The simple model versus the super model: translating experimental traumatic brain injury research to the bedside.

Despite considerable investigation in rodent models of traumatic brain injury (TBI), no novel therapy has been successfully translated from bench to bedside. Although well-described limitations of clinical trails may account for these failures, several modeling factors may also contribute to the lack of therapeutic translation from the laboratory to the clinic. Specifically, models of TBI may omit one or more critical, clinically relevant pathophysiologic features. In this invited review article, the impact of the limited incorporation of several important clinical pathophysiologic factors in TBI, namely secondary insults (i.e., hypotension and/or hypoxemia), coma, and aspects of standard neurointensive care monitoring and management strategies (i.e., intracranial pressure [ICP] monitoring and ICP-directed therapies, sedation, mechanical ventilation, and cardiovascular support) are discussed. Comparative studies in rodent and large animal models of TBI (which may, in some cases, represent super models) are also presented. We conclude that therapeutic breakthroughs will likely require a multidisciplinary approach, involving investigation in a range of models, including clinically relevant modifications of established animal models, along with development and application of new innovations in clinical trial design.

Isoflurane improves long-term neurologic outcome versus fentanyl after traumatic brain injury in rats.

Despite routine use of fentanyl in patients after traumatic brain injury (TBI), it is unclear if it is the optimal sedative/analgesic agent. Isoflurane is commonly used in experimental TBI. We hypothesized that isoflurane would be neuroprotective versus fentanyl after TBI. Rats underwent controlled cortical impact (CCI) and received 4 h of N2O/O2 (2:1) and either fentanyl (10 microg/kg i.v. bolus, 50 microg/kg/h infusion) or isoflurane (1% by inhalation) with controlled ventilation. Shams underwent identical preparation, without CCI. Functional outcome (beam balance, beam walking, Morris water maze [MWM] tasks) was assessed over 20 days. Lesion volume and hippocampal neuron survival were quantified on day 21. Additional rats underwent identical CCI and anesthesia with intracranial pressure (ICP) monitoring, and brain water content was assessed. Motor and MWM performances were better in injured rats treated with isoflurane versus fentanyl (p < 0.05). CA1 hippocampal damage was attenuated in isoflurane-treated rats (p < 0.05). Fentanyl-treated rats had higher mean arterial blood pressure after injury (p < 0.05); however, ICP and brain water were similar between groups. Isoflurane improved functional outcome and attenuated damage to CA1 versus fentanyl in rats subjected to CCI. Isoflurane may be neuroprotective by augmenting cerebral blood flow and/or reducing excitotoxicity, not by reducing ICP or brain water content. Alternatively, fentanyl may be detrimental. Isoflurane may mask beneficial effects of novel agents tested in TBI models. Additionally, fentanyl may not be optimal early after TBI in humans.

Development of mature microcystic lesions in the cochlear nuclei of the Mongolian gerbil, Meriones unguiculatus.

Microcystic lesions are a persistent final stage in a neurodegenerative disorder characteristic of the cochlear nuclei of gerbils. When gerbils of various ages raised under known acoustic conditions were examined, the volume density and number of lesions increased with age, however, the affected region was restricted to the posteroventral cochlear nucleus and adjacent portions of the dorsal cochlear nucleus, interstitial nucleus, and posterior anteroventral cochlear nucleus. Lesions were also noted in a separate locus in the auditory nerve trunk associated with the acoustic nerve nucleus. The fusiform and molecular layers of the dorsal cochlear nucleus were spared at all ages observed. The spherical cell region of the arteroventral cochlear nucleus was also largely spared. A good correlation was observed between the cumulative input from the auditory nerve fibers caused by the ambient acoustic environment acting over the life of the animal and the number of lesions in tonotopic subdivisions of the cochlear nuclei. The earliest microcysts formed in regions receiving auditory nerve fibers most strongly stimulated by the ambient noise. Thereafter, short exposures to higher levels of input or long exposures to lower levels of input were quantitatively equivalent in producing microcystic lesions.

A potential model of pediatric posttraumatic epilepsy.

Preclinical models of pediatric posttraumatic epilepsy (PTE) are lacking. We hypothesized that traumatic brain injury (TBI), induced by controlled cortical impact, in immature rats would cause electroencephalographic (EEG) epileptiform activity and behavioral seizures. TBI or sham craniotomy was performed on postnatal day 17. Using video-EEG monitoring 4-11 months post-TBI, most TBI rats (87.5%) showed EEG spiking and one had spontaneous, recurrent seizures. Controls showed neither EEG spikes nor electrographic/behavioral seizures. Late seizures were rare after TBI, but EEG spiking was common and may represent a surrogate for PTE.

