Extrapyramidal Function Research Articles

Characterization of swallowing and defecation in Parkinson's disease.

Despite the high prevalence of Parkinson's disease, the pathophysiology of its gastrointestinal symptoms remains poorly understood. to evaluate swallowing and defecatory function in patients with Parkinson's disease and age- and sex-matched controls and to correlate objective findings with subjective symptoms. The following studies were performed on 13 patients with Parkinson's disease and seven controls: extrapyramidal function assessment, gastrointestinal symptom survey, videoesophagram, colon transit study, defecography, and anorectal manometry. Abnormal salivation (frequency, %, control vs. Parkinson's disease: 14 vs. 77, p < 0.05), dysphagia (14 vs. 77, p < 0.05), constipation (14 vs. 31, p < 0.05), and defecatory dysfunction (29 vs. 77, p < 0.05) were more common among Parkinsonian patients. However, videoesophagographic abnormalities were equally common in both groups. Colon transit time was significantly prolonged in the Parkinson's disease group. Altered puborectalis function was noted on defecography in 31% of Parkinson's disease subjects, but in none of the controls (p < 0.05). Anorectal manometry identified several abnormalities in the Parkinson's disease group, which included decreased basal anal sphincter pressures, prominent phasic fluctuations on squeeze, and a hyper-contractile external sphincter response to the rectosphincteric reflex. Many patients exhibited both slow transit and manometric abnormalities, and symptoms were poor predictors of test results. In this group of patients with mild to moderate Parkinson's disease, videoesophagographic abnormalities were not confined to the patients with Parkinson's disease. Studies of colonic and anorectal function, in contrast, identified a number of abnormalities. Therefore, colonic and anorectal dysfunction appears to be an early gastrointestinal manifestation of Parkinson's disease, and may represent the direct involvement of the gut by this disease process.

The Neurologic Syndrome of Severe Alzheimer's Disease

To assess the possible association between functional decline and noncognitive neurologic signs in the severe stages of Alzheimer's disease (AD). Case series. Subjects from a dementia research referral center, longitudinally followed, when necessary, into residential home and nursing home settings. A consecutive sample of 56 patients (16 men, 40 women; mean age, 74.6 years) with a clinical diagnosis of probable AD in the moderately severe and severe stages. For global dementia severity, the Global Deterioration Scale and Mini-Mental State examination; for functional assessment, the Functional Assessment Staging Scale; and for assessment of neurologic function, nine release signs (primitive reflexes), 10 measures of extrapyramidal function, and five measures of pyramidal function, including deep-tendon reflexes and plantar signs. Changes in activity or presence of neurologic signs were rated on a seven-point scale. Results were analyzed in terms of prevalence and magnitude of change in relation to functional impairment. Prevalence and mean scores of certain release signs, certain extrapyramidal measures commonly referred to as bradykinesia, and certain pyramidal signs showed significant associations with the magnitude of functional impairment. Other neurologic measures, for example, the palmomental reflex, and certain extrapyramidal measures commonly seen in Parkinson's disease, including the glabellar blink reflex, cogwheeling, tremor, shuffling gait, and festination, did not show significant increments with continuing functional decline in AD. Functional decline in the advanced stages of AD appears to be associated with a particular combination of progressive cortical, extrapyramidal, and pyramidal system dysfunction. The characteristics of this neurologic syndrome of the severe stages of AD differ from those of other neurologic disorders. For example, the pattern of extrapyramidal system disease is different from that seen in Parkinson's disease. The neurologic syndrome of the severe stages of AD is amenable to description and deserves further investigation.

Major Neurological Disease and Occupational Exposure to Organic Solvents

Five patients are described who presented with major organic brain disease affecting one or more of pyramidal and extrapyramidal tracts, cerebellum, and higher cortical functions. All had a history of 10 years or more of regular occupational exposure to solvents in confined spaces, three in painting inside ships and the others in weapons maintenance and printing. All had been regularly exposed to high air vapour peaks as well as to skin contamination. Four showed some evidence of improvement after the exposure ceased. None was initially suspected of having a toxic encephalopathy by the consultant to whom he was referred. The spectrum of neurological disease presented by these men mirrors closely that described in solvent abusers. All were forced by illness to retire from their work, a circumstance which might have in the past have led to such conditions being missed in cross-sectional studies, which in general have not shown evidence of major disease. We suggest that when such disease occurs nowadays, its cause is usually not suspected. Further epidemiological study of the problem is necessary.

