Biomedical subjects

K Fouad

Publications and source records attributed to K Fouad.

At least 19 recordsLinked to original sources

PubMed2006

BDNF promotes connections of corticospinal neurons onto spared descending interneurons in spinal cord injured rats.

Although regeneration of injured axons is inhibited within the adult CNS, moderate recovery can be found in patients and animals with incomplete spinal cord injury (SCI). This can be partly attributed to sprouting of spared and injured axons, rostral and caudal to the lesion, respectively. Recently, it has been reported that following a thoracic SCI such sprouting can result in indirect reconnections of the lesioned axons to caudal targets via propriospinal interneurons (PrI). Here, we attempted to further promote this spontaneous repair mechanism by applying the neurotrophic factor BDNF (brain-derived neurotrophic factor), in the vicinity of the cell bodies of lesioned corticospinal neurons or NT-3, intrathecally to the cervical spinal cord. We performed a dorsal over-hemisection at the thoracic spinal cord sparing only the left ventrolateral quadrant. This type of lesion did not promote sprouting of injured corticospinal axons or re-routing via commissural PrI. Also, in rats that received NT-3 at the cervical enlargement, no increase in sprouting was found. However, animals receiving BDNF at the cell bodies of lesioned corticospinal neurons showed a significant increase in collateral sprouting and in the number of contacts with PrI. This was not observed when BDNF was administered to unlesioned animals. Although no statistical difference in the horizontal ladder walking was found between the groups, the increase in collateral sprouting and in the number of contacts correlated with the functional recovery. Hence, cell body treatment can promote plasticity of the injured CNS and may be a valuable treatment approach in conjunction with local regeneration promoting strategies.

Animals↗

PubMed2005

A new electrode configuration for recording electromyographic activity in behaving mice.

With the increasing use of normal and genetically modified mice in the field of motor physiology, there is a need for a simple and reliable technique for recording electromyographic (EMG) activity in behaving mice. Here, we describe a new method for the fabrication and implantation of fine EMG recording electrodes into multiple muscles of adult mice. This method minimizes surgical damage to the muscles and the connecting leads have only a modest influence on leg movements when electrodes are implanted into distal muscles. We demonstrate that excellent EMG recordings can be obtained during walking, swimming and scratching for the vastus lateralis, tibialis anterior and gastrocnemius muscles in normal adult mice. EMG recordings were also made in a mutant EphA4 mouse to demonstrate the utility of the method for examining motor patterns in genetically modified animals. We also developed a method for constructing highly reflective markers that could be viewed over a range of orientations to measure the kinematics of legs movements during stepping. A commercial motion analysis system was used to track six markers during walking and to synchronize video and EMG data during walking sequences.

Animals↗

PubMed2004

Regenerating corticospinal fibers in the Marmoset (Callitrix jacchus) after spinal cord lesion and treatment with the anti-Nogo-A antibody IN-1.

Neutralizing the myelin-associated growth inhibitor Nogo-A in adult spinal cord-injured rats can promote regeneration of injured and compensatory sprouting of uninjured axons. Nogo-A is present in humans, making its neutralization a possible novel treatment option for paraplegic patients. In this study we examined the effects of an extensively used anti-Nogo-A antibody (mAb IN-1) on the regenerative capabilities of lesioned corticospinal tract (CST) axons in a primate, the Marmoset monkey. Unilateral thoracic lesions of the CST were performed in six adult Marmosets, followed by the application of mAb IN-1 into the cerebrospinal fluid circulation by a graft of hybridoma cells. A unilateral injection of biotin dextran amine into the motor cortex was performed to analyse sprouting and regeneration of the lesioned axons. In the control antibody-treated animal CST fibers stopped rostral to the lesion site and often showed retraction bulbs. In contrast, in four out of five mAb IN-1-treated animals fine labeled neurites had grown into, through and around the lesion site. Thus, this study provides first anatomical evidence that in primates, the neutralization of the myelin-associated inhibitor Nogo-A results in increased regenerative sprouting and growth of lesioned spinal cord axons.

