Working memory and new learning following pediatric traumatic brain injury

Working memory (WM), the ability to monitor, process and maintain task relevant information on-line to respond to immediate environmental demands, is controlled by frontal systems (D'Esposito et al., 2006), which are particularly vulnerable to damage from a traumatic brain injury (TBI). This study employed the adult-based Working Memory model of Baddeley and Hitch (1974) to examine the relationship between working memory function and new verbal learning in children with TBI. A cross-sectional sample of 36 school-aged children with a moderate to severe TBI was compared to age-matched healthy Controls on a series of tasks assessing working memory subsystems: the Phonological Loop (PL) and Central Executive (CE). The TBI group performed significantly more poorly than Controls on the PL measure and the majority of CE tasks. On new learning tasks, the TBI group consistently produced fewer words than Controls across the learning and delayed recall phases. Results revealed impaired PL function related to poor encoding and acquisition on a new verbal learning task in the TBI group. CE retrieval deficits in the TBI group contributed to general memory dysfunction in acquisition, retrieval and recognition memory. These results suggest that the nature of learning and memory deficits in children with TBI is related to working memory impairment.     

Comprehensive assessment of memory functioning following traumatic brain injury in children

This study examined specific memory functions in 52 children with mild‐moderate or severe traumatic brain injury (TBI) and 29 noninjured controls using the Wide Range Assessment of Memory and Learning (WRAML). Children's recall varied as a function of injury severity and task demands. The participants with severe brain injuries performed worse than controls on global measures of visual memory, learning, and general memory functioning, as well as on specific subtests measuring recall of contextual verbal information. Children with mild‐moderate brain injuries performed similarly to controls except for poorer performance on 2 subtests measuring sound‐symbol learning and recall of geometric designs. Results suggest that the WRAML provides clinically useful information and that specific aspects of memory processing need to be evaluated following childhood TBI.     

The electrophysiological effects of a brain injury on auditory memory functioning. The QEEG correlates of impaired memory.

The effect of a brain injury on the quantitative EEG (QEEG) variables during an auditory memory activation condition was examined with 56 normal subjects and 85 mild traumatic brain-injured (MTBI) subjects. An analysis was conducted on the different response patterns of the two groups, the variables which were correlated with memory performance in the brain-injured group, and the variables which predicted the memory score for the combined two groups (normal and brain injured). The three conditions included the input task, the immediate recall, and the delayed recall task. The consistent effect of a brain injury was a lowering of the connectivity patterns in the beta1 and beta2 frequencies (phase and coherences) and increases predominantly in the relative power of beta1 (13-32Hz), which were correlated with the differences in recall. There is a subtle shift to right hemisphere/right temporal functioning and employment of the higher beta1 and beta2 frequencies (phase and coherence) in the response pattern of the MTBI subject. Memory functioning is predominantly positively correlated with connection activity (phase and coherence) and negatively correlated with beta activation at specific locations.     

Rey Auditory-Verbal Learning Test: the effects of age and gender, and norms for delayed recall and story recognition trials.

Immediate recall and three measures of delayed memory performance were evaluated in 134 healthy adults aged 16-76. Gender of subjects had no Influence on performance for any of the acquisition or retention trials. Age influenced acquisition as memory load began to exceed five to six words, with older subjects exhibiting decreased capacity. There was little loss of information between the immediate and delayed recall trials for any age group. Norms for a 30-min delayed recall trial, commission errors on delayed recall, and delayed recognition using Rey's story recognition procedure are presented, and implications for clinical use are discussed.     

Childhood Head Injury and Metacognitive Processes in Language and Memory

We studied the metacognitive functioning of children with severe and mild traumatic brain injury (TBI) and typically developing children. To test metacognition for memory, children were tested on a modified Judgment of Learning task. We found that children with severe TBI were impaired in their ability to predict recall of specific items prior to study-recall trials, but were unimpaired in predicting recall on a delayed test when the judgment was made after study-recall trials. Metacognitive knowledge impairment for memorial abilities was also demonstrated in children with severe TBI by poor estimation of memory span and exaggerated overconfidence in performance. To test metacognition within the language domain, we gave children a sentence anomaly detection and repair task in which spoken sentences were monitored for semantic anomalies. Children with severe TBI were impaired on the detection of semantic anomalies, especially under conditions of high memory load. However, metalinguistic knowledge in the form of adequate repairs of anomalous sentences, was preserved. Results are discussed in terms of effects of age at test and injury severity.     