Dimensions of Outcome with Clozapine

Various outcome measures following clozapine administration to neuroleptic-resistant schizophrenic patients are considered. The importance of a multidimensional perspective is emphasised. There was significant improvement in positive symptoms, some negative symptoms, quality of life, some types of cognitive function (e.g. semantic memory), extrapyramidal function, and tardive dyskinesia. Readmission to hospital, and family burden were markedly reduced, which achieved significant savings in the cost of treatment. Compliance with clozapine and weekly blood testing can be achieved in the majority of treatment-resistant cases. These benefits may occur independently of each other.

Identification and localization of muscarinic acetylcholine receptor proteins in brain with subtype-specific antibodies

mRNAs encoding five genetically distinct muscarinic ACh receptors are present in the CNS. Because of their pharmacological similarities, it has not been possible to detect the individual encoded proteins; thus, their physiological functions are not well defined. To characterize the family of proteins, a panel of subtype-selective antibodies was generated against recombinant muscarinic receptor proteins and shown to bind specifically to each of the cloned receptors. Using immunoprecipitation, three receptor proteins (m1, m2, and m4) accounted for the vast majority of the total solubilized muscarinic binding sites in rat brain. These receptor subtypes had marked differences in regional and cellular localization as shown by immunocytochemistry. The m1-protein was present in cortex and striatum and was localized to cell bodies and neurites, consistent with its role as a major postsynaptic muscarinic receptor. The m2-receptor protein was abundant in basal forebrain, scattered striatal neurons, mesopontine tegmentum, and cranial motor nuclei; this distribution is similar to that of cholinergic neurons and suggests that m2 is an autoreceptor. However, m2 was also present in noncholinergic cortical and subcortical structures, providing evidence that this subtype may presynaptically modulate release of other neurotransmitters and/or function postsynaptically. The m4-receptor was enriched in neostriatum, olfactory tubercle, and islands of Calleja, indicating an important role in extrapyramidal function. These results clarify the roles of these genetically defined receptor proteins in cholinergic transmission in brain.(ABSTRACT TRUNCATED AT 250 WORDS)

黒質の色素神経細胞と非色素神経細胞の比率 正常加齢と錐体外路系疾患における検討

Based on 45 normal cases aged from 32 to 106 years of age, a morphometric study revealed that, despite decrease in the number of both pigmented neurons (PN) and the non-pigmented neurons (NN) with advancing age, the ratio (PN/NN) did not change (4.8). It is well-known that both the substantia nigra and the striatum send fibers to each other. McGee demonstrated that the ratio of the number of large neurons to that of small neurons was constant, irrespective of different ages, although number of both neurons decreased with ageing. It was therefore apparent that this phenomenon in the putamen was the same as in the substantia nigra. It could be considered that "balanced depopulation of different neurons" in the nucleus of the strio-nigral circuit contribute to support normal extrapyramidal functions. Additionally, the centenarian cases showed larger numbers of both PN and NN than younger case. It was likely that they could be classified as so-called "excellent" centenarians. On the other hand, idiopathic Parkinson's disease (15 cases) showed that while the same number of NN remained as in age-matched controls, PN showed marked depopulation. Olivopontocerebellar atrophy of the sporadic type (OPCA, 10 cases) and progressive supranuclear palsy (PSP, 5 cases) showed a decrease in number of both PN and NN. However, NN in PSP showed much more decrease than OPCA. NN sends fibers to the pontine tegmentum as well as the thalamus, and PSP shows marked atrophy of the brainstem tegmentum. In this connection, it was considered that marked decrease of NN in PSP could be related to tegmental atrophy.

Immunoreactive interleukin-1β localization in the rat forebrain

To determine whether the cytokine, interleukin-1β, is present in the rat brain as has been reported in human brain, immunocytochemical studies were performed using an antiserum that recognizes recombinant, rat IL-1β. Immunoreaction product was present in the periventricular and medial hypothalamus, mossy fiber distribution in the hippocampus and olfactory tubercle. These studies demonstrate that IL-1β is part of a diffuse intrinsic neural system in the rat central nervous system, associated with regions involved with hypophysiotropic, autonomic, limbic and extrapyramidal functions.

Striatal dopamine after cortical injury: A reexamination

We reevaluated the effects of unilateral sensorimotor cortex ablation on dopamine and dihydroxyphenylacetic acid concentrations in the left and right neostriatum. We found no evidence for an asymmetry of either dopamine or dihydroxyphenylacetic acid in control or sham-operated animals and cortical ablation had no effect on dopamine or dihydroxyphenylacetic acid concentrations. These results suggest that the influence of sensorimotor cortex lesions on extrapyramidal function does not involve changes in striatal dopamine concentrations or turnover.