Animals↗

PubMed2002

Anatomical correlates of locomotor recovery following dorsal and ventral lesions of the rat spinal cord.

The present study was designed to relate functional locomotor outcome to the anatomical extent and localization of lesions in the rat spinal cord. We performed dorsal and ventral lesions of different severity in 36 adult rats. Lesion depth, spared total white matter, and spared ventrolateral funiculus were compared to the locomotor outcome, assessed by the BBB open-field locomotor score and the grid walk test. The results showed that the preservation of a small number of fibers in the ventral or lateral funiculus was related to stepping abilities and overground locomotion, whereas comparable tissue preservation in the dorsal funiculus resulted in complete paraplegia. The strongest relation to locomotor function was between the BBB score and the lesion depth as well as the BBB score and the spared white matter tissue in the region of the reticulospinal tract. Locomotion on the grid walk required sparing in the ventrolateral funiculus and additional sparing of the dorsolateral and dorsal funiculus, where the cortico- and rubrospinal tracts are located.

Anatomy, Cross-Sectional↗

PubMed2002

White matter glucose metabolism during intracortical electrostimulation: a quantitative [(18)F]Fluorodeoxyglucose autoradiography study in the rat.

[(18)F]Fluorodeoxyglucose (FDG) autoradiography was used to analyze the effects of intracortical electrostimulation on local cerebral metabolic rate for glucose (LCMRglu). The hindleg area in rat brains was electrically stimulated with different frequencies (0, 0.1, 0.25, 0.5, 0.75, 1 stimulus trains per second, two animals per condition). The major result was a strong positive correlation between stimulation frequency and LCMRglu in the callosal fibers originating in the stimulated cortical area. At the highest stimulation frequency callosal LCMRglu was 50.01 micromol/min/100 g compared to 27.87 micromol/min/100 g at baseline. LCMRglu in gray and white matter control areas was stable across conditions. Direct injection of FDG in the stimulated cortex failed to produce increased callosal uptake, excluding the possibility that FDG uptake in the corpus callosum is related to axonal diffusion. Although several previous autoradiographic studies have demonstrated alterations in LCMRglu in white matter, correlations between neural activity and LCMRglu have never been explicitly addressed. Changes in white matter metabolism most likely reflect changes of electrical fiber activity and thus the presented results bear important implications for brain imaging studies.

Animals↗

PubMed2002

Protective effects of oral creatine supplementation on spinal cord injury in rats.

STUDY DESIGN: To evaluate a potential protective effect of increased creatine levels in spinal cord injury (SCI) in an animal model. OBJECTIVES: Acute SCI initiates a series of cellular and molecular events in the injured tissue leading to further damage in the surrounding area. This secondary damage is partly due to ischemia and a fatal intracellular loss of energy. Phospho-creatine in conjunction with the creatine kinase isoenzyme system acts as a potent intracellular energy buffer. Oral creatine supplementation has been shown to elevate the phospho-creatine content in brain and muscle tissue, leading to neuroprotective effects and increased muscle performance. SETTING: Zurich, Switzerland. METHODS: Twenty adult rats were fed for 4 weeks with or without creatine supplemented nutrition before undergoing a moderate spinal cord contusion. RESULTS: Following an initial complete hindlimb paralysis, rats of both groups substantially recovered within 1 week. However, creatine fed animals scored 2.8 points better than the controls in the BBB open field locomotor score (11.9 and 9.1 points respectively after 1 week; P=0.035, and 13 points compared to 11.4 after 2 weeks). The histological examination 2 weeks after SCI revealed that in all rats a cavity had developed which was comparable in size between the groups. In creatine fed rats, however, a significantly smaller amount of scar tissue surrounding the cavity was found. CONCLUSIONS: Thus creatine treatment seems to reduce the spread of secondary injury. Our results favour a pretreatment of patients with creatine for neuroprotection in cases of elective intramedullary spinal surgery. Further studies are needed to evaluate the benefit of immediate creatine administration in case of acute spinal cord or brain injury.

Administration, Oral↗

PubMed2001

Cervical sprouting of corticospinal fibers after thoracic spinal cord injury accompanies shifts in evoked motor responses.

