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PubMed2002

GLT-1 glutamate transporter levels are unchanged in mice expressing G93A human mutant SOD1.

A decrease in expression of the glutamate transporter GLT-1 is thought to be responsible for the increase in extracellular glutamate observed in patients with amyotrophic lateral sclerosis (ALS) and in a transgenic mouse model of ALS. We examined protein levels of the glutamate transporters GLT-1, GLAST and EAAC1 in the G93A (SOD1) transgenic mouse model of ALS. GLT-1 was detected in two bands (72 and 150 kD). Semi-quantitative analysis of Western blots showed that GLT-1 levels in sensorimotor cortex, brain stem, and cervical and lumbar spinal cord of G93A mice did not differ significantly from controls, either at end stage or at 60- or 90-days old. Nevertheless, other differences were found in GLT-1 at end stage. The percentage of total GLT-1 in the 150 kD band increased significantly (p<0.05) in the spinal cord and was elevated in the brain stem and cortex. Furthermore, brain stem and spinal cord GLT-1 from G93A mice showed retarded mobility on gels compared to controls (M(r) approximately equal to 77.3+/-2.3 and 164.3+/-3.1 vs. 72.2+/-2.4 and 153.6+/-4.7, respectively). GLAST and EAAC1 were unchanged in both amount and mobility. These results show that a loss of GLT-1 protein is not necessary for ALS-like neurodegeneration in G93A mice. However, the changes in GLT-1 mobility and distribution indicate that GLT-1 is altered in mice with the SOD1 mutation.

Aging↗
PubMed1997

The effect of movement frequency on cerebral activation: a positron emission tomography study.

Knowledge of the effect of performance frequency on activation of motor areas in positron emission tomography (PET) studies is crucial to the interpretation of experiments in which performance is a variable. We studied this effect in six normal right-handed volunteers using H2(15)O PET to measure regional cerebral blood flow (rCBF). Subjects were scanned at rest and while executing joystick movements with the right hand in freely chosen directions at different frequencies. Significant frequency dependent increases in rCBF were demonstrated in contralateral sensorimotor cortex, lateral premotor cortex bilaterally, posterior supplementary motor area (SMA), and ipsilateral cerebellar hemisphere and vermis. The striatum and the right dorsal prefrontal cortex were also activated by joystick movement compared with rest, but the magnitude of activation found in these areas was independent of the frequency of movement. The results suggest that primary motor cortex, posterior SMA, lateral premotor cortex and cerebellum are involved in determining the basic parameters of movement. Frequency dependent activation in these areas suggests phasic activity related to movement. In contrast, activation of the dorsal prefrontal cortex and the striatum is not frequency dependent. This may reflect continuous rather than phasic activity in these areas during the task and suggests their role is not simply related to movement execution but higher level during this free selection joystick task.

Adult↗
PubMed1997

MR spectroscopy in amyotrophic lateral sclerosis/motor neuron disease.

Proton magnetic resonance spectroscopy (1H-MRS) and proton magnetic resonance spectroscopic imaging (1H-MRSI) have been used to identify neuronal dysfunction and/or loss in vivo in patients with various neurological diseases, including amyotrophic lateral sclerosis/motor neuron disease (ALS/MND). Both long and short echo time (TE) proton spectroscopy reveal the brain metabolites choline (Cho), creatine/phosphocreatine (Cr), and N-acetyl (NA) groups. Because NA groups are localized to mature neurons and Cr is homogeneously distributed throughout the brain, the NA/Cr ratio is considered an index of neuronal integrity. Long TE proton spectroscopic studies have revealed significantly decreased NA/Cr values in the sensorimotor cortex and brainstem of patients with ALS, consistent with neuronal dysfunction and/or loss. The amount of NA/Cr decrease appears to be directly proportional to the degree of clinical upper motor neuron deficit. Short TE 1H-MRS and 1H-MRSI also reveal other metabolites such as glutamate (Glu) and glutamine (Gln), which have been implicated in the ALS/MND disease process. Preliminary results of short TE 1H-MRSI of the medulla in patients with ALS/MND have revealed significantly decreased NA/Cr values and abnormally elevated Glu+Gln/Cr ratios, compared to control individuals. The latter values were higher in patients with more rapid disease. Although it is unclear whether the elevation of Glu+Gln/Cr precedes or follows the neuronal (and axonal) degeneration in the medulla of these patients, its occurrence provides in vivo evidence of abnormal glutamate metabolism in the CNS parenchyma of patients with ALS/MND.

