed normal ratings of wanting and hedonic appreciation, but significantly reduced viewing time or made no responses. Active withdrawal from liked stimuli could constitute the basic mechanism underlying poor motivation and social withdrawal associated with globus pallidus damage. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Manganese poisoning reduces strychnine-insensitive glycine binding sites in the globus pallidus of the mouse brain

Manganese (Mn) poisoning is characterized by central nervous system manifestations, including psychiatric disturbances and extrapyramidal disorders. This metal is thought to produce neuronal degeneration due to cytotoxic products originated by oxidative stress and through an indirect excitotoxic process. In previous studies, we have found a reduction in the density of N-methyl-D-aspartate (NMDA) recognition sites in some brain areas of Mn-treated mice. Due to the close relationship between NMDA sites and strychnine-insensitive glycine (Gly) modulatory sites in the NMDA receptor complex, the [3H]-glycine ([3H]-Gly) binding was analyzed by autoradiographic methods in the brain of mice treated with manganese chloride for 8 weeks. Among all analyzed areas, only the globus pallidus showed a significant reduction in [3H]-Gly binding (27-28%). The Gly binding decrease, focalized in the globus pallidus, could reflect a degeneration of structures containing strychnine-insensitive Gly receptors, since this area is the most frequently reported damaged brain region in Mn intoxication. However, it might also be due to a Gly receptor down-regulation to control NMDA complex activation during Mn poisoning.     

High signal intensity of globus pallidus on T1-weighted MRI in liver cirrhosis patients: clinical and pathological study

In some patients with liver cirrhosis, the globus pallidus shows high signal intensity on T1-weighted MRI. The relationship was examined between high signal intensity on T1-weighted images and pathological conditions such as liver function, portal venous pressure and metal concentrations in brain. The signal of the globus pallidus on T1-weighted imaging became highly enhanced in accordance with prolongation of prothrombin time, deterioration of ICG R15, or decrease in choline esterase and the Fisher ratio. Furthermore, the high signal intensity was also seen in patients with high portal pressure and large varices. In histopathological study, remarkable atrophy and loss of nerve cells were observed in globus pallidus with high signal intensity on T1-weighted imaging, changes that were similar to those in with patients with manganese poisoning. The manganese concentration in autopsied globus pallidus with high signal intensity on T1-weighted imaging showed a 9.5-fold increase compared with that with normal intensity. In conclusion, the deposition of manganese in the globus pallidus, which is accompanied with the nerve cell deciduation, brings about the high signal intensity of the globus pallidus on T1-weighted MRI in patients with liver cirrhosis.     

A patient with parkinsonism presenting hyperintensity in the globus pallidus on T1-weighted MR images: the correlation with manganese poisoning

We report a 55-year-old woman who developed symptoms resembling parkinsonism. Her psychiatric symptoms in the early stage, cervical dystonia and tremor increasing on movement were consistent with manganese poisoning. Manganese levels were elevated to 1.5 micrograms/l in the serum (normal; 0.3-1.1 micrograms/l) and to 1.4 micrograms/l in the urine (normal; less than 1.2 micrograms/l). Intravenous infusion of calcium disodium editate (CaEDTA; chelating agent) was followed by the marked excretion of manganese (27.3 micrograms/l) in the urine. These findings support manganese poisoning. Manganese poisoning is a disease which results from chronic exposure to manganese, but the source of manganese exposure remained obscure in this patient. T1-weighted MRI of the brain showed symmetric high signal intensity in the globus pallidus without any abnormality on T2-weighted images. There is a report that manganese induced brain lesions in Macaca fascicularis as revealed by MRI and the fascicularis developed signs of unsteady gait and hypoactivity. The patient responded to treatment with CaEDTA and the second MRI demonstrated regression of abnormal signal intensity. This may be due to enhanced manganese excretion. To our knowledge, this is the first case of probable manganese-induced human parkinsonism whom changes in MRI were noted after treatment with CaEDTA.     

Single subthalamic nucleus neurons project to both the globus pallidus and substantia nigra in rat

The organization of the major efferents of the rat subthalamic nucleus (STN) was investigated using a fluorescent retrograde double-labeling technique. Red fluorescent Evans Blue was injected into the globus pallidus and blue fluorescent DAPI-Primuline was injected into the substantia nigra. After retrograde axonal transport many double-labeled neurons were seen throughout the STN. Occasionaly double-labeled cells were seen in the lateral hypothalamus just medial to the STN and in a thin lateral strip of neurons extending laterally from the STN. Evidence for a mediolateral topography in both the STN-pallidal and STN-nigral pathways was obtained. The STN contains few, if any, local interneurons. Cell counts revealed that at least 94% of, and possibly all, STN neurons send axon collaterals to both the globus pallidus and substantia nigra.     