The adult central nervous system (CNS) of higher vertebrates displays a limited ability for self repair after traumatic injuries, leading to lasting functional deficits [1]. Small injuries can result in transient impairments, but the mechanisms of recovery are poorly understood [2]. At the cortical level, rearrangements of the sensory and motor representation maps often parallel recovery [3,4]. In the sensory system, studies have shown that cortical and subcortical mechanisms contribute to map rearrangements [5,6], but for the motor system the situation is less clear. Here we show that large-scale structural changes in the spared rostral part of the spinal cord occur simultaneously with shifts of a hind-limb motor cortex representation after traumatic spinal-cord injury. By intracortical microstimulation, we defined a cortical area that consistently and exclusively yielded hind-limb muscle responses in normal adult rats. Four weeks after a bilateral transsection of the corticospinal tract (CST) in the lower thoracic spinal cord, we again stimulated this cortical field and found forelimb, whisker, and trunk responses, thus demonstrating reorganization of the cortical motor representation. Anterograde tracing of corticospinal fibers originating from this former hind-limb area revealed that sprouting greatly increased the normally small number of collaterals that lead into the cervical spinal cord rostral to the lesion. We conclude that the corticospinal motor system has greater potential to adapt structurally to lesions than was previously believed and hypothesize that this spontaneous growth response is the basis for the observed motor representation rearrangements and contributes to functional recovery after incomplete lesions.

Animals↗

PubMed2001

Functional switch between motor tracts in the presence of the mAb IN-1 in the adult rat.

Fine finger and hand movements in humans, monkeys, and rats are under the direct control of the corticospinal tract (CST). CST lesions lead to severe, long-term deficits of precision movements. We transected completely both CSTs in adult rats and treated the animals for 2 weeks with an antibody that neutralized the central nervous system neurite growth inhibitory protein Nogo-A (mAb IN-1). Anatomical studies of the rubrospinal tracts showed that the number of collaterals innervating the cervical spinal cord doubled in the mAb IN-1- but not in the control antibody-treated animals. Precision movements of the forelimb and fingers were severely impaired in the controls, but almost completely recovered in the mAb IN-1-treated rats. Low threshold microstimulation of the motor cortex induced a rapid forelimb electromyography response that was mediated by the red nucleus in the mAb IN-1 animals but not in the controls. These findings demonstrate an unexpectedly high capacity of the adult central nervous system motor system to sprout and reorganize in a targeted and functionally meaningful way.

Animals↗

PubMed2001

Locomotor recovery in spinal cord-injured rats treated with an antibody neutralizing the myelin-associated neurite growth inhibitor Nogo-A.

The limited plastic and regenerative capabilities of axons in the adult mammalian CNS can be enhanced by the application of a monoclonal antibody (mAb), IN-1, raised against the myelin-associated neurite growth inhibitor Nogo-A. The aim of the present study was to investigate the effects of this treatment on the functional recovery of adult rats with a dorsal over-hemisection of the spinal cord. Directly after injury, half of the animals were implanted with mAb IN-1-secreting hybridoma cells, whereas the others received cells secreting a control antibody (anti-HRP). A broad spectrum of locomotor tests (open field locomotor) score, grid walk, misstep withdrawal response, narrow-beam crossing) was used to characterize locomotor recovery during the 5 weeks after the injury. In all behavioral tests, the recovery in the mAb IN-1-treated group was significantly augmented compared with the control antibody-treated rats. EMG recordings of flexor and extensor muscles during treadmill walking confirmed the improvement of the locomotor pattern in the mAb IN-1-treated rats; step-cycle duration, rhythmicity, and coupling of the hindlimbs were significantly improved. No differences between the two groups with regard to nociception were observed in the tail flick test 5 weeks after the operation. These results indicating improved functional recovery suggest that the increased plastic and regenerative capabilities of the CNS after Nogo-A neutralization result in a functionally meaningful rewiring of the motor systems.

Animals↗

PubMed2001

Reflex adaptations during treadmill walking with increased body load.

