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Mice with the deleted neurofilament of low molecular weight (Nefl) gene: 2. Effects on motor functions and spatial orientation.

Mice with a null mutation of the Nefl gene were compared with normal controls in tests of motor activity, equilibrium, and spatial orientation. Despite a normal capacity to ambulate, NFL -/- mice had fewer rears in an open field, crossed fewer segments on stationary beams, and fell more frequently when suspended on a horizontal bar. In addition, the distance swum before reaching the escape platform was greater in NFL -/- mice than in controls during acquisition of place learning in the Morris water maze at the start of training. The motor impairments were linearly correlated with increased cytochrome oxidase activity seen in cerebellum and brainstem. These results indicate that, as early as 6 months, depletion of the NFL protein is sufficient to cause mild sensorimotor dysfunctions and spatial deficits, but without overt signs of paresis.

Amyotrophic Lateral Sclerosis↗

Acoustic startle response, prepulse inhibition, and spontaneous locomotor activity in MPTP-treated mice.

Parkinson's disease (PD) is marked by characterised motor deficits and is accompanied by a severe degeneration of the nigrostriatal dopamine (DA) pathway. It has also been reported that PD patients exhibited additional behavioural deficits, including a deficiency in sensorimotor gating mechanisms. We therefore examined whether the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD in mice could lead to a sensorimotor gating deficit in the prepulse inhibition (PPI) of the acoustic startle response (ASR) paradigm. Two MPTP treatment schedules were separately examined here in male C57BL/6 mice. Post-mortem HPLC analysis confirmed that they were effective in depleting DA in the dorsal striatum (75-88%). PPI was evaluated on days 2, 9 and 16 after the last MPTP treatment; spontaneous locomotor activity was assessed 24 h before each PPI test. No significant change in the expression of PPI was detected across the three time points. On the other hand, the MPTP treatment reduced activity on post-treatment day 1. This effect subsided on post-treatment day 8, and was reversed on day 15. The possibility remains therefore that the reported sensorimotor gating deficits in PD patients might stem from structural or neurochemical aberrations beyond those induced by MPTP treatment.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

Deficits of anticipatory grip force control after damage to peripheral and central sensorimotor systems.

Healthy subjects adjust their grip force economically to the weight of a hand-held object. In addition, inertial loads, which arise from arm movements with the grasped object, are anticipated by parallel grip force modulations. Internal forward models have been proposed to predict the consequences of voluntary movements. Anesthesia of the fingers impairs grip force economy but the feedforward character of the grip force/load coupling is preserved. To further analyze the role of sensory input for internal forward models and to characterize the consequences of central nervous system damage for anticipatory grip force control, we measured grip force behavior in neurological patients. We tested a group of stroke patients with varying degrees of impaired fine motor control and sensory loss, a single patient with complete and permanent differentation from all tactile and proprioceptive input, and a group of patients with amyotrophic lateral sclerosis (ALS) that exclusively impairs the motor system without affecting sensory modalities. Increased grip forces were a common finding in all patients. Sensory deficits were a strong but not the only predictor of impaired grip force economy. The feedforward mode of grip force control was typically preserved in the stroke patients despite their central sensory deficits, but was severely disturbed in the patient with peripheral sensory deafferentation and in a minority of stroke patients. Moderate deficits of feedforward control were also obvious in ALS patients. Thus, the function of the internal forward model and the precision of grip force production may depend on a complex anatomical and functional network of sensory and motor structures and their interaction in time and space.

Afferent Pathways↗

Properties of cerebello-precerebellar reverberating circuits.