Childhood head injury and metacognitive processes in language and memory

We studied the metacognitive functioning of children with severe and mild traumatic brain injury (TBI) and typically developing children. To test metacognition for memory, children were tested on a modified Judgment of Learning task. We found that children with severe TBI were impaired in their ability to predict recall of specific items prior to study-recall trials, but were unimpaired in predicting recall on a delayed test when the judgment was made after study-recall trials. Metacognitive knowledge impairment for memorial abilities was also demonstrated in children with severe TBI by poor estimation of memory span and exaggerated overconfidence in performance. To test metacognition within the language domain, we gave children a sentence anomaly detection and repair task in which spoken sentences were monitored for semantic anomalies. Children with severe TBI were impaired on the detection of semantic anomalies, especially under conditions of high memory load. However, metalinguistic knowledge in the form of adequate repairs of anomalous sentences, was preserved. Results are discussed in terms of effects of age at test and injury severity.     

The effects of traumatic brain injuries on information processing.

Many individuals experience memory impairment subsequent to traumatic brain injuries (TBI). These memory deficits may result from general impairment of information processing rather than damage to memory critical neurological systems. The investigators examined learning time and recall errors for easy and hard word pairs in a distraction and no-distraction condition to examine learning patterns. Although results indicated that individuals with and without TBI generally showed the same learning and retrieval patterns, individuals with TBI did so in an accentuated manner. This suggests that attentional deficits associated with TBI are not responsible for subsequent memory deficits.     

Brain free magnesium concentration is predictive of motor outcome following traumatic axonal brain injury in rats.

A number of studies have supported a role for brain free magnesium as an important secondary injury factor in the development of neurologic deficits following traumatic brain injury. Despite this, few studies have characterised free magnesium changes in diffuse models of brain injury relevant to clinical trauma, and none have critically examined the association between brain free magnesium concentration and degree of neurologic deficit following graded trauma. In the present study, a combination of nuclear magnetic resonance spectroscopy and rotarod motor function tests were used to characterise the relationship between brain free magnesium concentration and neurologic motor function following graded traumatic axonal brain injury in rats. Induction of moderate or severe impact-acceleration induced traumatic brain injury resulted in a profound decline (p < 0.01) in brain free magnesium concentration that persisted for a minimum of 4 days post-trauma in both injury groups. Posttraumatic rotarod deficits assessed on a daily basis after injury were linearly correlated with brain free magnesium concentration measured in the same animals immediately after the motor tests were performed (r = 0.87; p < 0.001). These results suggest that brain free magnesium declines following graded diffuse axonal brain injury and that the concentration of the ion after trauma may be a prognostic indicator of motor outcome following.     

Sulforaphane improves cognitive function administered following traumatic brain injury

Recent studies have shown that sulforaphane, a naturally occurring compound that is found in cruciferous vegetables, offers cellular protection in several models of brain injury. When administered following traumatic brain injury (TBI), sulforaphane has been demonstrated to attenuate blood-brain barrier permeability and reduce cerebral edema. These beneficial effects of sulforaphane have been shown to involve induction of a group of cytoprotective, Nrf2-driven genes, whose protein products include free radical scavenging and detoxifying enzymes. However, the influence of sulforaphane on post-injury cognitive deficits has not been examined. In this study, we examined if sulforaphane, when administered following cortical impact injury, can improve the performance of rats tested in hippocampal- and prefrontal cortex-dependent tasks. Our results indicate that sulforaphane treatment improves performance in the Morris water maze task (as indicated by decreased latencies during learning and platform localization during a probe trial) and reduces working memory dysfunction (tested using the delayed match-to-place task). These behavioral improvements were only observed when the treatment was initiated 1 h, but not 6 h, post-injury. These studies support the use of sulforaphane in the treatment of TBI, and extend the previously observed protective effects to include enhanced cognition.     

Assessment of cognitive function following magnesium therapy in the traumatically injured brain.

