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PubMed2005

G protein-activated inwardly rectifying K+ channel inhibition and rescue of weaver mouse motor functions by antidepressants.

Antidepressants, including tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs), have been widely used for the treatment of not only depression but also other psychiatric disorders, although the molecular mechanisms of the drug effects have not yet been sufficiently revealed. Here, we investigated the in vivo effects of these antidepressants on G protein-activated inwardly rectifying K+ (GIRK) channels, which are important for regulating the excitability of various cells, by using weaver (wv) mice, which have mutant GIRK channels and show abnormal neuronal cell death and motor disturbances. First, we found that a widely used SSRI fluoxetine (also known as Prozac) effectively inhibited wv GIRK2 channels like wild-type GIRK channels, expressed in Xenopus oocytes. Next, we found that weaver motor disturbances were remarkably alleviated by chronic treatment with fluoxetine or desipramine. Furthermore, the chronic fluoxetine treatment substantially suppressed the abnormal neuronal cell death in the weaver mouse cerebellum and pontine nuclei. These results suggest that continuous inhibition of wv GIRK2 channels by a group of antidepressants caused substantial suppression of the neuronal cell death and resulted in improvement of motor abilities in weaver mice. These results provide evidence for in vivo GIRK channel inhibition by a group of antidepressants.

Animals↗

PubMed1989

Blockade of only spinal alpha 1 adrenoceptors is insufficient to attenuate DDT-induced alterations in motor function.

Male Fischer 344N rats were chronically implanted with an intrathecal cannula and gavaged with p,p'-DDT (1,1,1-trichloro-2,2-bis[p-chlorophenyl]ethane; 30 or 45 mg/kg) or corn oil. Seven hours later, subjects were intrathecally infused with vehicle, 15, 30, 60, or 120 micrograms of prazosin (an alpha 1-adrenergic antagonist). Spectral analysis of bodily movements was performed 7.5, 8, and 10 hr after DDT administration. In control rats, 15 micrograms of prazosin reduced the spectral profiles of spontaneous movements. A 30-micrograms dose produced motor impairments, without significantly changing the spectral profiles. Tremulous movements induced by DDT were unaffected by 15 or 30 micrograms, whereas 60 or 120 micrograms of intrathecal prazosin significantly reduced the spectral profiles of rats pretreated with 45 mg/kg of DDT. Other subjects were administered vehicle or DDT (45 mg/kg), intrathecally infused with 15 or 60 micrograms of prazosin (7 hr), and sacrificed (7.5 hr). Noncannulated rats were gavaged with 60 mg/kg of DDT, injected subcutaneously (sc) with 0.5 mg/kg of prazosin (5.5 hr), and sacrificed (8 hr). Cortical and spinal tissues were used in ex vivo binding assay utilizing [3H]prazosin. Fifteen or sixty micrograms of intrathecal prazosin occupied similar percentages of spinal [3H]prazosin binding sites, but produced a dose-related increase in cortical prazosin equivalents. Sixty micrograms of intrathecal or 0.5 mg/kg of sc prazosin resulted in similar concentrations of cortical prazosin equivalents. Together, these data indicate that while intrathecal prazosin will attenuate DDT-induced motor dysfunction, this effect requires blockade of alpha 1 adrenoceptors in regions other than solely the spinal cord.

Analysis of Variance↗

PubMed1997

Intracerebroventricular glial cell line-derived neurotrophic factor improves motor function and supports nigrostriatal dopamine neurons in bilaterally 6-hydroxydopamine lesioned rats.