Intracellular recordings were made from neurons of the red nucleus (RN) in cats where the cerebellar cortical effects were removed by chronic ablation of the intermediate part of the anterior lobe of the cerebellum. A prolonged depolarization could be elicited by stimulating the nucleus interpositus (IP) of the cerebellum, nucleus reticularis tegmenti pontis (NRTP) and the nucleus reticularis paramedianus (PMRN). This prolonged depolarization was abolished after cooling the inferior and middle cerebellar peduncles and persisted after ablation of the cerebral sensorimotor cortex. The prolonged depolarization was also recorded intracellularly from IP neurons. It was concluded that the prolonged depolarization set up in RN neurons is due to the repetitive discharges of IP neurons which produces tonic bombardment onto RN cells. The mechanisms of the repetitive discharges of IP neurons are considered to be due to impulse reverberation via the IP. The dynamic properties of the reverberating circuits were characterized by regenerative behavior. Above and below threshold, there were two states, the excited state where many constituent neurons were active, and the resting state where all neurons were inactive. It was found that cats with chronically stimulated cerebral peduncle (CP), and tested in an acute experiment, showed sometimes effective for inducing the prolonged depolarization and repetitive discharges of RN neurons by stimulation of IP. The prolonged depolarization thus produced could be reversibly abolished by cooling the middle and inferior cerebellar peduncles. The possible constituent neurons of the reverberating circuits were investigated in light of previous physiological investigations of stimulating the NRTP, PMRN, nucleus reticularis lateralis (LRN), nucleus olivaris inferior (IO) and recording EPSPs in RN cells. The RN cells receive axon reflex activation from NRTP and PMRN, and disynaptic excitation from NRTP, PMRN, LRN and IO. Based on these and other available data, the components of the cerebello-precerebellar reverberating circuits are discussed.

Animals↗

Motor subcircuits mediating the control of movement extent and speed.

The functional correlates of movement extent, speed, and covariates were investigated using PET mapping of regional cerebral blood flow (rCBF) in 13 healthy right-handed adults. A whole-arm smooth pursuit tracking task was used to strictly control potential confounds such as movement duration, error, and feedback control. During each of four scans, images of relative rCBF were obtained while subjects matched the constant velocity movements of a target using a joystick-controlled cursor. Between scans, subjects were completely adapted to one of four joystick-to-cursor gains, thereby allowing constant visual stimulation and eye movements across arm movements that ranged in extent from 6 to 24 cm. Subjects were unaware of the changes in visuomotor gain. Analyses of arm and eye movements indicated that the only significant difference in behavior across the four gain conditions was the extent and velocity of arm movements, which were closely correlated with each other. Parametric statistical methods identified brain areas where rCBF covaried with the mean movement extent of individual subjects during individual scans. Increasing movement extent was associated with parallel increases of rCBF in bilateral basal ganglia (BG; putamen and globus pallidus) and ipsilateral cerebellum. Modest extent effects were detected also in the sensorimotor cortices bilaterally. No significant inverse relations were found. We conclude that a small subcircuit within the motor control system contributes to the control of movement extent and covariates and that the BG and cerebellum play central roles in the operation of that circuit.

Adult↗

Neural substrates of two different rhythmical vibrissal movements in the rat.

Normal rats show two types of rhythmical vibrissal movement, one synchronized precisely with alpha waves (about 9 Hz) of the thalamocortical system, and the other often synchronized with theta waves (about 7 Hz) of the septohippocampal system. The alpha-synchronized vibrissal movements appear while the rat stands still with a slow respiratory pattern, and are of small amplitude (a fine tremor). The theta-synchronized vibrissal movements appear during exploratory sniffing behavior, and are of large amplitude. Thus, a group of facial motoneurons which constitute the final common pathway for vibrissal movement apparently receive input convergently from these two neural systems. In the present study, we observed the following: (1) the two types of movement rarely, if ever, appeared simultaneously and the same was true of the two brain wave patterns. Topographically, the predominant appearance of the alpha waves was in the frontal (sensorimotor) cortex, whereas that of the theta waves was in the occipital cortex and hippocampus. (2) Bilateral ablation of either the entire neocortex or just its anterior (but not posterior) half eliminated the vibrissal alpha-tremor movement while leaving vibrissal theta-sniffing movement normal. In anterior decorticate rats, the tremor movements started to recover by 1-4 months, and were abolished again by the removal of the remaining posterior cortex. (3) Lesions of the medial septum or the fornix eliminated hippocampal theta waves, but had no effect on vibrissal sniffing movement or alpha wave-vibrissal tremor. (4) Cerebellectomy and, to a lesser extent, pharmacological lesions of the inferior olive slowed, but did not block, alpha waves. In addition, vibrissal tremor movement became intermittent and less vigorous. The same manipulations, however, did not affect theta wave-vibrissal sniffing movement. (5) Harmaline (30 mg/kg, i.p.) did not induce alpha-tremor, which, in combination with the results with cerebellectomy and inferior olive lesions, indicates that alpha-tremor is generated by a neural mechanism that is different from that for harmaline-induced generalized tremor of 10 Hz. These findings confirmed that there exist two patterns of synchrony between vibrissal movement and rhythmical brain activity in the rat, i.e. alpha wave-vibrissal tremor movement and theta wave-vibrissal sniffing movement, and suggest that the two patterns reflect a rhythmical mode of functioning of two different neural systems, probably the thalamocortical and the septohippocampal system, respectively.

