Enduring suppression of hippocampal long-term potentiation following traumatic brain injury in rat.

This study investigated changes in synaptic responses (population spike and population EPSP) of CA1 pyramidal cells of the rat hippocampus to stimulation of the Schaffer collateral/commissural pathways 2-3 h after traumatic brain injury (TBI). TBI was induced by a fluid percussion pulse delivered to the parietal epidural space resulting in loss of righting responses for 4.90-8.98 min. Prior to tetanic stimulation, changes observed after the injury included: (1) decreases in population spikes threshold but not EPSP thresholds; (2) decreases in maximal amplitude of population spikes as well as EPSPs. TBI also suppressed long-term potentiation (LTP), as evidenced by reductions in post-tetanic increases in population spikes as well as EPSPs. Since LTP may reflect processes involved in memory formation, the observed suppression of LTP may be an electrophysiological correlate of enduring memory deficits previously demonstrated in the same injury model.

Cerebral circulation and metabolism after severe traumatic brain injury: the elusive role of ischemia.

Although experimental and pathological studies suggest an important role for ischemia in the majority of fatal cases of traumatic brain injury, ischemia has been a rare finding in most clinical studies of cerebral blood flow (CBF) in head-injured patients. The hypothesis of the present study was that cerebral ischemia occurs in the first few hours after injury, but that CBF measurements have not been performed early enough. Early measurements of CBF (by the 133Xe intravenous method) and arteriovenous oxygen difference (AVDO2) were obtained in 186 adult head-injured patients with a Glasgow Coma Scale score of 8 or less, and were correlated with neurological status and outcome. During the first 6 hours after injury, CBF was low (22.5 +/- 5.2 ml/100 gm/min) but increased significantly during the first 24 hours. The AVDO2 followed the opposite course; the decline of AVDO2 was most profound in patients with low motor scores, suggesting relative hyperemia after 24 hours. A significant correlation between motor score and CBF was found in the first 8 hours after injury (Spearman coefficient = 0.69, p less than 0.001), but as early as 12 hours postinjury this correlation was lost. A similar pattern was found for the relationship between CBF and outcome. Cerebral blood flow below the threshold for infarction (CBF less than or equal to 18 ml/100 gm/min) was found in one-third of the studies obtained within 6 hours, the incidence rapidly decreasing thereafter. A low CBF after 24 hours was not generally associated with a high AVDO2, and was probably a reflection of low oxidative metabolism rather than frank ischemia. In 24 patients, a CBF of 18 ml/100 gm/min or less was found at some point after injury; the mortality rate was significantly higher in this subgroup, and survivors did worse. In some cases, ischemia was successfully treated by reducing hyperventilation or inducing arterial hypertension. These results support the above hypothesis, and suggest that early ischemia after traumatic brain injury may be an important factor determining neurological outcome. Moreover, these data indicate that early hyperventilation or lowering of blood pressure to prevent brain edema may be harmful.

High-frequency septal stimulation suppresses long-term potentiation (LTP) in the CA1 region of rat hippocampus.

The effects of high-frequency stimulation (HFS) of the medial septum/diagonal band (MSDB) on long-term potentiation (LTP) of CA1 extracellular field potentials were assessed in anesthetized rats. Ten rats received HFS of the Schaffer collateral pathway alone, and 10 received MSDB HFS 10 min prior to hippocampal HFS. Septal HFS suppressed LTP development assessed by change in population spike (PS) amplitude 60 min after hippocampal HFS (ANOVA, P less than 0.03). Septal inhibition of LTP development was most prominent when septal HFS had little direct effect on the CA1 PS. These results provide a novel demonstration of the functional heterogeneity of septohippocampal pathways and in vivo modulation of hippocampal LTP by HFS of natural afferent inputs.

Cerebral blood flow and metabolism in severely head-injured children. Part 2: Autoregulation.