In order to evaluate the efficacy of glial cell line-derived neurotrophic factor (GDNF) in a model of advanced Parkinson's disease, we studied rats with extensive bilateral lesions of the nigrostriatal pathway. Adult male F344 rats were injected bilaterally into the medial forebrain bundle with the neurotoxin 6-hydroxydopamine. Locomotor ability as measured by total distance traveled in an open field over 20 min, as well as von Frey hair testing of sensorimotor neglect, was monitored weekly. Rats demonstrating severe motor impairment and sensorimotor neglect were used for this study and were sorted to achieve similar average behavioral scores between the two treatment groups. After 2 weeks of pretesting, the rats received 250 microg GDNF or vehicle injected into the right lateral cerebral ventricle. Three weeks later, an additional 500 microg GDNF or vehicle was injected into the contralateral ventricle. The rats were monitored for another 2 weeks prior to sacrifice. Behavioral results indicated that von Frey hair scores were inconsistent between tests for each rat and were unchanged following GDNF treatment. However, GDNF recipients demonstrated significant improvement in locomotor ability compared to vehicle recipients. High-pressure liquid chromatography-electrochemical detection analysis of neurotransmitter levels revealed a significant increase in dopamine content within the substantia nigra and ventral tegmenta, but not the striata, of GDNF-treated rats. Further, immunohistochemical staining of tissues from matched pairs of rats revealed increased numbers of tyrosine hydroxylase-positive ventral mesencephalic neurons in one of the two pairs of rats examined. These results suggest that intracerebroventricular GDNF administration improves motor ability and supports nigrostriatal dopaminergic neurons in a model of severe Parkinson's disease.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1990

Effect of methylprednisolone on motor function and spinal cord blood flow after spinal cord compression in rats.

The effect of methylprednisolone (MP) on neurologic recovery and spinal cord blood flow (SCBF) was investigated up to 4 days after a spinal cord compression injury in rats. The injury was produced at midthoracic level by applying a load of 35 g on a 2.2 x 5.0 mm compression plate for 5 min, which resulted in transient paraparesis. MP was given as a bolus dose of 30 mg/kg i.v. 60 min after injury (n = 20) and controls were given saline (n = 10). The motor performance was assessed daily as the capacity angle on the inclined plane and SCBF was measured by 14C-iodoantipyrine autoradiography on Days 1 or 4. On Day 1 the capacity angle was reduced from about 63 degrees preoperatively to 33 +/- 2 degrees (mean +/- SEM) in the control group and to 50 +/- 1 degrees in the group treated with MP (p less than 0.05). Thereafter there was a slight improvement in both groups, but the difference persisted throughout the observation period. On Day 4 both gray and white matter SCBF was better preserved in MP-treated animals than in the control group (59 +/- 4 versus 49 +/- 3 ml/min/100 g tissue for gray matter and 13.6 +/- 0.6 versus 10.7 +/- 0.8 ml/min/100 g tissue for white matter). Posttraumatic treatment with MP, thus, improved both the neurologic recovery during the first 4 days and SCBF as measured on Day 4. It is speculated that the effect of MP is at least partly exerted on the vascular bed.

Animals↗

PubMed1986

Quantitative measurement of interresponse times to assess forelimb motor function in rats.

Eight rats were trained to use their left paw to rapidly press the right lever of an operant chamber once and the left lever twice to obtain a food reward. Between-levers interresponse times and same lever interresponse times were measured daily for several weeks before and after bilateral removal of frontal motor/sensory cortex. This surgery resulted in a permanent deficit in most rats' ability to rapidly alternate between levers, but resulted in only a temporary deficit in their ability to rapidly press the same lever. Sham surgery and removal of hindlimb motor cortex had little immediate effect on interresponse times. The data demonstrate that sequential motor behavior tested in the between-levers tasks is chronically affected by cortical lesions, but the speed of the same repetitive movement tested in the same lever task is not. Measuring the time to rapidly alternate between two different levers, therefore, provides a quantitative method for measuring acute and chronic forelimb motor deficits due to motor cortex injury in rats which could be applied to any mammal.

Animals↗

PubMed1990

Pyloric motor function during emptying of a liquid meal from the stomach in the conscious pig.

