Kim T Ng

Factors influencing outcome following mild traumatic brain injury in adults

This study aimed to investigate outcome in adults with mild traumatic brain injury (TBI) at 1 week and 3 months postinjury and to identify factors associated with persisting problems. A total of 84 adults with mild TBI were compared with 53 adults with other minor injuries as controls in terms of postconcussional symptomatology, behavior, and cognitive performance at 1 week and 3 months postinjury. At 1 week postinjury, adults with mild TBI were reporting symptoms, particularly headaches, dizziness, fatigue, visual disturbance, and memory difficulties. They exhibited slowing of information processing on neuropsychological measures, namely the WAIS-R Digit Symbol subtest and the Speed of Comprehension Test. By 3 months postinjury, the symptoms reported at 1 week had largely resolved, and no impairments were evident on neuropsychological measures. However, there was a subgroup of 24% of participants who were still suffering many symptoms, who were highly distressed, and whose lives were still significantly disrupted. These individuals did not have longer posttraumatic amnesia (PTA) duration. They were more likely to have a history of previous head injury, neurological or psychiatric problems, to be students, females, and to have been injured in a motor vehicle accident. The majority were showing significant levels of psychopathology. A range of factors, other than those directly reflecting the severity of injury, appear to be associated with outcome following mild TBI.

Neuronal–glial interactions and behaviour

Both neurons and glia interact dynamically to enable information processing and behaviour. They have had increasingly intimate, numerous and differentiated associations during brain evolution. Radial glia form a scaffold for neuronal developmental migration and astrocytes enable later synapse elimination. Functionally syncytial glial cells are depolarised by elevated potassium to generate slow potential shifts that are quantitatively related to arousal, levels of motivation and accompany learning. Potassium stimulates astrocytic glycogenolysis and neuronal oxidative metabolism, the former of which is necessary for passive avoidance learning in chicks. Neurons oxidatively metabolise lactate/pyruvate derived from astrocytic glycolysis as their major energy source, stimulated by elevated glutamate. In astrocytes, noradrenaline activates both glycogenolysis and oxidative metabolism. Neuronal glutamate depends crucially on the supply of astrocytically derived glutamine. Released glutamate depolarises astrocytes and their handling of potassium and induces waves of elevated intracellular calcium. Serotonin causes astrocytic hyperpolarisation. Astrocytes alter their physical relationships with neurons to regulate neuronal communication in the hypothalamus during lactation, parturition and dehydration and in response to steroid hormones. There is also structural plasticity of astrocytes during learning in cortex and cerebellum.

Use of the Westmead PTA scale to monitor recovery of memory after mild head injury

Study objective: Duration of post-traumatic amnesia (PTA) is an important index of severity of head injury. Retrospective assessment of PTA duration is arguably unreliable. Existing objective measures of PTA duration are designed for use over a 24-hour timeframe and, therefore, are not useful for assessing PTA following mild head injury (MHI). A revised version of the Westmead PTA scale was developed for assessing patients with MHI in the Emergency Department (ED) at hourly intervals. The objective of this study was the field testing of this scale in EDs and assessment of validity and reliability of test items. Methods: The scale contained 12 items, assessing orientation, memory for a face and name in a photograph and three pictures of objects. This revised scale, administered by nursing staff, was completed at least four times at hourly intervals by 147 adults with MHI in the ED and again at follow-up 1 week later. It was also completed by 109 demographically similar controls. Results were compared with Glasgow Coma scores and retrospective estimates of PTA duration based on patient report and medical records. Results: Thirty-six per cent of MHI participants made errors on the scale in the ED, a significantly greater proportion than in MHI or controls at follow-up. Removal of the items 5 (day of week) and 9 (recall of name of face in photograph) improved the validity of the measure significantly. Scores correlated significantly with Glasgow Coma Scale scores and estimated duration of PTA. Conclusion: The Westmead Scale (minus items 5 and 9) is a valid measure of PTA duration in adult patients with MHI in ED. Its use will allow for more appropriate timing of discharge and accurate prognostic information.