Animals↗

Behavioral and neuroplastic changes in the blind: evidence for functionally relevant cross-modal interactions.

The study of blind individuals provides insight into the brain re-organization and behavioral compensations that occur following sensory deprivation. While behavioral studies have yielded conflicting results in terms of performance levels within the remaining senses, deafferentation of visual cortical areas through peripheral blindness results in clear neuroplastic changes. Most striking is the activation of occipital cortex in response to auditory and tactile stimulation. Indeed, parts of the "unimodal" visual cortex are recruited by other sensory modalities to process sensory information in a functionally relevant manner. In addition, a larger area of the sensorimotor cortex is devoted to the representation of the reading finger in blind Braille readers. The "visual" function of the deafferented occipital cortex is also altered, where transcranial magnetic stimulation-induced phosphenes can be elicited in only 20% of blind subjects. The neural mechanisms underlying these changes remain elusive but recent data showing rapid cross-modal plasticity in blindfolded, sighted subjects argue against the establishment of new connections to explain cross-modal interactions in the blind. Rather, latent pathways that participate in multisensory percepts in sighted subjects might be unmasked and may be potentiated in the event of complete loss of visual input. These issues have important implications for the development of visual prosthesis aimed at restoring some degree of vision in the blind.

Adaptation, Psychological↗

A test for detecting long-term sensorimotor dysfunction in the mouse after focal cerebral ischemia.

The mouse is an excellent model for investigations of stroke and neural injury. However, there is a paucity of long term functional outcome measurements for the mouse. We, therefore, developed a sensorimotor functional test (corner test) and applied this test to a model of focal cerebral ischemia in the mouse. Male C57/6J mice (n=20) were subjected to embolic middle cerebral artery (MCA) occlusion. Reduction of cerebral blood flow (CBF) was measured by perfusion weighted MRI at 1 h after ischemia. The corner test, which is sensitive to chronic sensorimotor and postural symmetries, a general neurological test battery, and a foot fault test were performed between 2 and 90 days after ischemia. Infarct volume was measured at 90 days after ischemia. Multivariable analysis revealed that the corner test was highly predictive for infarct volume measured at 90 days after stroke, with R(2) values ranging from 0.73 to 0.93. The foot-fault test and neurological score did not detect chronic behavioral impairments. A significant (P<0.001) correlation between the infarct volume and the corner test was detected at 90 days after mild focal cerebral ischemia, whereas, there was no correlation between the infarct volume and neurological score or foot-fault. The data demonstrate that the corner test is a sensitive and objective test, which can be applied to evaluate long term functional outcome after stroke in the mouse.

Animals↗

Biology of the congenitally hypothyroid hyt/hyt mouse.