Autoregulation of cerebral blood flow ("CBF15") was tested in a series of 26 pediatric patients (mean age 13.2 years) with severe head injury (average Glasgow Coma Scale (GCS) score 5.5) in the acute stage. A baseline 133Xe CBF measurement was performed and then repeated, after blood pressure was increased by 29% with intravenous phenylephrine or decreased by 26% with intravenous trimethaphan camsylate. Correlations were made between CBF and clinical condition, outcome, time after injury, intracranial pressure (ICP), and pressure-volume index (PVI) changes, and the site of injury (hemispheres, diencephalon, or brain stem). The site of injury was determined with multimodality evoked potential measurements. Autoregulation was intact in 22 (59%) of 37 measurements. There was no correlation with GCS score, outcome, time after injury, site of injury, or way of testing (decreasing or increasing blood pressure). Autoregulation was statistically significantly more often impaired when CBF was either below normal -2 standard deviations (SD) (reduced flow) or above normal +2 SD (absolute hyperemia). In cases with intact autoregulation, mean ICP decreased from 17.5 to 15.0 mm Hg with higher blood pressure and increased from 19.0 to 21.3 mm Hg with lower blood pressure. When PVI was measured during the blood pressure manipulations, it was found to change in a direction opposite to the ICP change. The consequences of these findings in the management of ICP problems with blood pressure control are discussed.

Transient suppression of event-related evoked potentials produced by mild head injury in the cat.

Studies in humans have shown that sensory stimuli, presented in the context of certain tasks, can elicit a late positive component (LPC), namely P300, in the scalp-recorded evoked potential believed to reflect neural activity related to attentional processes. A similar LPC has been reported in cats and monkeys. In this study, the LPC of the auditory evoked potential (AEP) in the cat was used to detect impairment in attention to a relevant stimulus after low levels of cerebral concussion produced by a fluid percussion device. A hollow screw (for fluid percussion) and stainless steel screws (for AEP recording) were surgically placed in the skull. After recovery from surgery, animals were trained in the paradigm to obtain an LPC. Pupillary dilation was conditioned to tones. A random sequence of two discriminable tones was presented. The lower tone had a probability of 0.1 and was followed by a tail shock (tone-shock). After 400 to 1000 tone-shock presentations, animals attended to the lower tone stimulus as inferred by selective pupillary dilation. In the AEP an early positive component at 50 to 120 msec related to an alerting response was enhanced, and an LPC at 250 to 450 msec appeared in response to the paired tone-shock. Animals were then subjected to cerebral concussion. Complete recovery of normal reflexes, motor coordination, and orienting response was seen within 2 hours after injury. The LPC was suppressed for a period of at least 3 days, suggesting that low magnitudes of brain injury can disrupt higher-order neural activities. This disruption can persist despite recovery of other neurological functions.

Utility of multimodality evoked potentials in cerebral injury.

With technical rigor and a few modifications, reliable recordings of multimodality evoked potentials can be obtained in patients suffering head injury. The integrity or complexity of the EP waveform appears to be the best indicator of the reversibility of injury to the CNS. A multimodality approach is recommended in head trauma to enhance the sample of brain tissue evaluated, as a single pathway courses a very limited region of brain. In head injury, the EP and clinical findings do not correlate perfectly, although they are generally in agreement. In most cases, the EPs are accurate prognostic indicators and the rate of error of prediction is actually slightly lower than that of the clinical examination in head trauma. Serial evaluations are often necessary as a patient's course and prognosis may change. These changes may not be readily apparent on clinical examination. The information provided by MEP studies is quite helpful when the clinical examination is incomplete or inconsistent. Even when clinical data are available, the EP results, when combined with other indicators of neurologic integrity, afford a firmer basis for diagnostic and prognostic decisions.

Failure of prophylactic barbiturate coma in the treatment of severe head injury.