1. In six conscious pigs antral, pyloric and duodenal pressures were recorded with a 5.5 cm sleeve sensor and multiple perfused side holes. The manometric assembly was positioned by dual point transmucosal potential difference measurement. Gastric emptying was measured by drainage of the proximal duodenum through a Thomas cannula. Pressures were correlated with emptying of ingested radiolabelled 5% dextrose. Alteration of emptying was produced by infusion into the more distal duodenum of nutrient and non-nutrient solutions of differing osmolalities. 2. Motor activity of the pylorus and antrum was stimulated by ingestion and modulated by intraduodenal infusion. Duodenal infusion of normal saline was associated with antro-pyloric pressure waves and rapid emptying of the ingested liquid. Duodenal infusion of dextrose, fatty acid, amino acids and hyperosmolar saline was associated with stimulation of isolated pyloric pressure waves, suppression of antral pressure waves and slowing of gastric emptying. 3. The dose-response relationship of these effects was investigated using varying rates of intraduodenal dextrose infusions. The emptying rate of the ingested liquid was inversely related to the rates of delivery of dextrose to the duodenum, directly related to the rate of antro-pyloric pressure waves and inversely related to the rate of isolated pyloric pressure waves. 4. Clearly defined episodes of pulsatile flow produced slightly more than half of the total emptying that occurred. This pulsatile flow was intimately associated in time with antro-pyloric pressure waves. Sequences of isolated pyloric pressure waves were associated with near cessation of emptying. When there were periods of absent pyloric antral pressure waves, flow rates intermediate between the rapid emptying of pulsatile flow during antro-pyloric pressure waves and the near cessation of flow during isolated pyloric pressure waves occurred. 5. The findings suggest a major role for the pylorus in the control of emptying of liquids from the stomach, both as a component of an antro-pyloric peristaltic pump and as a resistor to transpyloric flow during nutrient and hyperosmolar stimulation of duodenal receptors.

Animals↗

PubMed1993

Visual and sensory-motor functioning in the classroom: a preliminary report of ergonomic demands.

Observations were made in 11 4th and 5th grade classrooms of the specific ergonomic conditions including physical space, lighting conditions, and academic task demands placed on the students. The data indicate remarkable homogeneity, including the findings that light levels were consistently lowest in the front of the classroom, and that more than 50 percent of the students' time involved near task demands. Observations of behavioral compliance with the task demands will be discussed. We conclude that classroom ergonomic conditions require extensive near work and students with ocular motor dysfunctions may have difficulty meeting the behavioral expectations of the classroom. Implications for future research will be discussed.

Child↗

PubMed1980

Effect of bile acid perfusion on colonic motor function in patients with the irritable colon syndrome.

A study was performed to determine the effect of bile acid perfusion on motility in the sigmoid colon of patients with the irritable colon syndrome compared with normal subjects. Deoxycholic acid (15 mM) statistically significantly increased motility in normal subjects (control 25.0 +/- 6.4%, perfusion 71.4 +/- 7.2%, P < 0.05) but neither chenodeoxycholic acid nor cholic acid had any apparent effect. In patients with the irritable colon syndrome, however, deoxycholic acid at 5 mM concentration (control 29.8 +/- 4.2%, during perfusion 57.4 +/- 6.5%, P < 0.05) as well as at 15 mM concentration (control 19.4 +/- 5.7+, perfusion 57.8 +/- 9.6%, P < 0.05) statistically significantly increased rectosigmoid motility. Patients with the irritable colon syndrome had a high resting 0.033-0.066 Hz (2-4 c/m) electrical activity, whereas in normal subjects 0.1-0.15 Hz (6-9 c/m) activity was greater. However, there was no statistically significant alteration in either electrical rhythm during the period of bile acid perfusion. In conclusion, additional evidence is presented to suggest that deoxycholic acid is the only bile acid likely to be implicated in the motor disorder of the irritable colon syndrome.

Bile Acids and Salts↗

PubMed1977

Body weight: its relation to tissue composition, segment distribution, and motor function. II. Development of Macaca mulatta.

The relative composition of skin, muscle, and bone and their distribution patterns throughout the body are given for a series of Macaca mulatta from 171 days conceptual age through adulthood. In terms of percent of total body weight, the musculature of these animals doubles during the firs postnatal year whereas bone and skin decrease. Regionally, the muscles of the thighs, back extensors, truncal-forelimb and upper arms increase most markedly. The thighs double and the upper arms increase whereas the trunk, hands, feet, and tail decrease. The biomechanical implications of these changes for motor development are discussed.

Age Factors↗

PubMed1994

Compartmentalization of pattern-initiation and motor functions in the B31 and B32 neurons of the buccal ganglia of Aplysia californica.