Complex Roles of Glutamate in the Gibbs—Ng Model of One-trial Aversive Learning in the New-born Chick

Glutamate is the most widespread excitatory transmitter in the CNS and is probably involved in LTP, a neural phenomenon which may be associated with learning and memory formation. Intracerebral injection of large amounts of glutamate between 5 min and 2.5 min after passive avoidance learning in young chicks inhibits short-term memory, which occurs between 0 and 10 min post-learning in a three-stage model of memory formation first established by Gibbs and Ng(25) [Physiol. Behav. 23:369-375; 1979]. This effect may be attributed to non-specific excitation. Blockade of glutamate uptake by L-aspartic and beta-hydroxamate also abolishes this stage of memory, provided the drug is administered within 2.5 min of learning. Interference with either production of percursors for transmitter glutamate in astrocytes or with glutamate receptors is also detrimental to memory formation, but the effects appear much later. After its release from glutamatergic neurons, glutamate is, to a large extent, accumulated into astrocytes where it is converted to glutamine, which can be returned to glutamatergic neurons and reutilized for synthesis of transmitter glutamate, and partly oxidized as a metabolic substrate. The latter process leads to a net loss of transmitter glutamate which can be compensated for by de novo synthesis of a glutamate precursor alpha-ketoglutarate (alpha KG) in astrocytes, a process which is inhibited by the astrocyte-specific toxin fluoroacetate (R. A. Swanson, personal communication). Intracerebral injection of this toxin abolishes memory during an intermediate stage of memory processing occurring between 20 and 30 min post-training (50) [Cog. Brain Res, 2:93-102; 1994]. Injection of methionine sulfoximine (MSO), a specific inhibitor of glutamine synthetase, which interferes with the re-supply of transmitter glutamate to neurons by inhibition of glutamine synthesis in astrocytes, has a similar effect. This effect of MSO is prevented by intracerebral injection of glutamate, glutamine, or a combination and alpha KG and alanine. MSO must be administered before learning, but does not interfere with acquisition since short-term memory remains intact. Administration of either the NMDA antagonist AP5, the AMPA antagonist DNQX, or the metabotropic receptor antagonist MCPF, also induces amnesia. Memory loss in each case does not occur until after 70 min post-training, during a protein synthesis-dependent long-term memory stage which begins at 60 min following learning. However, to be effective, AP5 must be administered within 60 s following learning, MCPG before 15 min post-learning, and DNQX between 15 and 25 min after learning. Together, these findings suggest that learning results in an immediate release of glutamate, followed by a secondary release of this transmitter at later stages of processing of the memory trace, and that one or both of these increases in extracellular glutamate concentration are essential for the consolidation of long-term memory. Since both fluoroacetate and MSO act exclusively on glial cells, the findings also show that neuronal-glial interactions are necessary during the establishment of memory.

Reciprocal changes in forebrain contents of glycogen and of glutamate/glutamine during early memory consolidation in the day-old chick.

Passive avoidance learning is with advantage studied in day-old chicks trained to distinguish between beads of two different colors, of which one at training was associated with aversive taste. During the first 30-min post-training, two periods of glutamate release occur in the forebrain. One period is immediately after the aversive experience, when glutamate release is confined to the left hemisphere. A second release, 30 min later, may be bilateral, perhaps with preponderance of the right hemisphere. The present study showed increased pool sizes of glutamate and glutamine, specifically in the left hemisphere, at the time when the first glutamate release occurs, indicating de novo synthesis of glutamate/glutamine from glucose or glycogen, which are the only possible substrates. Behavioral evidence that memory is extinguished by intracranial administration at this time of iodoacetate, an inhibitor of glycolysis and glycogenolysis, and that the extinction of memory is counteracted by injection of glutamine, supports this concept. A decrease in forebrain glycogen of similar magnitude and coinciding with the increase in glutamate and glutamine suggests that glycogen rather than glucose is the main source of newly synthesized glutamate/glutamine. The second activation of glutamatergic activity 30 min after training, when memory is consolidated into stable, long-term memory, is associated with a bilateral increase in pool size of glutamate/glutamine. No glycogenolysis was observed at this time, but again there is a temporal correlation with sensitivity to inhibition by iodoacetate and rescue by glutamine, indicating the importance of de novo synthesis of glutamate/glutamine from glucose or glycogen.

Inhibition of glutamine synthetase activity prevents memory consolidation

Methionine sulfoximine, a specific inhibitor of the exclusively glial enzyme glutamine synthetase, was shown, at a concentration of 3.5-4.5 mM, to prevent consolidation of memory for a passive avoidance task in day-old chicks. Provided the drug was administered 5-20 min before the learning task, significant retention loss was observed from the normal time of onset of the second of three postulated stages in the memory formation sequence but the drug had to be administered considerably earlier. The amnestic effect of methionine sulfoximine was successfully counteracted by L-glutamine (10 mM) and monosodium glutamate (4 mM), and also by a cocktail of alpha-ketoglutarate (5 mM) and alanine (5 mM). This effect of methionine sulfoximine is attributed to its blockade of the production of glutamine via the glutamate-glutamine cycle, leading to a reduced capacity of neurons to replenish their transmitter glutamate.