Load dependent reflex adaptations were studied in healthy subjects walking on a split-belt treadmill. Compensatory reflex responses were elicited in the right leg extensor muscles during mid-stance by a short acceleration of the right treadmill belt. Electromyographic activity (EMG) was recorded from the right medial gastrocnemius (GMR), soleus (SO) and tibialis anterior (TA) muscles of the right leg as well as from the gastrocnemius of the left unperturbed leg (GML). To study the adaptational reflex behavior, multiple measurements were taken during walking with normal (control) and increased body load and after removing the load. In most experiments the compensatory EMG response in the GMR consisted of a short inhibitory and a subsequent excitatory component. Both reflex components were larger when the body was loaded. During the course of continuous loading, divergent reflex adaptations of different degrees and directions were observed in the subjects. In one group of subjects the reflex response increased to a higher level of EMG activity. In a second group EMG activity first increased and afterwards decreased to baseline level. A subsequent removal of body loading resulted in a slow adaptation to the control reflex values in both groups. Neither the EMG activity in the GM nor the reflex responses in the GMR after increasing the load changed differently in the two groups. Our results suggest that load information is not simply used in a fixed input/output relationship of the actual biomechanical conditions of a subject. Load information is rather used to slowly modify the reflex response, to achieve the desired posture during walking.

Adaptation, Physiological↗

PubMed2001

Improving axonal growth and functional recovery after experimental spinal cord injury by neutralizing myelin associated inhibitors.

Injuries of the spinal cord often result in an irretrievable loss of motor and sensory functions of all body parts situated below the lesion site. Functional recovery is restricted mainly due to the limited regeneration and plasticity of injured axons in the adult central nervous system. Over the last few years different experimental approaches have led to axonal growth and functional benefits in animal models. This review focuses on the effects of the neutralization of myelin-associated neurite growth inhibitors, in particular Nogo-A, using the monoclonal antibody IN-1. Acute mAb IN-1 treatment of adult CNS lesioned rats results in extensive plastic changes of neuronal connections and regenerative fiber growth. In two different lesion paradigms (i.e. pyramidal tract lesion and incomplete spinal cord lesion in adult rats), the mAb IN-1-treated animals always showed a higher degree of recovery in various behavioral tests. These observations, together with electrophysiological results, suggest that neuronal CNS circuits of mAb IN-1-treated animals can be rearranged, and that sprouting and regenerating axons form functionally meaningful connections.

Animals↗

PubMed2001

Neuronal coordination of arm and leg movements during human locomotion.

We aimed to study the neuronal coordination of lower and upper limb muscles. We therefore evaluated the effect of small leg displacements during gait on leg and arm muscle electromyographic (EMG) activity in walking humans. During walking on a split-belt treadmill (velocity 3.5 km/h), short accelerations or decelerations were randomly applied to the right belt during the mid or end stance phase. Alternatively, trains of electrical stimuli were delivered to the right distal tibial nerve. The EMG activity of the tibialis anterior (TA), gastrocnemius medialis (GM), deltoideus (Delt), triceps (Tric) and biceps brachii (Bic) of both sides was analysed. For comparison, impulses were also applied during standing and sitting. The displacements were followed by specific patterns of right leg and bilateral arm muscle EMG responses. Most arm muscle responses appeared with a short latency (65-80 ms) and were larger in Delt and Tric than in Bic. They were strongest when deceleration impulses were released during mid stance, associated with a right compensatory TA response. A similar response pattern in arm muscles was obtained following tibial nerve stimulation. The arm muscle responses were small or absent when stimuli were applied during standing or sitting. The arm muscle responses correlated more closely with the compensatory TA than with the compensatory GM responses. The amplitude of the responses in most arm muscles correlated closely with the background EMG activity of the respective arm muscle. The observations suggest the existence of a task-dependent, flexible neuronal coupling between lower and upper limb muscles. The stronger impact of leg flexors in this interlimb coordination indicates that the neuronal control of leg flexor and extensor muscles is differentially interconnected during locomotion. The results are compatible with the assumption that the proximal arm muscle responses are associated with the swinging of the arms during gait, as a residual function of quadrupedal locomotion.