1. The B31 and B32 cells in the buccal ganglia of Aplysia californica have unusual electrophysiological features. The somata of these strongly coupled cells do not sustain conventional action potentials. Brief depolarization of the soma produces a complex, sustained regenerative slow depolarization that is followed by a hyperpolarization. This activity in B31/B32 is correlated with a patterned burst of activity expressed in many of the neurons of the buccal ganglia. 2. Intracellular fills of B31/B32 showed that they have many neurites adjacent to the soma, as well as peripheral axons leaving the buccal ganglia via the radular nerve and innervating the Intrinsic-2 (I2) muscle of the buccal mass. Varicosities of B31/B32 axons are seen within the muscle. Backfills from I2 filled two adjacent B31/B32 cells as well as two newly identified neurons: B61 and B62. 3. Intracellular recording from the B31/B32 axons shows that they sustain conventional action potentials. These are recorded in the soma as approximately 10-mV fast depolarizations. Failed spikes in B31/B32, and conventional spikes in B61/B62, are correlated one for one with end-junction potentials (EJPs) in the I2 muscle. The EJPs are present even when the ganglia and muscles are bathed in high-divalent cations seawater. Thus B31/B32 and B61/B62 are motor neurons to the I2 muscle. 4. To determine whether the ability of B31/B32 to initiate patterned bursts is mediated by spikes in the axon or by slow potentials in the soma, the B31/B32 axon was stimulated directly while recording from the B31/B32 soma. Patterned bursts were never seen in the absence of slow potentials in the soma. Thus the ability of B31/B32 to initiate patterned bursts is localized to the soma and adjacent neurites. Slow potentials influence and cause spiking in adjacent neurons even in the absence of axon spikes. 5. These data show that the B31/B32 cells serve two functions that are compartmentalized in different regions of the cell and are mediated via different electrical signaling mechanisms. The B31/B32 somata utilize slow, sustained potentials as part of a network initiating patterned activity in the buccal ganglia. The B31/B32 axons utilize conventional action potentials, and act as motor neurons to the I2 muscle.

Animals↗

PubMed2004

Quantified measurement of activity provides insight into motor function and recovery in neurological disease.

BACKGROUND: A direct quantitative measurement of locomotor activity in an individual's own environment over an extended period may help in evaluating the impact of impairments in neurological disorders. OBJECTIVE: To investigate the reliability and validity of activity monitoring in neurological patients and healthy subjects. METHODS: Initial reliability studies were completed on 10 healthy subjects and 10 mobility restricted neurological patients. Validity was investigated using 7 days of ambulatory monitoring with the Step Watch( step activity monitor, laboratory based measures of gait and the Rivermead Mobility Index (RMI) in 10 patients with multiple sclerosis, 10 with Parkinson's disease, and 10 with a primary muscle disorder. Additionally, 30 healthy subjects participated in the study. Two clinical illustrations of ambulatory monitoring are provided. RESULTS: The mean (range) right step count of 7 days of monitoring in both healthy and neurological patients proved a reliable measure of activity (intra-class correlations 0.89 and 0.86 respectively). The 7 day mean (range) right step count was 5951 (2886-9955) in healthy subjects, 3818 (1611-5391) in patients with Parkinson's disease, 3003 (716-5302) in those with muscular disorders, and 2985 (689-5340) in those with multiple sclerosis. A moderate correlation was noted between 7 day mean step count and gait speed (r = 0.45, p = 0.01) in the grouped neurological patients but not the RMI (r(s) = 0.3, p = 0.11). CONCLUSION: Ambulatory monitoring provides a reliable and valid measure of activity levels. Neurological patients, living independently, demonstrate lower activity levels than healthy matched controls. Ambulatory monitoring as an outcome measure has potential for improving the evaluation of ambulation and providing insight into participation.

Adult↗

PubMed2003

Intravenous administration of bone morphogenetic protein-7 after ischemia improves motor function in stroke rats.