Many studies have examined the preclinical efficacy of Mg2+ therapy in models of traumatic brain injury. However, more of these studies have examined sensorimotor and motor performance than cognitive performance following injury. The present paper reviews the use of Mg2+ therapy to facilitate cognitive recovery in several models of cortical injury in the rodent. The first study examined the ability of daily injections of MgCl2 (1 or 2 mmol) to impair acquisition of a reference memory task in the Morris Water Maze. Additional studies examined the ability of MgCl2 to improve cognitive function following bilateral anterior medial cortex ablations, bilateral frontal cortex contusions, and unilateral frontal contusions. The results from these studies indicate that MgCl2 therapy is biologically active and readily crosses the blood-brain barrier because daily injections of MgCl2 impaired learning of a reference memory task in intact rats. Mg2+ therapy for brain injury revealed that administration of post-injury MgCl2 effectively improved recovery of cognitive deficits following injury. These results suggest that Mg2+ therapy is effective in facilitating cognitive recovery of function following brain injury; however, there are task and dose-dependent aspects to this recovery.     

Cognitive performance in multiple trauma patients 3 years after injury.

OBJECTIVES: Patients with sequelae from multiple trauma commonly display cognitive disturbances, specifically in the areas of attention and memory. This study was designed to assess cognitive functioning 3 years after severe multiple trauma and to investigate how cognitive performance is related to head injury severity and psychological distress respectively. METHODS: Sixty-eight multiple trauma patients were tested with a screening battery consisting of six neuropsychological tasks 3 years after injury. A measure of psychological distress (20-item General Health Questionnaire, or GHQ-20) was also administered. RESULTS: Patients who neither showed signs of reduced consciousness on admission to the hospital nor reported significant psychological distress at follow-up tended to have normal test performance. In five of the six tasks, cognitive impairment was related to the severity of the traumatic brain injury as measured by the Glasgow Coma Scale (GCS). In both attention span tasks, patients designated as cases by the GHQ had significantly lower scores than noncase patients. These bivariate relationships were upheld in multiple regression analyses, in which age, sex, and GCS and GHQ scores were entered as independent variables. When patients with severe head injuries were excluded from the analyses, GCS scores still contributed to the variance in tests of verbal attention span and delayed recall, but performance on attentional tasks was more strongly related to psychological distress than to GCS scores. CONCLUSIONS: Cognitive deficits in multiple trauma patients were related both to the severity of the traumatic brain injury and to the degree of psychological distress. The strength of the association between brain injury as indicated by GCS scores and cognitive performance differed between different tasks. Neuropsychological testing may assist in differentiating primary organic from secondary psychogenic impairments.     

The effects of depression and anxiety on memory performance.

The effects of depression and anxiety, as assessed by MMPI D and Pt scales, on memory performance was examined in 3999 veterans who completed the California Verbal Learning Test (CVLT). Depressive symptoms (without anxiety) had an adverse effect on immediate recall of new information and the total amount (but not rate) of acquisition; however, retrieval and retention were unaffected. On the other hand, high levels of anxiety did not have significant detrimental effects on any aspect of memory functioning assessed including immediate recall, total amount acquired, retention, and retrieval of novel information. However, when depression was compounded by anxiety, there was not only an adverse effect on immediate recall and amount (but not rate) of acquisition, but also on the retrieval of newly learned information. We conclude that the presence of comorbid anxiety may, in part, account for the variability in previous research findings regarding the effects of depression on memory functioning.     

Nitric oxide in traumatic brain injury

Nitric oxide (NO) is a gaseous chemical messenger which has functions in the brain in a variety of broad physiological processes, including control of cerebral blood flow, interneuronal communications, synaptic plasticity, memory formation, receptor functions, intracellular signal transmission, and release of neurotransmitters. As might be expected from the numerous and complex roles that NO normally has, it can have both beneficial and detrimental effects in disease states, including traumatic brain injury. There are two periods of time after injury when NO accumulates in the brain, immediately after injury and then again several hours-days later. The initial immediate peak in NO after injury is probably due to the activity of endothelial NOS and neuronal NOS. Pre-injury treatment with 7-nitroindazole, which probably inhibits this immediate increase in NO by neuronal NOS, is effective in improving neurological outcome in some models of traumatic brain injury (TBI). After the initial peak in NO, there can be a period of relative deficiency in NO. This period of low NO levels is associated with a low cerebral blood flow (CBF). Administration of L-arginine at this early time improves CBF, and outcome in many models. The late peak in NO after traumatic injury is probably due primarily to the activity of inducible NOS. Inhibition of inducible NOS has neuroprotective effects in most models.     