Perseverations during paired-associate learning in Huntington''s disease

Raw 30-MHz intravascular ultrasound data have been captured from postmortem coronary arteries (n = 4) to develop radio frequency analysis techniques for the characterisation of atherosclerotic plaque. Digitised data acquired from positions (n = 8) within diseased sections of artery were compared with the corresponding histology and radiology. Scan-converted images were used to locate regions of interest (ROI = 33) within areas of tissue composition: loose fibrotic tissue (LFT), dense fibrotic tissue (DFT) and calcium (CA). A range of parameters was extracted from the normalised power spectrum of each ROI within the bandwidth 17-42 MHz. Significant discrimination between LFT/DFT and between LFT/CA was provided by maximum power and spectral slope (dBMHz-1). However, the greatest discriminative power was given by the y-axis (0 Hz) intercept of the spectral slope: LFT/DFT (p = 0.001); LFT/CA (p = 0.0001); and DFT/CA (p = 0.089).     

Selective innervation of neostriatal interneurons by a subclass of neuron in the globus pallidus of the rat

A subpopulation of neurons in the globus pallidus projects to the neostriatum, which is the major recipient of afferent information to the basal ganglia. Given the moderate nature of this projection, we hypothesized that the pallidostriatal projection might exert indirect but powerful control over principal neuron activity by targeting interneurons, which comprise only a small percentage of neostriatal neurons. This was tested by the juxtacellular labeling and recording of pallidal neurons in combination with immunolabeling of postsynaptic neurons. In addition to innervating the subthalamic nucleus and output nuclei, 6 of 23 labeled pallidal neurons projected to the neostriatum. Both the firing characteristics and the extent of the axonal arborization in the neostriatum were variable. However, light and electron microscopic analysis of five pallidostriatal neurons revealed that each neuron selectively innervated neostriatal interneurons. A large proportion of the boutons of an individual axon (19-66%) made contact with parvalbumin-immunoreactive interneurons. An individual parvalbumin-immunoreactive neuron (n = 27) was apposed on average by 6.7 boutons (SD = 6.1) from a single pallidal axon (n = 2). Individual pallidostriatal boutons typically possessed more than one symmetrical synaptic specialization. In addition, 3-32% of boutons of axons from four of five pallidal neurons contacted nitric oxide synthase-immunoreactive neurons. Descending collaterals of pallidostriatal neurons were also found to make synaptic contact with dopaminergic and GABAergic neurons of the substantia nigra. These data imply that during periods of cortical activation, individual pallidal neurons may influence the activity of GABAergic interneurons of the neostriatum (which are involved in feed-forward inhibition and synchronization of principle neuron activity) while simultaneously patterning neuronal activity in basal ganglia downstream of the neostriatum.     

Sertraline in the treatment of severe aggressiveness in Huntington''s disease

Sertraline, a selective serotonin reuptake inhibitor, was used to treat two consecutive cases of genetically confirmed Huntington's disease in which severe irritability and aggressiveness required inpatient admission. The complete cessation of aggressive behavior in both cases has been maintained on follow-up. This report adds to the literature implicating serotonergic mechanisms in irritability and aggressiveness in both neuropsychiatric and idiopathic psychiatric disorders.     

Neurophysiological abnormalities in the Westphal variant of Huntington''s disease

Infants with cystic fibrosis (CF) often are infected with Staphylococcus aureus (S. aur.), which is followed by colonization with Pseudomonas aeruginosa (P. aerug.). In spite of an excessive, neutrophil-dominated inflammatory response in the respiratory tract, patients with CF often succumb to pulmonary infections with P. aerug. Because peripheral blood neutrophils of these patients have normal functions, we examined whether hypothesized alterations of the airway surface liquids (ASL) in these patients significantly impair neutrophil bactericidal activity in the microenvironment of the CF lung. The ionic composition of CF ASL is still not entirely defined and has been speculated to be abnormally high or abnormally low in Na+ and Cl- concentrations; estimates of osmolarities have ranged from 200 (hypo-osmolar) to 285 (iso-osmolar) to > 300 meq/L (hyper-osmolar). Our data indicate that bacterial killing activity of human peripheral blood neutrophils against P. aerug. or S. aur. is not decreased in buffers in which NaCl was replaced with equimolar concentrations of choline Cl, KCl, or N-methyl-D-glucamine chloride to maintain isotonicity. Amiloride or benzamil, known modulators of Na+ transport in neutrophils, did not interfere with this neutrophil function. Deviations from isotonicity of +/- 50% also failed to diminish bactericidal activity of neutrophils significantly. In contrast, superoxide production and enzyme secretion in response to the chemotactic peptide N-formylmethionylleucylphenylalanine appeared to be sensitive to the ionic milieu of the assay buffers. Our results suggest that the postulated alterations in the ionic composition of ASL in CF lungs are insufficient to explain why neutrophils fail to clear infections with P. aerug. in these patients.     