Properties and distribution of vasoactive intestinal polypeptide receptors in the rat brain

Vasoactive intestinal polypeptide (VIP) interaction with the rat brain synaptic membrane was examined using 125I-labeled VIP as a tracer molecule. Ion, pH and incubation time significantly influenced VIP receptor binding. Scatchard analysis suggested that the rat brain membrane had a single binding site with an apparent dissociation constant (Kd) of 9.8×10 −9 M. The receptor activity was sensitive to trypsin and phospholipase A digestion, and heating at 100°C for 5 min completely destroyed the binding activity. This indicates that protein and phospholipid moieties are essential for VIP binding. Thiol reagents reduced receptor binding activity, suggesting that an intrachain disulfide bond might be an important constituent of the VIP binding site. High levels of binding were found in the hippocampus, striatum and cerebral cortex, and binding was very low in the medulla/pons and cerebellum. The receptor density did not always parallel the brain distribution of immunoreactive VIP (IR-VIP) concentration. The cerebral cortex had the highest ratio of IR-VIP-to-receptor, and the striatum had the lowest ratio of IR-VIP-to receptor. Although intra-nigral or intra-striatal injection of 6-hydroxydopamine had no effect on striatal VIP-binding, an intra-striatal injection of kainic acid resulted in a substantial lowering of striatal VIP receptors. The neurotoxic effects of kainic acid have been shown to be dependent on the corticostriatal tract, and this suggests that the striatum receives the VIPergic innervation from the cerebral cortex. Our findings indicate that endogenous VIP and VIP receptors might act as a neurotransmission modulator of extrapyramidal function in the striatum.

GABA and respiratory function

The inhibitory neurotransmitter y-aminobutyric acid (GABA) is involved in many CNS functions and in behaviour (see, e.g. Krogsgaard-Larsen et al., 1979; Mandel and DeFeudis, 1979, 1983; DeFeudis and Mandel, 1981; Okada and Roberts, 1982). Thus, GABA appears to play roles in the control of specific sensory systems (e.g. vision, audition), motor functions (e.g. posture and reflexes, extrapyramidal function) and homeostatic mechanisms (e.g. hormonal secretion, cardiovascular function, respiration). Review articles have already been written about the involvement of GABA in cardiovascular regulation (e.g. DeFeudis, 1981; Roberts and Krause, 1982) and in hormonal secretion (Racagni et al., 1982; DeFeudis, 1984). Herein, studies of GABA and respiratory function will be briefly discussed and analyzed.

The ascent of cholecystokinin (CCK) — From gut to brain

Cholecystokinin (CCK), a classical gastrointestinal polypeptide hormone, appears to have an equally important role as a brain neurotransmitter. CCK is widely distributed throughout both the central and peripheral nervous system. Of the known brain peptides, only CCK and VIP are predominately cerebral cortical peptides. In the pituitary, CCK is found in the posterior pituitary, while gastrin-like peptides are present in the anterior and intermediate lobes. Phylogenetically, gastrin-CCK-like peptides arose extremely early in evolution being present in the primitive nerve cells of the coelenterate, Hydra. Specific high affinity CCK-receptors have been demonstrated in rat and guinea-pig brains with highest concentrations in the cerebral cortex, caudate nucleus and olfactory bulb. Alterations in CCK binding have been reported during fasting and in genetically obese rats and mice. The low levels of CCK receptors in patients with Huntington's Chorea, the coexistance of CCK with dopamine in the same mesolimbic neurons and the rotational syndrome produced after central administration in rats suggests a potential physiological role for CCK in the regulation of extra-pyramidal function. CCK and/or gastrin have been demonstrated to have a number of effects on anterior pituitary hormones and the high concentrations in the posterior pituitary suggest a possible neuromodulatory role in the regulation of vasopressin and/or oxytocin release. CCK is a putative satiety hormone which appears to produce satiety both by peripheral and central effects. The presence of CCK in the periaqueductal gray and the fact that it produces naloxone reversible analgesia suggest a potential role for CCK in the regulation of pain perception. Central administration of CCK produces hyperglycemia which appears to be partly mediated via an adrenal mechanism. CCK also produces mild hypothermia and appears to be a central nervous system depressant. Present evidence indicating that CCK is a central neurotransmitter or neuromodulator includes its regional distribution with localization within neuronal cell bodies and axons; the demonstration that it can be synthesized in neuronal tissue; the fact that it is released by depolarizing stimuli in vitro ; the presence of specific, high affinity receptors for CCK in the brain; and the finding that it can activate isolated neurons. The high concentrations of CCK in the cerebral cortex suggest that future studies will produce further surprises concerning the physiological role of this gall-bladder contracting hormone which came of age with the discovery of its wide distribution in the central nervous system.