Amyotrophic Lateral Sclerosis↗
PubMed1998

Effects of thalamic hemorrhage on cortical hemodynamic parameters assessed by perfusion MR imaging: preliminary report.

Thalamic lesions may induce a diffuse hypometabolism and subsequent decrease of cortical cerebral blood flow (rCBF) and cerebral blood volume (rCBV). Up to now PET was used to assess these changes. However this latter method cannot be applied routinely to stroke patients because it is expensive and not currently available. The purpose of this preliminary study was to evaluate the effects of 'pure metabolic depression' induced by thalamic stroke on rCBV and rCBF by using a non invasive method perfusion-MRI. Two patients experienced aphasia, with motor and sensory impairment related to thalamic hemorrhage. Four weeks later, dynamic T2*-weighted echo planar imaging was used to produce perfusion-MR images during an intravenous bolus injection of gadopentetate dimeglumine. A decrease of cortical rCBV and rCBF mainly confined to sensorimotor cortex was observed in both cases ipsilateral to the lesion. Although a sequential assessment of this abnormalities is needed in a larger series of patients in order to establish relevant correlations with neurological status, this preliminary study indicates that perfusion-MRI might be a practical and promising tool in the assessment of cortical rCBV and rCBF changes.

Cerebral Cortex↗
PubMed1999

Idiopathic cortical myoclonus restricted to the lower limbs: correlation between MEPs and 99mTc-ECD single photon emission computed tomography activation study.

We report a 63-year-old woman with cortical reflex myoclonus restricted to the bilateral lower limbs. Somatosensory evoked cortical potentials to posterior tibial nerve stimulation were enlarged with C-responses. Jerk-locked back averaging of the EEG identified a cortical spike related to myoclonic jerks. Motor evoked potentials recorded from the abductor hallucis muscle showed an exaggerated late response. These findings suggest hyperexcitability of the sensorimotor cortex. 99mTc-ECD single photon emission computed tomography (SPECT) after stimulation of the posterior tibial nerve showed increased perfusion in the contralateral peri-Rolandic area which corresponded to the hyperexcitable region. A SPECT activation study as well as MEPs therefore can be employed to determine the hyperexcitable region in cortical myoclonus.

Brain↗
PubMed2000

CNS plasticity and assessment of forelimb sensorimotor outcome in unilateral rat models of stroke, cortical ablation, parkinsonism and spinal cord injury.

We have reviewed a battery of useful tests for evaluating sensorimotor function and plasticity acutely and chronically in unilateral rat models of central nervous system injury. These tests include forelimb use for weight shifting during vertical exploration in a cylindrical enclosure, an adhesive removal test of sensory function, and forelimb placing. These tests monitor recovery of sensorimotor function independent of the extent of test experience. Data are presented for four models, including permanent focal ischemia, focal injury to the forelimb area of sensorimotor cortex, dopaminergic neurodegeneration of the nigrostriatal system, and cervical spinal cord injury. The effect of the dendrite growth promoting factor, Osteogenic Protein-1 (OP-1) on outcome following permanent middle cerebral artery (MCA) occlusion was used as an example to illustrate how the tests can be applied preclinically. OP-1 showed a beneficial effect on limb use asymmetry in the cylinder test.

Animals↗
PubMed1998

Exercise-induced slow waves in the EEG of cats.

The aim of the present study was to investigate the early signs of fatigue. Cats were chronically implanted with electrodes in the frontal and occipital cortical areas, and a thermocouple was inserted into the nasal orifice to record respiratory rate. After a recovery of 10 days, the animals were trained for running on treadmill. On the day before recording, a catheter was tied into one of the common carotid arteries to record arterial blood pressure. The electroencephalogram (EEG), arterial blood pressure, and respiration were recorded continuously. At the time of deceleration of running high amplitude, slow waves appeared both in the sensorimotor and occipital cortical regions. The power spectra showed a significant increase in frequencies of 1-6 Hz in the sensorimotor cortex, and of 1-10 Hz in the occipital cortex, with a great increase in the total power. During rest the pre-running, brain activity reappeared gradually. The arterial blood pressure, the heart rate, and the respiratory rate were elevated during running, but no special changes occurred at the onset of the slow waves in the EEG. The blood glucose level was somewhat higher after the first 2-min running than the pre-running level. It is concluded that the appearance of slow waves in the EEG is an early manifestation of fatigue. The cardiorespiratory changes and the blood sugar concentrations play no role in the slowing of the electrocorticogram. The present results show the involvement of brain mechanisms in the onset of tiredness.

Animals↗
PubMed2002

Inosine stimulates axon growth in vitro and in the adult CNS.