Effects of inertial load and cervical-spine orientation on a head-tracking task in the alert cat.

Simultaneous video-fluoroscopic and neck muscle EMG data were recorded from one cat performing +/-15 degrees sinusoidal (0.25 Hz) head-tracking movements in the sagittal plane in a standing body posture with two initial neck orientations and four inertial loads. Radio-opaque markers were inserted into the anterior/posterior and lateral aspects of the occipital ridge and C(1)-C(7) to measure vertebral displacement. Kinematic data were analyzed, and a computer model was applied to the data to characterize the limits of movement in the cervical spine and to estimate the moment arms of the neck muscles at different orientations of head-neck movement. For each initial neck orientation, the cat utilized a distinct set of vertebral alignments, relative joint movements, and muscle-activation patterns to achieve the same movement outcome. As inertial load increased, vertebral alignments and relative joint movements were constant with a vertically oriented neck but differed when the neck was more horizontally oriented. Different muscle-activation patterns were used to maintain the same kinematic pattern with increased inertial loads. Some muscle EMG response gains (rectus capitis major and splenius capitis) increased with increasing mass, while others (biventer cervicis and occipitoscapularis) demonstrated an initial increase and then a plateau. EMG phases were not affected by changing the mass of the system but were affected by changing neck orientation. The model predicted that muscle moment arms would vary little for the different vertebral alignments, suggesting a robust biomechanical system minimally compensates for small changes in task geometry.

Kinematics of the freely moving head and neck in the alert cat.

In this study we examined connections between the moment-generating capacity of the neck muscles and their patterns of activation during voluntary head-tracking movements. Three cats lying prone were trained to produce sinusoidal (0.25 Hz) tracking movements of the head in the sagittal plane, and 22.5 degrees and 45 degrees away from the sagittal plane. Radio-opaque markers were placed in the cervical vertebrae, and intramuscular patch electrodes were implanted in five neck muscles, including biventer cervicis, complexus, splenius capitis, occipitoscapularis, and rectus capitis posterior major. Videofluoroscopic images of cervical vertebral motion and muscle electromyographic responses were simultaneously recorded. A three-dimensional biomechanical model was developed to estimate how muscle moment arms and force-generating capacities change during the head-tracking movement. Experimental results demonstrated that the head and vertebrae moved synchronously, but neither the muscle activation patterns nor vertebral movements were constant across trials. Analysis of the biomechanical model revealed that, in some cases, modification of muscle activation patterns was consistent with changes in muscle moment arms or force-generating potential. In other cases, however, changes in muscle activation patterns were observed without changes in muscle moment arms or force-generating potential. This suggests that the moment-generating potential of muscles is just one of the variables that influences which muscles the central nervous system will select to participate in a movement.

The influence of forearm crutches on pelvic and hip kinematics in children with myelomeningocele: don't throw away the crutches.

Gait analysis was performed on 16 children with high-sacral-level myelomeningocele who walked with and without crutches to evaluate the influence of crutches on their unique walking pattern. All of the patients used solid ankle-foot orthoses (AFOs). Deviations in coronal and transverse planes improved with assisted walking. The timing of stance phase pelvic depression and the magnitude of stance phase hip abduction improved with crutch walking. Pelvic rotation, which was seven times the normal range of motion during no-crutch walking, decreased to four times normal with crutches. Walking velocity was not significantly different between conditions. The results demonstrated that deviations in pelvic and hip kinematics are related to muscle weakness and improve with crutch use. Crutches enable the patient to transfer some weight bearing to their upper extremities which decreases the demand on weak lower-extremity musculature. This allows them to maintain functional ambulation with a closer to normal gait pattern.

Cerebral perfusion during anesthesia with fentanyl, isoflurane, or pentobarbital in normal rats studied by arterial spin-labeled MRI.

The influence of anesthetic agents on cerebral blood flow (CBF) was tested in normal rats. CBF is quantified with arterial spin-labeled MRI in rats anesthetized with either an opiate (fentanyl), a potent inhalation anesthetic agent (isoflurane), or a barbiturate (pentobarbital) using doses commonly employed in experimental paradigms. CBF values were found to be about 2.5-3 times lower in most regions analyzed during anesthesia with either fentanyl (with N(2)O/O(2)) or pentobarbital vs. isoflurane (with N(2)O/O(2)), in agreement with findings utilizing invasive measurement techniques. CBF was heterogeneous in rats anesthetized with isoflurane (with N(2)O/O(2)), but relatively homogeneous in rats anesthetized with either fentanyl (with N(2)O/O(2)) or pentobarbital, also in agreement with studies using other techniques. Magn Reson Med 46:202-206, 2001.