Cortical modulation of striatal function

The effect of bilateral section of the corticostriatal projections or of selective bilateral ablation of the frontal cortex on behavioral and biochemical parameters related to striatal function were investigated in the rat. Either lesion almost completely prevented the cataleptogenic action of haloperidol: this effect was observed as soon as 3 days and lasted for at least 3 months after surgery, paralleling a reduction in striatal glutamate uptake. Also, such lesions enhanced the apomorphine-induced stereotyped behavior (as measured 21 days after surgery). In the striatum, dopamine, dihydroxyphenylacetic acid, acetylcholine and substance P levels as well as choline acetyltransferase and glutamic acid decar☐ylase activities were unaffected 10 or 21 days after either type of lesion. In the substantia nigra, substance P levels were unchanged 10 days following suction of the frontal cortex, but glutamic acid decar☐ylase was reduced at 21 days postsurgery. Cortical lesions only partially prevented the reduction in striatal acetylcholine concentrations and did not affect the increase in striatal dihydroxyphenylacetic acid caused by haloperidol. Finally, lesions of the corticostriatal pathways failed to affect the apomorphine-induced increase in striatal acetylcholine levels, reduction of the potassium (20 mM) evoked [ 3H]acetylcholine release in striatal slices preloaded with [ 3H]choline and decrease of striatal dihydroxyphenylacetic acid concentrations. These findings indicate that the frontal cortex influences extrapyramidal function by a mechanism which — in behavioral terms — is antagonistic to dopamine-mediated events. As indicated by the biochemical data, this mechanism does not involve changes in striatal dopaminergic and cholinergic neuron activity. This mechanism may utilize: (1) corticostriatal glutamatergic neurons as suggested by the reduction in striatal glutamate uptake following lesions; and (2) GABAergic pathways as suggested by the reduction of nigral glutamic acid decar☐ylase activity as well as by the finding that GABA receptor agonists reinstate haloperidol-induced catalepsy.

Anatomical and biochemical basis of the extrapyramidal disorders

1. Degeneration of various components of the extrapyramidal system has been correlated with specific clinical syndromes. 2. In Parkinson's disease, loss of ascending nigrostriatal fibers is associated with reduction of presynaptic dopamine binding and increase of postsynaptic dopamine binding. The latter is reversed by treatment with dopamine agonists. 3. In Huntington's disease, multiple types of striatal neurons are lost, with their corresponding enzymes and receptors. 4. In tardive dyskinesias, there are no specific neuropathological findings, but increased amounts of striatal dopamine receptors. 5. Knowledge of the chemical nature of the pallidal outflow to the thalamus may be the next most important step in the pharmacological control of extrapyramidal function.

Physiological and behavioral studies with muscimol.

Muscimol has been used to increase our knowledge of central GABAergic systems, CNS physiology, and behavior. Some studies concerning the neurophysiological and behavioral effects of muscimol and its analogs have been reviewed and analyzed. In vivo iontophoretic studies have greatly increased our knowledge of the active conformation(s) adopted by GABA during its interaction with neuronal synaptic (or extrasynaptic) receptors, and behavioral studies have supported the notion that central GABAergic systems might be involved in convulsions, extrapyramidal functions, and other behaviors. However, behavioral studies with muscimol remain difficult to interpret in terms of central GABAergic systems, especially since muscimol is extensively metabolized and since it appears to interact with membrane sites other than GABA receptors. Muscimol does not appear to be useful for reversing human neurologic-psychiatric disorders.

Interaction of striatal dopaminergic, cholinergic and GABA-ergic neurons: relation to extrapyramidal function

Interaction of striatal dopaminergic, cholinergic and GABA-ergic neurons: relation to extrapyramidal function

The topographical distribution of serotoninergic terminals in the neostriatum of the rat and the caudate nucleus of the cat