Unlike mammals, lower vertebrates can regenerate their optic nerves and certain other CNS pathways throughout life. To identify the molecular bases of this phenomenon, we developed a cell culture model and found that goldfish retinal ganglion cells will regenerate their axons in response to the purine nucleoside inosine. Inosine acts through a direct intracellular mechanism and induces many of the changes in gene expression that underlie regenerative growth in vivo, e.g., upregulation of GAP-43, T alpha-1 tubulin, and the cell-adhesion molecule, L1. N-kinase, a 47-49-kDa serine-threonine kinase, may mediate the effects of inosine and serve as part of the modular signal transduction pathway that controls axon growth. In vivo, inosine stimulates extensive axon growth in the mature rat corticospinal tract. Following unilateral transection of the corticospinal tract, inosine applied to the intact sensorimotor cortex stimulated layer 5 pyramidal cells to upregulate GAP-43 expression and to sprout axon collaterals. These collaterals crossed the midline at the level of the cervical enlargement and reinnervated regions whose normal connections had been served. Further understanding of the molecular changes that lie upstream and downstream of N-kinase may lead to new insights into the control of axon growth and to novel methods to improve functional outcome in patients with CNS injury.

Animals↗
PubMed2004

Adaptive behavior of cortical neurons during a perturbed arm-reaching movement in a nonhuman primate.

This chapter provides evidence of spatial and temporal changes in the behavior of neurons within Areas 5 and 4 of the sensorimotor cortex of a nonhuman primate while it was executing a perturbed arm-reaching task. Chronically implanted electrode arrays were used to record simultaneously from 37 to 58 neurons. Also measured were the trajectory of arm movement, EMG activity in selected arm muscles and the perturbation force applied to the arm. The adaptation in Area 4 neurons' behavior usually involved a reduction in the latency from the onset of the perturbation to the peak-firing rate of the cell. In contrast, Area 5 neurons exhibited no such adaptive change in this latency. In each cortical area, the adaptation was not uniform across all neurons, and the spatial pattern of neuronal population behavior changed over the period of behavioral adaptation. We also found that the direction of arm movement and its configuration were important in determining which control strategy (predictive trajectory compensation or stiffness control) the animal used to overcome the externally applied perturbation for an improved performance of the reaching task.

Adaptation, Physiological↗
PubMed2006

Cortical oscillatory changes occurring during somatosensory and thermal stimulation.

Brief somatosensory stimuli are followed by amplitude decreases (event-related desynchronization, ERD) of the 10 and 20 Hz oscillations over the bilateral primary sensorimotor cortices, and by post-stimulus synchronization (event-related synchronization, ERS) of the 20 Hz oscillations in the contralateral primary sensorimotor cortex and in the supplementary motor area (SMA). The 10 and 20 Hz ERD differentiate weak and strong somatosensory stimuli but not fine intensity gradations, and the ipsilateral ERD is especially sensitive to habituation. Stimulus anticipation, motor imagery, action viewing as well as voluntary movements modulate the stimulus-related changes of cortical oscillations. Noxious laser stimuli, selectively activating Adelta and/or C fibers, and innocuous warm and cold stimuli are associated with 10 and 20 Hz ERD but not with the post-stimulus 20 Hz ERS suggesting that the post-stimulus ERS is only related to neuronal transmission in the lemniscal system. It is proposed that phase-unlocked cortical oscillations modulate the preparedness of a particular sensory channel for upcoming somatosensory processing.

Animals↗
PubMed2002

Disconnection of speech-relevant brain areas in persistent developmental stuttering.

BACKGROUND: The neuronal basis of persistent developmental stuttering is unknown. The disorder could be related to a reduced left hemisphere dominance, which functional neuroimaging data suggest might lead to right hemispheric motor and premotor overactivation. Alternatively, the core deficit underlying stuttering might be located in the speech-dominant left hemisphere. Furthermore, magnetoencephalography study results show profound timing disturbances between areas involved in language preparation and execution in the left hemisphere, suggesting that persistent developmental stuttering might be related to impaired neuronal communication, possibly caused by a disruption of white matter fibre tracts. We aimed to establish whether disconnection between speech-related cortical areas was the structural basis of persistent developmental stuttering. METHODS: We analysed the speech of 15 people with persistent developmental stuttering and 15 closely matched controls for the percentage of syllables stuttered. We used diffusion tensor imaging to assess participants' brain tissue structure, and used and two-sample t test to compare diffusion characteristics between groups. FINDINGS: Diffusion characteristics of the group with persistent developmental stuttering and controls differed significantly immediately below the laryngeal and tongue representation in the left sensorimotor cortex (mean difference in fractional anisotropy 0.04 [95% CI 0.03-0.05]). INTERPRETATION: Our findings show that persistent developmental stuttering results from disturbed timing of activation in speech-relevant brain areas, and suggest that right hemisphere overactivation merely reflects a compensatory mechanism, analogous to right hemisphere activation in aphasia.