BACKGROUND AND PURPOSE: We and others have previously reported that bone morphogenetic protein-7 (BMP-7), given before middle cerebral artery occlusion (MCAO), reduces ischemic injury in brain. Recent studies have indicated that receptors for BMP are upregulated after brain ischemia. It is possible that this upregulation may facilitate endogenous neurorepair in the ischemic brain. The purpose of this study was to determine the neuroregenerative effects of BMP-7 given parenterally after ischemia/reperfusion injury. METHODS: Adult Sprague-Dawley rats were anesthetized with chloral hydrate. The middle cerebral artery was transiently occluded by a filament inserted through the right internal carotid artery. The filament was removed after 60-minute ischemia to allow reperfusion. Some animals were killed 24 hours after MCAO to examine BMP-7 mRNA expression. Other animals received a single dose of intravenous BMP-7 or vehicle at 24 hours after MCAO and were used for subsequent behavioral studies and BMP-7 immunostaining. RESULTS: BMP-7 mRNA was upregulated 24 hours after MCAO in untreated animals. BMP-7 immunoreactivity was dose-dependently increased on the ischemic side of the hippocampus/dentate on day 6 after MCAO in animals receiving intravenous injection of BMP-7. Animals receiving BMP-7 also showed a decrease in body asymmetry from day 7 to day 14 and an increase in locomotor activity on day 14 after MCAO. CONCLUSIONS: Our data indicate that BMP-7, given parenterally after stroke, can pass through the blood-brain barrier on the ischemic side and induce behavioral recovery in stroke animals at longer testing times.

Animals↗

PubMed2001

Over-expression of inducible HSP70 chaperone suppresses neuropathology and improves motor function in SCA1 mice.

Many neurodegenerative diseases are caused by gain-of-function mechanisms in which the disease-causing protein is altered, becomes toxic to the cell, and aggregates. Among these 'proteinopathies' are Alzheimer's and Parkinson's disease, prion disorders and polyglutamine diseases. Members of this latter group, also known as triplet repeat diseases, are caused by the expansion of unstable CAG repeats coding for glutamine within the respective proteins. Spinocerebellar ataxia type 1 (SCA1) is one such disease, characterized by loss of motor coordination due to the degeneration of cerebellar Purkinje cells and brain stem neurons. In SCA1 and several other polyglutamine diseases, the expanded protein aggregates into nuclear inclusions (NIs). Because these NIs accumulate molecular chaperones, ubiquitin and proteasomal subunits--all components of the cellular protein re-folding and degradation machinery--we hypothesized that protein misfolding and impaired protein clearance might underlie the pathogenesis of polyglutamine diseases. Over-expressing specific chaperones reduces protein aggregation in transfected cells and suppresses neurodegeneration in invertebrate animal models of polyglutamine disorders. To determine whether enhancing chaperone activity could mitigate the phenotype in a mammalian model, we crossbred SCA1 mice with mice over-expressing a molecular chaperone (inducible HSP70 or iHSP70). We found that high levels of HSP70 did indeed afford protection against neurodegeneration.

Animals↗

PubMed1993

The relationship between visuospatial ability and perceptual motor function in Parkinson's disease.

To assess the contribution of visuoperceptual function to complex visuomotor responding in Parkinson's disease, 14 patients with idiopathic PD and 12 normal controls matched for age, education and general intellectual function were administered a visual tracing task. No difference was found between the groups on two visuoperceptual tests, the Benton Line Orientation test and a test of trajectory judgement. However, patients were significantly impaired in tracing a sawtooth design when two consecutive angles of the sawtooth were occluded. This impairment occurred in reproducing the basic form of the stimulus and not with accuracy of fine detail. These results suggest higher-order perceptual motor dysfunction independent of any breakdown in basic visuoperceptual processing or loss of fine motor control. It is concluded that Parkinsonian patients are unable to use sensory information accurately to plan and execute complex or new movements.

Activities of Daily Living↗

PubMed2004

The role of cutaneous sensation in the motor function of the hand.