The hyt/hyt mouse has an autosomal recessive, fetal onset, characterized by severe hypothyroidism that persists throughout life and is a reliable model of human sporadic congenital hypothyroidism. The hypothyroidism in the hyt/hyt mouse reflects the hyporesponsiveness of the thyroid gland to thyrotropin (TSH). This is attributable to a point mutation of C to T at nucleotide position 1666, resulting in the replacement of a Pro with Leu at position 556 in transmembrane domain IV of the G protein-linked TSH receptor. This mutation leads to a reduction in all cAMP-regulated events, including thyroid hormone synthesis. The diminution in T3/T4 in serum and other organs, including the brain, also leads to alterations in the level and timing of expression of critical brain molecules, i.e. selected tubulin isoforms (M beta 5, M beta 2, and M alpha 1), microtubule associated proteins (MAPs), and myelin basic protein, as well as to changes in important neuronal cytoskeletal events, i.e. microtubule assembly and SCa and SCb axonal transport. In the hyt/hyt mouse, fetal hypothyroidism leads to reductions in M beta 5, M beta 2, and M alpha 1 mRNAs, important tubulin isoforms, and M beta 5 and M beta 2 proteins, which comprise the microtubules. These molecules are localized to layer V pyramidal neurons in the sensorimotor cortex, a site of differentiating neurons, as well as a site for localization of specific thyroid hormone receptors. These molecular abnormalities in specific cells and at specific times of development or maturation may contribute to the observed neuroanatomical abnormalities, i.e. altered neuronal process growth and maintenance, synaptogenesis, and myelination, in hypothyroid brain. Abnormal neuroanatomical development in selected brain regions may be the factor underlying the abnormalities in reflexive, locomotor, and adaptive behavior seen in the hyt/hyt mouse and other hypothyroid animals.

Animals↗

The contributions of motor cortex, nigrostriatal dopamine and caudate-putamen to skilled forelimb use in the rat.

Skilled forelimb use was studied in rats with unilateral lesions of the sensorimotor cortex, the caudate-putamen, or the dopaminergic nigrostriatal bundle, in a task involving reaching for food. Limb preference and efficiency were evaluated, as well as the relationship between limb use, spontaneous, and methamphetamine-induced rotation bias, both preoperatively and postoperatively. To induce use of the nonpreferred limb, a bracelet, which prevented reaching but not other movements, was attached to the forearm of the preferred forelimb. Whereas small cortical lesions of the forepaw area of the sensorimotor cortex mildly influenced limb preference and use, larger lesions changed preference. Furthermore, medium-sized sensorimotor cortex lesions impaired contralateral limb use, although surprising recovery occurred on the forced tests with the bracelet. Large cortical lesions abolished effective reaching even on the forced tests. Impairments similar to those following sensorimotor cortex lesions were also obtained following small and large caudate-putamen lesions. By contrast, unilateral dopamine depletions not only blocked use of the limb contralateral to the depletion but also impaired use of the ipsilateral limb. There was recovery in use of the ipsilateral forelimb but not the contralateral forelimb. Correlational analysis showed a weak relation between methamphetamine-induced rotation and limb preference preoperatively but no significant relation between these two variables postoperatively. The similarity in the deficits following sensorimotor cortex lesions and basal ganglia lesions suggests that skilled forelimb use depends upon a shared neural organization within the two systems.

Animals↗

BOLD fMRI signal increases with age in selected brain regions in children.

To determine whether the BOLD signal used in fMRI is age dependent in childhood, 332 healthy children (age 4.9-18.9 years) performed tasks in a periodic block design during 3 T fMRI: (1) a verb generation task interleaved with a finger tapping task; (2) a word-picture matching task interleaved with an image discrimination task. Significant correlations between percent signal change in BOLD effect and age occurred in left Broca's, middle frontal, Wernicke's, and inferior parietal regions, and anterior cingulate during the verb generation task; in precentral, postcentral, middle frontal, supplementary motor, and precuneus regions during the finger tapping task; and in bilateral lingula gyri during the word-picture matching task. Thus, BOLD effect increases with age in children during sensorimotor and language tasks.

Adolescent↗

Effect of chronic neonatal morphine and naloxone on sensorimotor and social development of young rats.

Chronic morphine treatment of newborn Long-Evans rat pups between 3-26 days of age (thrice daily starting with 0.5 mg/kg, increased daily by 0.5 mg/kg to 10 mg/kg) led to lags of 1 to 3 days in physical development (body weights and eye opening times) and motor coordination (catalepsy test, grasping, swimming). Chronic naloxone treatment (5 mg/kg administered thrice daily from day 3-26), in contrast, led to modest gains in development on a number of measures (body weights, vaginal opening). Morphine animals also lagged behind controls and naloxone-tested animals in social behaviors, such as homing and play. Chronic naloxone did not block or retard social development; in fact naloxone-treated animals exhibited more rapid acquisition of homing behavior than controls.