Adult↗
PubMed1987

Enrichment versus exercise effects on motor impairments following cortical removals in rats.

Groups of rats were exposed to an enriched environment, given access to an activity wheel, or individually housed in wire mesh cages, impoverished. Rats were exposed in groups of four to the enriched environment or placed individually in the activity wheel for 2 h per day for 25 days preoperatively. Within each exposure group, rats sustained bilateral removals of sensorimotor cortex, or were sham-operated controls. Animals were trained preoperatively to locomote across a narrow elevated runway. Postoperatively, locomotor testing was initiated 17 days after surgery throughout which time all animals were maintained under impoverished conditions. Locomotor deficits following cortical damage were a function of preoperative exposure: enriched rats were least impaired; impoverished rats were most impaired. Rats allowed running wheel activity initially showed the same marked deficits as impoverished animals but recovered more rapidly. The opportunity for physical exercise afforded wheel animals preoperatively may have enhanced motor capabilities that aided recovery. However, physical activity alone did not yield the same protective effects from initial impairment as enrichment. Greater elaboration of neural structures associated with perceptual-motor enrichment probably accounted for the initial sparing of the enriched group.

Animals↗
PubMed1999

Application of positron emission tomography to determine cerebral glucose utilization in conscious infant monkeys.

Cerebral glucose metabolism has been used as a marker of cerebral maturation and neuroplasticity. In studies addressing these issues in young non-human primates, investigators have used positron emission tomography (PET) and [18F]2-fluoro-2-deoxy-D-glucose (FDG) to calculate local cerebral metabolic rates of glucose (1CMRG1c). Unfortunately, these values were influenced by anesthesia. In order to avoid this confounding factor, we have established a method that permits reliable measurements in young conscious vervet monkeys using FDG-PET. Immature animals remained in a conscious, resting state during the initial 42 min of FDG uptake as they were allowed to cling to their anesthetized mothers. After FDG uptake, animals were anesthetized and placed in the PET scanner with data acquisition beginning at 60 min post-FDG injection. FDG image sets consisted of 30 planes separated by 1.69 mm, parameters sufficient to image the entire monkey brain. Our method of region-of-interest (ROI) analysis was assessed within and between raters and demonstrated high reliability (P < 0.001). To illustrate that our method was sensitive to developmental changes in cerebral glucose metabolism, quantitative studies of young conscious monkeys revealed that infant monkeys 6-8 months of age exhibited significantly higher 1CMRG1c values (P < 0.05) in all regions examined, except sensorimotor cortex and thalamus, compared to monkeys younger than 4 months of age. This method provided high resolution images and 1CMRG1c values that were reliable within age group. These results support the application of FDG-PET to investigate questions related to cerebral glucose metabolism in young conscious non-human primates.

Age Factors↗
PubMed1998

Developmental changes in purinergic calcium signalling in rat neocortical neurones.

The changes in cytoplasm free calcium concentration ([Ca2+]i transients) were measured in Fura-2/AM loaded pyramidal neurones of sensorimotor cortex in acutely prepared slices isolated from 14 days (P14) and 30 (P30) days old rats. Ni2+ (50 microM) diminished the [Ca2+]i transients evoked by 50 mM KCl bath application by 47%+/-8% in neurones of the P14 group and only by 15%+/-6% in those of P30 group (P<0.002). Nifedipine and verapamil in concentration 100 microM reduced the calcium transients amplitude triggered by depolarization to about the same extent in both groups of neurons-on average by 50% and 35%, respectively. The amplitude of [Ca2+]i transients induced by application of 100 microM ATP reached 103+/-6 nM in P14 neurones and 72+/-8 nM in the P30 ones. The ATP-[Ca2+]i induced transient could be evoked in Ca2+-free external solution, indicating the presence of metabotropic (P2y) purinoreceptors. Almost all (90%) P14 neurones were endowed with such receptors. At the same time only 1/3 of the tested (n=42) P30 neurones presented responses to ATP applications in Ca2+-free solution. The share of ionotropic (P2x) purinoreceptors in generation of calcium signal was the same in both groups of neurons. No caffeine-induced Ca2+-release has been observed in the P14 neurons. To the contrary, in 28 cells from 42 investigated neurones of the P30 group application of 40 mM caffeine for 10 s induced considerable [Ca2+]i transients, which did not disappear in calcium-free solution. A conclusion is made about substantial changes in the expression of Ca2+-handling mechanisms which are occurring in neocortical neurones at the third-fourth week of postnatal development.