In certain subgroups of severely head-injured patients, the mortality rate remains unacceptably high. The authors describe a randomized, controlled trial of prophylactic pentobarbital therapy in a group of these patients. Pentobarbital was started as soon as possible after the head injury, regardless of the intracranial pressure (ICP), and was continued for a prescribed period of time. The study included 53 consecutive head-injured patients over the age of 12 years, who had either an acute intradural hematoma (subdural and/or intracerebral, large enough to warrant surgical decompression), or no mass lesion but whose best motor response was abnormal flexion or extension. All patients in the study were randomly assigned to a control group (26 cases) or a pentobarbital-treated group (27 cases) once the diagnosis had been made and informed consent obtained. All patients were treated with the same protocol of aggressive resuscitation, prompt diagnosis and treatment of mass lesions, and intensive care, with close follow-up monitoring. The randomization was effective in producing a close match between the control and treated groups with respect to age, sex distribution, cause of injury, neurological status, intracranial lesions, prevalence of early systemic insults, midline shift, and initial ICP. Outcome was essentially the same in each group. There was no difference between groups in the incidence of elevated ICP, the duration of ICP elevation, or the response of ICP elevations to treatment. Arterial hypotension occurred in 14 patients (54%) in the treated group and only two patients (7%) in the untreated group. Based on these data the authors cannot recommend the prophylactic use of pentobarbital coma in the treatment of patients with severe head injury. They also believe that its use is accompanied by significant side effects which can potentially worsen the condition of a patient with severe head injury.

Evoked potentials in severe head injury.

Provided herein is a summary of findings by the authors and other investigators regarding the application of evoked potential studies to the assessment of neurologic function in severely head-injured patients in the acute and subacute stages postinjury. Multimodality Evoked Potentials (MEP's) are reportedly useful in three primary areas: 1) diagnosis; 2) prognosis; and 3) monitoring recovery. In diagnosis, the abnormalities in MEP's can be associated specifically with focal sensory/motor deficits such as hemiparesis and, generally, with the severity and extent of brain dysfunction. MEP abnormalities that are severe reflect irreversible damage while the mild abnormalities point to transient, reversible CNS dysfunction. Definition of the severity and extent of brain dysfunction by MEP's allows an accurate prediction of outcome, or the potential for recovery. Their accuracy is superior to many commonly used indices and MEP results add strength to clinical indicators of prognosis. Changes in MEP results obtained within a patient over time can be used to trace recovery and assess, for an individual, the functional consequences of secondary neurologic insult or medical complication. The authors conclude that MEP studies may serve a useful function as noninvasive indices of neurologic function in the management of severely head-injured patients.

Effects of therapeutic pentobarbital coma on multimodality evoked potentials recorded from severely head-injured patients.

We sought to determine whether pentobarbital (PB) coma compromises the use of evoked potentials (EPs) in the assessment of brain dysfunction and of the prognosis of severely head-injured patients. Therefore, the effects of therapeutic PB on somatosensory (SEPs, BSEPs), visual (VEPs), and auditory (BAEPs) evoked potentials recorded from 20 patients early after injury were analyzed. Seventeen head-injured patients served as controls. EP studies were obtained shortly after admission (Mean Day 2, PB present) and approximately 2 weeks after injury (Mean Day 15, PB absent). The mean serum level of PB in the treatment group was 1.9 mg/100 ml. The drug effect was assessed by comparisons between the PB and the control groups. Statistical analyses were based on differences observed between two studies in the same patient. Analyses of covariance (F tests) were performed on data from all modalities. Wave form complexity was minimally affected by the drug. Middle and long latency components of the SEP were depressed by PB, and latencies of BSEP peaks and the early components of the SEP were delayed. The amplitude of some VEP peaks was reduced by PB. The BAEP was not significantly altered. All of the observed effects of PB were determined to be due to the hypothermia exhibited by PB-treated patients (mean temperature, 36.1 degrees C), which was not seen in the control group (mean, 37.8 degrees C). It is concluded that, with appropriate interpretation, EPs can be used to monitor brain function in head-injured patients when PB therapy is used.

The dynamics of neuronal dysfunction and recovery following severe head injury assessed with serial multimodality evoked potentials.

Serial studies of visual, auditory, and somatosensory evoked potentials (EP's) obtained from 139 severely head-injured patients up to 1 year after trauma were analyzed to ascertain whether or nor EP's can be used to monitor neurological recovery or deterioration following secondary insults. The EP data were analyzed using a grading system of abnormality developed previously, and patients were grouped by the most severe EP abnormality found in any modality during an early study (mean Day 3). The findings showed differential recovery trends depending on the severity of EP abnormality obtained on the initial study and presence of secondary insult. If EP's were normal early after injury, they remained so for up to 1 year, and these patients did well clinically. The EP's that were absent did not improve, and the patients had poor outcomes. Secondary insults did not affect the EP's or the outcomes of patients in these two groups. When EP's that were initially mildly abnormal became normal or remained no worse than mildly abnormal, patients had favorable outcomes in spite of complications. In contrast, deterioration of EP's with secondary insult indicated poor patient outcome. Severe EP abnormalities which improved over time led to favorable outcomes. However, persistence or deterioration of severe abnormalities indicated a poor outcome. Changes in EP's over time were better indicators of outcome than the presence or absence of complications. The results suggest that EP's may be used to assess neural recovery and the consequences of secondary insults to the brain. Four case reports are included to exemplify results.