Electrophysiological and Fos immunohistochemical evidence for the excitatory nature of the parafascicular projection to the globus pallidus

Extracellular recordings and immunohistological detection of c-Fos-like immunoreactive proteins were used to determine the synaptic effect of the parafascicular projection to the globus pallidus. Electrical stimulation of the parafascicular neurons induced a single-spike excitatory response with a stable latency of 2.3 ms, suggesting a monosynaptically driven effect. Pharmacological stimulation of the parafascicular nucleus with carbachol increased tonically the pallidal discharge rate by 142%. The discharge rate of the pallidal neurons was described by 37% in parafascicular-lesioned rats. These results demonstrate the excitatory nature and the tonic action of the parafasciculopallidal projection. Carbachol activation of parafascicular neurons also induced the synthesis of c-Fos-like immunoreactive proteins in the pallidal neurons. Control experiments in subthalamic-lesioned rats showed that the parafascicular excitation of the pallidal neurons remained, but both electrophysiological and expression of c-Fos-like immunoreactive proteins were attenuated. This suggests that the direct parafascicular excitation of the pallidal neurons is indirectly reinforced by the previously described parafascicular excitatory input to the subthalamic nucleus. Conversely, the effect of this last input to the subthalamic nucleus is dramatically enhanced in rats with pallidal lesion. Our results demonstrate the complex role of the parafascicular nucleus in activating both the globus pallidus and the subthalamic nucleus, two closely related structures. These results illustrate the integrative capacities of the globus pallidus, whose activity is modulated by multiple afferents.     

Differential effects of unique profile antipsychotic drugs on extracellular amino acids in the ventral pallidum and globus pallidus of rats

The effects of antipsychotic drugs (APDs) on brain dopamine receptors in the striatum are ultimately expressed through efferent projections which primarily use amino acid transmitters, including gamma-aminobutyric acid and glutamate. The present study examined the effects of APDs on extracellular amino acid levels in the rat ventral pallidum (VP) and globus pallidus (GP), areas that receive projections from distinct striatal subregions. Clozapine, an APD with low motor side effect liability, and metoclopramide, a low-potency APD with high motor side effect liability, were compared with haloperidol, a widely used APD with high motor side effect liability. Drugs were administered subcutaneously and amino acid levels were monitored concurrently in the VP and GP by intracranial microdialysis. High doses of haloperidol and metoclopramide increased and clozapine decreased extracellular gamma-aminobutyric acid levels in the GP but not the VP. Low, but not high, doses of the three drugs tended to increase extracellular glutamate levels in both pallidal regions. Clozapine, but not the other two drugs, decreased extracellular threonine in the GP and glycine and threonine in the VP. Results indicate a correlation between increased gamma-aminobutyric acid levels in the GP and the propensity of the APDs tested to induce motor side effects. The novel effects of clozapine on extracellular glycine and threonine further distinguish this drug as a unique antipsychotic compound.     

Effect of switching off the globus pallidus on alimentary and electrophysiologic responses induced by stimulation of the hypothalamus]

In chronic experiments on eight cats a direct electrical stimulation of the lateral hypothalamus evoked: 1) food eating in a state of satiation and 2) a reproduction of a conditioned food-procuring reflex, preliminarily elaborated to an acoustic signal. Bilateral electrolytic ablation of the globus pallidum abolished both reactions, but for different time periods. The first one was restored spontaneously on the 20th to the 46th day; the second disappeared for 2.5 to 8.5 months without spontaneous restoration. Stimulation of the lateral hypothalamus alimentary zones brought about a statistically significant rise of the thresholds of desynchronization reactions in the ipsi- and contralateral sensorimotor cortex. The activating role of the globus pallidum in the organization of a motivational alimentary excitation is discussed.     

Activated immune system in patients with Huntington''s disease

Abnormalities of immune system compartments were determined in 12 patients with Huntington's disease (eight males, four females; age 42.4+/-11.7 years) and 11 controls (7 males, 4 females; age 47.0+/-12.0). All patients were free from infectious diseases. Serum concentrations of a panel of serum soluble markers of immune activation were investigated, namely neopterin, 55-kDa-type soluble tumor necrosis factor receptor (sTNF-R), interleukin-2-receptor (sIL-2R), kynurenine, tryptophan, immunoglobulins (Ig) A, M and G as well as routine laboratory tests. Compared to controls, we found significantly higher serum levels of IgA (p<0.01), sTNF-R, sIL-2R, neopterin, and complement component C3 (all p<0.05), and serum tryptophan was decreased (p<0.001). Higher concentrations of circulating immune complexes, cardiolipin antibodies, IgM, neopterin and lower tryptophan were associated with loss of cognitive function as assessed by the mini-mental-test. Five patients died within 1 year after measurements were performed. In these patients IgM, circulating immune complexes and neopterin concentrations were higher compared to survivors and serum tryptophan was lower. The data indicate an activation of various immune system compartments in Huntington's disease and that systemic immunological alterations might be important in the course of the disease.     

Disturbances of the rat motor activity during multiple microinjections of picrotoxin into the globus pallidus and caudal neostriatum

RNA-localization mechanisms involve specific sequences in the localized RNA and proteins that bind to these sequences and mediate the interaction with cytoskeletal elements. Until recently, it seemed as though two separate types of mechanisms were operating for mRNA localization--involving interaction with either microtubules or actin microfilaments. However, it is now clear that some of the protein components involved in mRNA localization can participate in both microtubule- and actin-dependent localization pathways. This, combined with new evidence for evolutionary conservation of some of these proteins, suggests a previously unanticipated uniformity in mRNA-localization mechanisms.