Adult↗

PubMed2000

Efficient testing of motor function in spinal cord injured rats.

In experimental spinal cord injury studies, animal models are widely used to examine anatomical and functional changes after different treatments and lesion types. A variety of behavioral paradigms exists in the literature, but definitions and criteria for motor performance vary considerably. In this study, we examined the outcome and relation of tests such as the BBB open field locomotion score, footprint analysis, kinematic analysis, placing response, grid walk and narrow beam crossing following two different lesion types. The information obtained was used to design an efficient and reliable testing strategy, which includes a broad spectrum of parameters to enhance sensitivity. This approach should help to standardize modular testing procedures across different laboratories working on spinal cord injury.

Animals↗

PubMed2000

Compensatory sprouting and impulse rerouting after unilateral pyramidal tract lesion in neonatal rats.

After lesions of the developing mammalian CNS, structural plasticity and functional recovery are much more pronounced than in the mature CNS. We investigated the anatomical reorganization of the corticofugal projections rostral to a unilateral lesion of the corticospinal tract at the level of the medullary pyramid (pyramidotomy) and the contribution of this reorganization and other descending systems to functional recovery. Two-day-old (P2) and adult rats underwent a unilateral pyramidotomy. Three months later the corticofugal projections to the red nucleus and the pons were analyzed; a relatively large number of corticorubral and corticopontine fibers from the lesioned side had crossed the midline and established an additional contralateral innervation of the red nucleus and the pons. Such anatomical changes were not seen after adult lesions. Intracortical microstimulation of the primary motor cortex with EMG recordings of the elbow flexor muscles were used to investigate possible new functional connections from the motor cortex of the pyramidotomy side to the periphery. In rats lesioned as adults, stimulation of the motor cortex ipsilateral to the pyramidotomy never elicited EMG activity. In contrast, in P2 lesioned rats bilateral forelimb EMGs were found. EMG latencies were comparable for the ipsilateral and contralateral responses but were significantly longer than in unlesioned animals. Transient inactivation of both red nuclei with the GABA receptor agonist muscimol led to a complete loss of these bilateral movements. Movements and EMGs reappeared after wash-out of the drug. These results suggest an important role of the red nucleus in the reconnection of the cortex to the periphery after pyramidotomy.

Afferent Pathways↗

PubMed2000

Treadmill training in incomplete spinal cord injured rats.

Treadmill training has been shown to accelerate locomotor recovery and to improve weight bearing during treadmill walking in spinal cats. In human patients treadmill training is increasingly used in rehabilitation after incomplete spinal cord injury. In this study we examined training effects in spinal cord injured rats with an incomplete dorsal lesion. Recovery was examined with an open field locomotor score, kinematic analysis on the treadmill, and several functional tests (i.e. foot print evaluation, narrow beam crossing, grid walking, open field exploratory activity). During the course of 5 weeks after the injury, a substantial amount of recovery occurred in the treadmill trained as well as in the untrained rats. If compared to the control lesioned rats, which showed a high level of spontaneous hindlimb movements at 7-14 days post lesion, no additional beneficial effect of a 5-week daily treadmill training on the locomotor outcome could be detected in the trained group. The only change observed was a slightly larger exploratory activity of the trained rats. It is probable that the spared ventral and ventro-lateral fibers allowed spontaneous recovery and 'self-training' to occur to such an extend that systematic treadmill training did not provide additional improvement.

Animals↗

PubMed1999

Spasticity in rats with sacral spinal cord injury.