The topographical distribution of serotoninergic terminals in the neostriatum of the rat and the caudate nucleus of the cat was established owing to the combined use of microdissection techniques and biochemical microassays. The density of 5-HT terminals in various areas of both structures was quantified first by measuring 5-HT levels in microdiscs of frozen tissue. Since the high affinity uptake process for 5-HT appeared undamaged in isotonic homogenates of previously frozen (−5 °C) tissues, it was possible to confirm the findings obtained with the measurement of 5-HT levels by also determining 5-HT uptake activity in these microdiscs. However, in the rat neostriatum, but not in the cat caudate nucleus, [ 3H]5-HT even at a very low extracellular concentration ( 4.4 × 10 −8 M ) was taken up not only by serotoninergic terminals but also to a significant extent by dopaminergic terminals. In presence of benztropine, this second component was suppressed and [ 3H]5-HT uptake activity could then be considered as a specific marker of serotoninergic terminals also in the neostriatum of the rat. In both species, 5-HT terminals were mainly localized in the ventrocaudal area of the structure. In this area, 5-HT levels were among the highest values found in the brain (17 ng/mg protein). The density of 5-HT terminals decreased progressively from the caudal to the rostral planes of the neostriatum in rats or the caudate nucleus in cats. The poorest area, i.e. the dorsorostral zone, contained about 4 times less 5-HT than the ventrocaudal zone of the structure. Electrolytic lesion of the dorsalis (B7) and centralis superior (B8) raphe nuclei during early life resulted in a large decrease of 5-HT levels (−90%) in various parts of the neostriatum of adult rats. The present findings might be of interest to further analyze the role of serotoninergic neurons in extrapyramidal functions.

Opposing effects of dopaminergic to cholinergic compounds on a cerebral dopamine-activated adenylate cyclase.

In contrast to antipsychosis drugs which inhibit the dopamine-activated adenylate cyclase [ATP pyrophosphate-lyase (cyclizing), EC 4.6.1.1] of caudate nucleus, dopaminergic drugs for treatment of Parkinson's disease stimulate this cyclase. Stimulants and inhibitors of cholinergic neurons inhibited this adenylate cyclase activity competitively and specifically. Thus, the mechanism by which dopaminergic medications ameliorate the effects of Parkinson's disease includes activation of the dopamine-sensitive adenylate cyclase. Excessive activation might be present during the psychotic episodes seen in patients with parkinsonism who are overtreated. The enzymatic effects of the drugs that affect cholinergic mechanisms seem to be generally in keeping with the pharmacological reciprocity between psychoses and extrapyramidal function, except for the anticholinergic ones which inhibited this cyclase although they can be hallucinogenic.

Aging and extrapyramidal function.

Measurements on human brain samples of some enzymes concerned with neurotransmitter synthesis suggest serious losses with age. The most severe loss found was that in striatal tyrosine hydroxylase activity, the rate-controlling enzyme in the synthesis of dopamine. Cell counts in the substantia nigra where this dopaminergic tract originates suggest that the decrease in enzyme activity is partly due to cell loss, but must largely reflect decreased activity of residual cells. It is possible that this loss may account for some of the difficulties in movement seen in aged individuals and that it might be less if pigment formation in these cells could be inhibited.

Blepharospasm-oromandibular dystonia syndrome (Brueghel's syndrome). A variant of adult-onset torsion dystonia?

Thirty-nine patients with the idiopathic blepharospasm-oromandibular dystonia syndrome are described. All presented in adult life, usually in the sixth decade; women were more commonly affected than men. Thirteen had blepharospasm alone, nine had oromandibular dystonia alone, and 17 had both. Torticollis or dystonic writer's camp preceded the syndrome in two patients. Eight other patients developed toritocollis, dystonic posturing of the arms, or involvement of respiratory muscles. No cause or hereditary basis for the illness were discovered. The evidence to indicate that this syndrome is due to an abnormality of extrapyramidal function, and that it is another example of adult-onset focal dystonia akin to spasmodic torticollis and dystonic writer's cramp, is discussed.

The importance of extrapyramidal function for the induction and antagonism of harmine tremor

The brain lesion technique was used to investigate the role of paleostriatum and the nigro-neostriatum in harmine-induced tremor and in its antagonism by dopaminergic agonists, apomorphine, l-dopa, piribedil, d- and l-amphetamine. Bilateral lesions of the caudate-putamen or substantia nigra failed to modify the intensity of tremor or its antagonism by dopaminergic agonists. Bilateral lesions of the globus pallidus markedly reduced the intensity of tremor and the results indicated that such lesions were also able to reduce the effectiveness of dopaminergic agonists as tremor antagonists. The data suggest that the integrity of the paleostriatum is more important than that of the neostriatum for the mediation of harmine tremor and its antagonism by dopaminergic agonists. The results are discussed in relation to the proposed clinical relationship between paleostriatal dopamine dysfunction and tremor mechanisms.