Cyclosporin A, an inhibitor of calcineurin, impairs memory formation in day-old chicks

Considerable evidence exists that changes in the phosphorylation state of neuronal proteins are correlated with learning and that inhibition of various protein kinases disrupts memory formation. Given the reversible nature of protein phosphorylation, a role for protein phosphatases in memory processing also seems likely. It has been shown recently that administration of the phosphatase inhibitor, okadaic acid, disrupts memory formation in day-old chicks, with retention deficits first appearing at approximately 40 min post-training [93]. In the present study the intracranial administration of the immunosuppressant cyclosporin A was also found to produce retention deficits in day-old chicks trained on a single-trial, passive-avoidance task, but the deficits were not significant until 85 min post-training. The difference could not be attributed to differences in the pharmacokinetics of the drugs. Since okadaic acid preferentially inhibits protein phosphatases 1 and 2A, while cyclosporin A is reported to inhibit only the Ca2+/calmodulin-dependent protein phosphatase, calcineurin, it is possible that different phosphatases may be involved in distinct stages of memory formation, as has been reported previously for protein kinases. The possibility that cyclosporin A may, in addition, act through inhibition of cyclophilins peptidyl-prolyl-cis/transisomerase activity is also canvassed.

Administration of DL-2-amino-5-phosphonovaleric acid (AP5) induces transient inhibition of reminder-activated memory retrieval in day-old chicks.

DL-2-Amino-5-phosphonovaleric acid (50 microM) administered immediately after a visual reminder presented to day-old chickens between 7.5 min and 24 h following a single trial passive avoidance learning task produced transient losses of memory on retention test, an effect not observed in the absence of a reminder or when the reminder was given 48 h post learning. The duration of the transient deficits decreased with increasing interval between training and the reminder trial. The time of onset of memory loss after the reminder trial appeared to increase with increasing interval between the training and the reminder trials. The results suggest that, for a period of at least up to 24 h after passive avoidance training, retrieval of memory may lead to processes which are sensitive to inhibition by the NMDA receptor antagonist AP5, with the duration of sensitivity post retrieval decreasing as the period of memory consolidation increases. The results extend previously reported findings and suggest the possibility that consolidation of a stable memorial representation of a learning experience may take over several days and may entail the concurrent laying down of a stable retrieval mechanism.

Memory retrieval in the day-old chick: a psychobiological approach.

This review integrates a series of studies conducted examining memory retrieval processes in the day-old chick. On the basis of these studies it is proposed that two processes are activated following retrieval of a memory. The first is an immediate memory recall or retrieval mechanism responsible for the chicks ability to remember the information and respond appropriately to the stimulus. The second process is activated following the completion of the first immediate retrieval phase. Further, it is proposed that the function of this secondary phase may be to allow for the modification of a memory undergoing storage processes. It is proposed that the processes of memory formation and memory retrieval are parallel at a cellular level, but at the functional level of information transfer they are interdependent.

Inhibition of guanylate cyclase and protein kinase G impairs retention for the passive avoidance task in the day-old chick.

Nitric oxide (NO) is a highly labile chemical messenger which has previously been implicated in memory processes in a variety of learning paradigms and species. However, there is only limited evidence to suggest which enzymes are acted upon by NO during the formation of memory. The present study investigates the role of guanylate cyclase (GC) and protein kinase G (PKG) in a form of passive avoidance learning known to be dependent on nitric oxide activity. It was determined that in vivo pharmacological inhibition of GC using either 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one or 6-anilino-5,8-quinolinedione resulted in two transitory memory retention deficits centred around 40 and 120 min posttraining, respectively. In contrast, inhibition of PKG with N-[2-(methylamino)ehtyl]-5-isoquinoline-sulfornamide hydrochloride (H-8) resulted in a single temporary retention loss centered at 120 min posttraining. These temporary retention losses appear to be specific to memory since they were dose-dependent and could not be explained by nonspecific performance effects. Further, these results suggest that these agents inhibit memory retrieval rather than formation, since memory is subsequently available. The current findings indicate that guanylyl cyclase mediates two memory retrieval processes, the latter of which appears to be PKG-dependent. In contrast, since inhibition of NO results in a permanent retention loss, it is suggested that NO is required for memory formation through GC-independent processes.