Prognostic implications of early multimodality evoked potentials in severely head-injured patients. A prospective study.

Results of multimodality evoked potential (MEP) studies recorded from 100 comatose patients soon after severe head injury were analyzed prospectively, using a previously established grading system, to assess the prognostic value of MEP's with respect to patient outcome, to evaluate the effect of clinically relevant sequelae of head injury on the prediction of outcome by MEP's and to describe time to clinical recovery as a function of initial MEP grade. Graded MEP's when recorded in the first few days after head injury, could predict patient outcome at 1 year with approximately 80% accuracy. Exclusion from the analysis of patients who died from causes unrelated to the brain and those with severe systemic complications that occurred after the evoked potentials were recorded improved the accuracy of outcome prediction to nearly 100%. The presence of a mass lesion requiring surgery reduces the probability if good to moderate outcome for a given MEP grade by approximately 25% to 40% from the seen in patients without mass lesions. The clinical outcome predicted shortly after head injury by MEP grades may not be realized for many months. Patients with mild MEP abnormality (Grade I or II) generally reach their outcome by 3 to 6 months, whereas those with more severe deficits (Grade III) may not show improvement for at least 1 year.

The use of the laser in neurological surgery.

Lasers generate unidirectional beams of monochromatic, and temporally and spatially coherent electromagnetic radiation that are capable of vaporizing and coagulating biological tissue. Specific physical characteristics of laser energies of different wavelengths impart to each form of surgical laser specific potentials for clinical use in neurological surgery. The major advantages of surgical lasers appear to be improved precision, reduction of surgically related mechanical trauma, reduction of blood loss, and decreased operative time. Improvement of operative mortality and morbidity and increased longevity that might result from its use would make the laser cost effective.

Behavioral and physiological studies of non-narcotic analgesia in the rat elicited by certain environmental stimuli.

These experiments characterized the analgesia resulting from exposure to certain noxious and/or stressful manipulations. Rats exposed either to electric grid shock (0.35-2.0 mA for 10-30 sec) or to 5 min of presumably non-painful centrifugal rotation (about 7.0 transverse g's) were analgesic as measured by tail-flick, hot plate and responses to applications of a calibrated paw pinch or alligator clip. Analgesia produced by shock (SA) or centrifugal rotation (RA) persisted after termination of these manipulations. Neither SA nor RA were attended by generalized sensory, attentional or motoric deficits. Intraperitoneal injection of hypertonic saline also increased tail-flick latencies. Exposure to brief ether anesthesia or horizontal oscillation, both of which have been reported to increase ACTH secretion (a commonly used indicator of stress), did not produce analgesia as measured by the tail-flick test. The use of classical conditioning procedures to pair shock with environmental stimuli resulted in increased tail-flick latencies. The narcotic antagonist naloxone (1 mg/kg, i.p.) did not reduce the tail-flick inhibition produced by shock, rotation, hypertonic saline or classical conditioning. Chlordiazepoxide (5 mg/kg, i.p.) also failed to antagonize the increased tail-flick latencies produced by shock or conditioning. Tail-flick inhibition produced by shock or rotation was markedly reduced by complete spinal cord transection at thoracic levels. These results suggest that: (1) the selective modulation of nociceptive input at the level of the spinal cord can be mediated by a supraspinal system or systems physiologically distinct from those involved in analgesia produced by the administration of opiates; (2) non-narcotic modulation of nociceptive input occurring within the spinal cord can be learned by exposure to classical conditioning procedures; and (3) noxious stimuli are sufficient but not necessary to produce a non-narcotic analgesia; stress alone, however, is not always sufficient to produce this analgesia.