Aging↗
PubMed2002

The behavioral and dendritic growth effects of focal sensorimotor cortical damage depend on the method of lesion induction.

Using different models of focal cortical injury in adult rats, the neural structural and behavioral outcomes of unilateral lesions of the forelimb representation of the sensorimotor cortex (SMC) were assessed. Lesions were produced using either electrolytic, aspiration, or combined ('electroaspiration') techniques. Measurements of dendritic arborization in layer V of the motor cortex opposite the lesion revealed a growth of pyramidal neuron dendritic processes following electrolytic lesions in comparison to shams. This effect was not found in either the aspiration or electroaspiration lesion groups. Behaviorally, animals in all lesion groups developed a hyper-reliance on the forelimb ipsilateral to the lesion and proportionate disuse of the contralateral (impaired) forelimb for postural support behaviors. In comparison to sham-operated animals, the initial asymmetries in behaviors expressed during movement were similar between lesion groups, but were less enduring following electrolytic lesions than following aspiration and electroaspiration lesions. Furthermore, both aspiration lesion groups had more prevalent adduction of the impaired forelimb than the electrolytic-only lesion rats. Thus, cortical aspiration resulted in more severe and enduring forelimb impairments than the electrolytic lesions, despite similar lesion sizes, as assessed using cortical volume measures. These findings suggest that the aspiration lesion procedures, at least as performed in the present study, exacerbate the behavioral effects of focal cortical injury and limit compensatory plasticity in the contralateral cortex.

Animals↗
PubMed2004

Consequences of forced disuse of the impaired forelimb after unilateral cortical injury.

Extreme over-reliance on the impaired forelimb following unilateral lesions of the forelimb representation area of the rat sensorimotor cortex (FL-SMC) leads to exaggeration of injury when overuse is begun during the first week, but not later periods, after injury. Behavioral impairment is partially worsened by the additional tissue loss. In the present study, we show that complete disuse of the impaired forelimb during the first post-operative week renders surviving tissue vulnerable to later overuse of the same limb, in effect extending the window of vulnerability in which use-dependent exaggeration of brain injury can occur. Behavioral recovery is disrupted by complete disuse, but the degree of impairment is variable depending on the nature of the behavioral test employed. Our results uphold the idea that mild rehabilitative training early after injury is beneficial, while either extreme overuse or complete disuse may disrupt functional recovery.

Animals↗
PubMed1980

Asymmetric distribution of side preference in hamsters can be reversed by lesions of the caudate nucleus.

Side preferences were tested in Syrian hamsters (Mesocricetus auratus) by placing them on an elevated centerboard which divided a rectangular arena in two equal compartments. When descending from the centerboard all animals turned more often right (79%) than left (21%). After small electrolytic lesions of the left caudate nucleus the side preference was reversed: 31% to the right and 69% to the left. Combined lesions of the left caudate nucleus and left sensorimotor cortex showed similar results; lesions of the left cortex alone had only minor effects. These observations support the hypothesis [28] that side preferences depend on asymmetries of the nigrostriatal system.

Animals↗
PubMed1999

The effect of rubrospinal tractotomy on a conditioned limb response in the cat.

Five cats were trained to perform a forelimb conditioned response to a paired tone CS/shock UCS. Rubrospinal tract section ipsilateral to the trained limb was carried out following criterion CR performance. Lesion sites were identified histologically and further confirmed by observation of cellular changes in the red nucleus contralateral to the trained limb. Tractotomy resulted in total or near-total loss of the CR. Prolonged postoperative training resulted in no increase in CR performance levels. The UCR remained unaffected, as did limb placing, accuracy of striking at moving objects, grooming, running and walking. Training of the opposite limb in two subjects resulted in mean scores of 90 and 85% within three sessions. Control lesions in those subjects resulted in no changes in CR performance scores. The red nucleus receives a substantial input from sensorimotor cortex and cerebellum, both of which have been shown to represent essential parts of the brain circuitry involved in associative learning and memory. Since pyramidotomy has no effect on limb CR performance [Vonedia TJ. Exp Neurol 1976;19:483-493], the possible role of the red nucleus/rubrospinal tract is discussed in terms of a critical trigger area for the expression of a learned motor response.

Animals↗

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