Animals↗

Mechanisms of recovery of dexterity following unilateral lesion of the sensorimotor cortex in adult monkeys.

The mechanisms of recovery of manual dexterity after unilateral lesion of the sensorimotor cortex in adult primates remain a matter of debate. It has been proposed that the cortical zone adjacent to the lesion may take over part of the function of the damaged cortex. To investigate further this possibility, two adult (4-5 years old) macaque monkeys were trained to perform a natural precision-grip task to assess hand dexterity. Intracortical microstimulations (ICMS) were used to map the hand area in M1 on both hemispheres. Ibotenic acid was then injected intracortically to damage the representation in M1 of the preferred hand. Subsequent histological analysis indicated that the hand representation in M1 was indeed lesioned, but, due to a spread of ibotenic acid, the lesion encroached a significant extent of the hand representation in the primary somatosensory cortex. A few minutes after infusion of ibotenic acid, there was a complete loss of dexterity of the preferred hand, which lasted for 1-2 months. Later, a progressive functional recovery of the affected hand took place over a 3- to 4-month period, reaching a stable level corresponding to 30% of the pre-lesion behavioral score. ICMS remapping, conducted nine months after the lesion, revealed that stimulation of the intact or lesioned M1 did not induce any visible movement of the recovered hand. The M1 hand representation on the intact hemisphere was similar to that observed before the lesion. Transient inactivation of the M1 hand/arm areas or of the dorsal and ventral premotor cortical areas (PM) on both hemispheres was undertaken by using microinjections of the GABA-agonist muscimol. Inactivations of M1 had no effect. Inhibition of PM in the damaged hemisphere suppressed the recovered manual dexterity of the affected hand. These results suggest that PM plays a significant role in the incomplete functional recovery of hand dexterity following unilateral damage of the sensorimotor cortex in adult monkeys.

Animals↗

EEG evidence for mirror neuron dysfunction in autism spectrum disorders.

Autism spectrum disorders (ASD) are largely characterized by deficits in imitation, pragmatic language, theory of mind, and empathy. Previous research has suggested that a dysfunctional mirror neuron system may explain the pathology observed in ASD. Because EEG oscillations in the mu frequency (8-13 Hz) over sensorimotor cortex are thought to reflect mirror neuron activity, one method for testing the integrity of this system is to measure mu responsiveness to actual and observed movement. It has been established that mu power is reduced (mu suppression) in typically developing individuals both when they perform actions and when they observe others performing actions, reflecting an observation/execution system which may play a critical role in the ability to understand and imitate others' behaviors. This study investigated whether individuals with ASD show a dysfunction in this system, given their behavioral impairments in understanding and responding appropriately to others' behaviors. Mu wave suppression was measured in ten high-functioning individuals with ASD and ten age- and gender-matched control subjects while watching videos of (1) a moving hand, (2) a bouncing ball, and (3) visual noise, or (4) moving their own hand. Control subjects showed significant mu suppression to both self and observed hand movement. The ASD group showed significant mu suppression to self-performed hand movements but not to observed hand movements. These results support the hypothesis of a dysfunctional mirror neuron system in high-functioning individuals with ASD.

Adolescent↗

Orbitofrontal cortex dysfunction in abstinent cocaine abusers performing a decision-making task.

Cocaine abusers demonstrate faulty decision-making as manifested by their inability to discontinue self-destructive drug-seeking behaviors. The orbitofrontal cortex (OFC) plays an important role in decision-making. In this preliminary study we tested whether 25-day-abstinent cocaine abusers show alterations in normalized cerebral blood flow (rCBF) in the OFC using PET with (15)O during the Iowa Gambling Task (a decision-making task). This task measures the ability to weigh short-term rewards against long-term losses. A control task matched the sensorimotor aspects of the task but did not require decision-making. Cocaine abusers (N = 13) showed greater activation during performance of the Iowa Gambling Task in the right OFC and less activation in the right dorsolateral prefrontal cortex (DLPFC) and left medial prefrontal cortex (MPFC) compared to a control group (N = 13). Better Iowa Gambling Task performance was associated with greater activation in the right OFC in both groups. Also, the amount of cocaine used (grams/week) prior to the 25 days of enforced abstinence was negatively correlated with activation in the left OFC. Greater activation in the OFC in cocaine abusers compared to a control group may reflect differences in the anticipation of reward while less activation in the DLPFC and MPFC may reflect differences in planning and working memory. These findings suggest that cocaine abusers show persistent functional abnormalities in prefrontal neural networks involved in decision-making and these effects are related to cocaine abuse. Compromised decision-making could contribute to the development of addiction and undermine attempts at abstinence.