We studied the effect of abolishing cutaneous sensation (by infiltrating local anaesthetic around the median nerve at the wrist) on the ability of 10 healthy volunteers (a) to maintain a submaximal isometric pinch-grip force for 30 s without visual feedback, and (b) to perform a fine finger-manipulation 'handwriting' task. Blocking cutaneous sensation had no effect on ability to maintain pinch force, suggesting that muscle afferents have the major role in force-control feedback. However, a near-linear fall in force, present with or without block (mean slope=-1.3+/-0.2% s(-1)), which cannot be attributed to motor fatigue, reveals a shortcoming of the afferent feedback system. Blocking cutaneous sensation did impair ability to perform the more demanding writing task, as judged by an 18+/-6% increase in the length of the path between target points, a 22+/-9% increase in the duration of the movement and a 63+/-24% in 'normalised averaged rectified jerk', an averaged time-derivative of acceleration (all significantly nonzero, P < 0.04). These experiments demonstrate the relative importance of muscular and cutaneous afferent feedback on two aspects of hand performance, and provide a way to quantify the deficit resulting from the lack of cutaneous sensation.

Electromyography↗

PubMed1991

Delayed neuropsychiatric sequelae after acute hydrogen sulfide poisoning: affection of motor function, memory, vision and hearing.

A shipyard worker was poisoned by hydrogen sulfide (H2S), and rescued after 15-20 min. He regained consciousness after 2 days. Three days later his condition deteriorated, and he was more or less comatose for a month. When he woke up, he was amnesic, nearly blind, had reduced hearing, and had a moderate spastic tetraparesis and ataxia. Two months after the accident, he had greatly improved. Audiograms showed hearing loss with maximum at 2000 Hz and significantly poorer speech discrimination. EEG showed generalized dysrhythmia. At follow-up 5 years later he had not been able to resume his work, and had slight motor, memory and visual symptoms. CT and MRI showed slight cerebral atrophy. EEG and evoked responses were normal.

Adult↗

PubMedDate not supplied

Improvement of motor function in multiple sclerosis by use of protopam chloride.

PAM, a cholinesterase reactivator, was administered orally and parenterally to 37 patients with multiple sclerosis and a control group of 24 patients with other neurological diseases and pain syndromes. The effects of the administration of this compound in these patients with and without electrical stimulation of the spinal cord were studied. The clinical response to the drug follows a known time course and is dose related. Administration of large doses orally or intravenously aggravates existing neurological dysfunction. With a dose of 1,000 mg intravenously, a characteristic response is the temporary appearance of new ophthalmological abnormalities, followed by significant improvement in motor control and behavior, which gradually subsides. Parenteral administration is superior to oral. Tolerance to the drug is observed. The presence of electrical stimulation of the spinal cord complements the action of the drug. When electrical stimulation is withdrawn, the effect of the drug reproduces the effect of the electrical stimulation. It is suggested there is a defect in cholinesterase in multiple sclerosis patients, and its reactivation may have a significant relationship to signs and symptoms.

Administration, Oral↗

PubMed2000

Visual-motor function of very low birth weight and full-term children at 3 1/2 to 4 years of age.

Improvements in perinatal and neonatal management have not only led to a higher survival rate of very low birth weight infants (VLBW; < or = 1,500 g or < 32 weeks gestational age), but also to a better outcome of these children. However the percentage of VLBW children who need special education because of later school problems remains high even in children considered neurologically normal during infancy. We assessed 40 VLBW children and 83 healthy full-term children at age 3 to 4 years by means of a simple and short test for visual-motor deficits. The test included the copying and cutting-out of geometric shapes, the building of models, the recognition of colours and the observation of the concentration and cooperation during the test. All VLBW children had had a good perinatal outcome and had been considered neurologically normal at one year of age. Most VLBW children scored within 1 standard deviation (S.D.) of the test mean, but on average the VLBW children scored significantly lower than the full-term infants in the copying of figures, the cutting-out of geometric forms, the building of models and in the overall concentration and cooperation during the test. Children who attended a nursery school achieved significantly better test results. Girls tended to have better results, but this was not statistically significant. Social factors and age had a significantly greater impact on results than perinatal factors. In summary, VLBW children scored significantly less in almost every test item compared to their term peers. Our test battery could serve as a short introductory test to screen for deficits in visual-motor skills, especially in VLBW children.

Adolescent↗