We have investigated sacral spinal cord lesions in rats with the goal of developing a rat model of muscular spasticity that is minimally disruptive, not interfering with bladder, bowel, or hindlimb locomotor function. Spinal transections were made at the S2 sacral level and, thus, only affected the tail musculature. After spinal transection, the muscles of the tail were inactive for 2 weeks. Following this initial period, hypertonia, hyperreflexia, and clonus developed in the tail, and grew more pronounced with time. These changes were assessed in the awake rat, since the tail is readily accessible and easy to manipulate. Muscle stretch or cutaneous stimulation of the tail produced muscle spasms and marked increases in muscle tone, as measured with force and electromyographic recordings. When the tail was unconstrained, spontaneous or reflex induced flexor and extensor spasms coiled the tail. Movement during the spasms often triggered clonus in the end of the tail. The tail hair and skin were extremely hyperreflexive to light touch, withdrawing quickly at contact, and at times clonus could be entrained by repeated contact of the tail on a surface. Segmental tail muscle reflexes, e.g., Hoffman reflexes (H-reflexes), were measured before and after spinalization, and increased significantly 2 weeks after transection. These results suggest that sacral spinal rats develop symptoms of spasticity in tail muscles with similar characteristics to those seen in limb muscles of humans with spinal cord injury, and thus provide a convenient preparation for studying this condition.

Animals↗

PubMed1999

Adaptive changes in motor activity associated with functional recovery following muscle denervation in walking cats.

In this investigation we examined the changes in the pattern of activity in the medial gastrocnemius (MG) muscle in walking cats following transection of the nerves innervating synergist muscles (lateral gastrocnemius, soleus, and plantaris). Immediately following the nerve transections, there was a large increase in ankle flexion during early stance (from approximately 10 to approximately 30 degrees ) and a marked increase in the magnitude of the MG bursts during stance. We attribute this increase in the magnitude of the MG bursts to an increase in afferent feedback from the abnormally stretched MG muscle. During the week after the nerve transections, there was a progressive decrease in ankle yield. This improvement in ankle function was correlated with an increase in magnitude of two components of the MG bursts; the initial component starting during late swing and ending approximately 40 ms after ground contact, and a late component associated with stance. The time courses of the increases in the initial and late components of the MG bursts were different. Large and significant increases in the late component occurred the day after the nerve transections, whereas increases in the initial component occurred more gradually. This difference in time course was reflected in the kinematics of ankle movement. Over the first few days after the nerve transections, improvement in ankle movement occurred primarily late in the stance phase, and there was little change in ankle yield during early stance. At 1 wk, however, there was a significant reduction in ankle yield during early stance. This decreased yield was most likely due to an increase in stiffness of the MG muscle at the time of ground contact resulting from the increase in magnitude of the initial component of the MG bursts. The increases in the magnitude of the initial and late components of the MG bursts, as well as the improvement in ankle function, depended on use of the leg. All these changes were delayed by immobilizing the leg for 6 days in an extended position. We discuss possible mechanisms underlying the increase in the magnitude of the MG bursts and propose that proprioceptive signals from the stretched MG muscles provide an error signal for rescaling the magnitude of the centrally generated initial component. Our data support the concept that proprioceptive feedback functions to scale the magnitude of feed-forward motor commands to ensure they are appropriate for the biomechanical properties of the musculoskeletal system.

Adaptation, Physiological↗

PubMed1998

Enhancement and resetting of locomotor activity by muscle afferents.

The generation of the normal motor pattern for walking in mammals requires feedback from muscle proprioceptors. Two characteristics of the motor pattern particularly dependent on proprioceptive signals are (1) the magnitude of activity in knee and ankle extensor muscles and (2) the duration of extensor bursts during stance. Sensory regulation of these characteristics ensures that the level of activity in extensor muscles during stance is appropriate for the load carried by the leg and that the swing phase is not initiated when a leg is loaded. Many different groups of afferents from flexor and extensor muscles can influence the locomotor pattern. Most attention has focused on the action of group I afferents from ankle extensors. Electrical stimulation of these afferents during extension increases the duration and the magnitude of extensor activity. The prolongation of extensor activity depends in part on excitation of the extensor half-center by group Ib afferents from Golgi tendon organs. The enhancement of the magnitude of extensor bursts is produced primarily via disynaptic and polysynaptic pathways opened only during locomotion. The involvement of the proprioceptive signals in the generation of locomotor activity means that the gains in reflex pathways must be constantly calibrated according to the biomechanical properties of the locomotor system. Alteration of these properties by weakening ankle extensor muscles has recently been found to produce compensatory changes in proprioceptive influences on the locomotor pattern.

Animals↗