Adult↗

The effect of the sodium channel blocker QX-314 on recovery after acute spinal cord injury.

There is evidence that elevated intracellular sodium ([Na+]i) activity potentiates spinal cord injury (SCI) and the hypoxic/ischemic cell death. In this study, we examined the effect of QX-314, a potent Na+ channel blocker, on recovery after SCI in vivo. QX-314 (2.0 and 10 nmol) or vehicle was microinjected (2 microL) into the injury site 15 min after SCI. Injury was performed by compression of the spinal cord at C7-T1 for 1 min with a modified aneurysm clip exerting a closing force of 35 g. Neurological function was assessed 1 day after injury and weekly thereafter until 6 weeks by the inclined plane method and by the modified Tarlov technique. After 6 weeks of injury, the origin of descending axons at the injury site was determined by retrograde labeling with fluorogold (FG), and a computer-assisted morphometric assessment of the injury site was performed. There was a significant improvement in counts of retrogradely labeled neurons in the red nucleus and rostral ventrolateral medulla (RVLM) in rats treated with either 2 nM (1338 +/- 366 and 28.8 +/- 16) or 10 nM (1390 +/- 511 and 46.3 +/- 31) QX-314 as compared to vehicle (902 +/- 403 and 13.8 +/- 8). There was a trend to increased neuronal counts in the sensorimotor cortex (170.8 +/- 226.8) and vestibular nuclei (1096.2 +/- 970.2) with QX-314 (10 nM) as compared to the vehicle-treated group. There was no significant difference in the extent of neurological recovery between the control and treated groups. Our results suggest that the Na+ channel blocker QX-314 partially preserves the integrity of descending motor axons after SCI. However, in this study, the effects were insufficient to result in sustained improvements in behavioral neurological function.

Anesthetics, Local↗

Sensorimotor functions in transgenic mice expressing the neurofilament/heavy-LacZ fusion protein on two genetic backgrounds.

NFH-LacZ transgenic mice are characterized by expression of a non-endogenous fusion protein between a truncated form of mouse NFH (neurofilament of heavy molecular weight) and the complete Escherichia coli beta-galactosidase protein. These transgenic mice were compared to their respective controls on two background strains (C3H and FVB) in several sensorimotor tests. NFH-LacZ mice were deficient in tests requiring balance and equilibrium in a manner generally independent of genetic background. In particular, NFH-LacZ mice fell more quickly than controls from two stationary beams and had fewer rears in an open-field. The transgenic mice were also impaired during the initial trials of sensorimotor learning on the rotorod. We conclude that despite the absence of overt signs of sensorimotor weakness in their home cage, the disruption of the NFH gene, causing neurofilament accumulations in the cell body and diminished axonal calibers of motoneurons, is sufficient to cause motor deficits that resemble the early stages of amyotrophic lateral sclerosis.

Animals↗

Piagetian principles: simple and effective application.

A simplified version of Piaget's sensorimotor levels was employed to teach a group of 25 extremely impaired individuals who live in a large residential facility. Throughout the facility, all available formal assessments using the Vineland Adaptive Behaviour Scales (VABS) were compared. Using this tool, an average of 13% of individuals from the common population pool increased their scores over a 6-year time period. All of the individuals who received training within the experimental group demonstrated increased scores. Scores increased such that an average gain of nearly 1 month in overall age equivalency per individual per year was realized. A matched group comparison, a prediction test for like sensorimotor skill attainment (the primary distinction of this curriculum methodology), and an historical review of subject skill training, all support the cognitively geared methodology as being primarily responsible for this accelerated progress.

Activities of Daily Living↗