Detection of changes in material-specific memory following temporal lobectomy using the Wechsler Memory Scale-Revised.

To determine the utility of the Wechsler Memory Scale-Revised (WMS-R) in measuring material-specific memory changes, within-subject comparisons of the Verbal-Visual Memory Index discrepancy and discrepancy scores using short-term and delayed Logical Memory and Visual Reproduction subtests from the WMS-R were studied prior to and following temporal lobectomy among 30 patients with left temporal lobectomy, 30 with right temporal lobectomy, and 50 epileptic, non-surgical controls. The groups were matched on age, sex, handedness, age at seizure onset, duration of epilepsy, and presurgical Verbal and Performance IQ; the right temporal group had a higher mean educational level (p <.05). All surgical patients were left hemisphere dominant for speech; those who had persistent postoperative seizures were excluded from study. On retesting, left temporal lobectomy was associated with a marked change in short-term and delayed memory discrepancy scores primarily due to a drop in verbal memory. Right temporal lobectomy was not associated with a drop in visual memory, suggesting that the WMS-R appears to reflect decrements in material-specific memory following left but not right temporal lobectomy. The nonsurgical controls showed increases in both short-term and delayed memory discrepancy scores due to increases in short-term and delayed verbal memory. Relative to these controls, the absence of comparable increases in verbal memory among the right temporal patients suggests that right temporal lobectomy may be associated with risk to verbal memory.     

Brain-derived neurotrophic factor administration after traumatic brain injury in the rat does not protect against behavioral or histological deficits

Brain-derived neurotrophic factor has been shown to be neuroprotective in models of excitotoxicity, axotomy and cerebral ischemia. The present study evaluated the therapeutic potential of brain-derived neurotrophic factor following traumatic brain injury in the rat. Male Sprague-Dawley rats (N=99) were anesthetized and subjected to lateral fluid percussion brain injury of moderate severity (2.4-2.8 atm) or sham injury. Four hours after injury, the animals were reanesthetized, an indwelling, intraparenchymal cannula was implanted, and infusion of brain-derived neurotrophic factor or phosphate-buffered saline vehicle was initiated from a mini-osmotic pump and continued for two weeks. In Study 1 (N=48), vehicle or 12 microg/day of brain-derived neurotrophic factor was infused into the dorsal hippocampus. In Study 2 (N=51), vehicle or brain-derived neurotrophic factor at a high (12 microg/day) or low dose (1.2 microg/day) was infused into the injured parietal cortex. All animals were evaluated for neurological motor function at two days, one week and two weeks post-injury. Cognitive function (learning and memory) was assessed at two weeks post-injury using a Morris Water Maze. At two weeks post-injury, neuronal loss in the hippocampal CA3 and dentate hilus and in the injured cortex was evaluated. In Study 2, neuronal loss was also quantified in the thalamic medial geniculate nucleus. All of the above outcome measures demonstrated significant deleterious effects of brain injury (P<0.05 compared to sham). However, post-traumatic brain-derived neurotrophic factor infusion did not significantly affect neuromotor function, learning, memory or neuronal loss in the hippocampus, cortex or thalamus when compared to vehicle infusion in brain-injured animals, regardless of the infusion site or infusion dose (P>0.05 for each).In contrast to previous studies of axotomy, ischemia and excitotoxicity, our data indicate that brain-derived neurotrophic factor is not protective against behavioral or histological deficits caused by experimental traumatic brain injury using the delayed, post-traumatic infusion protocol examined in these studies.     

Early brain injury in children: development and reorganization of cognitive function

Children who sustain congenital or acquired brain injury typically experience a diffuse insult that impacts many areas of the brain. Yet research has only recently begun to examine the development of these children, who often provide excellent examples of the presence or absence of neural plasticity. Development and recovery after such injuries reflects both restoration and reorganization of cognitive functions. To understand these processes, research should focus on questions and assessment paradigms oriented toward the acquisition (rather than the recovery) of cognitive functions. Outcomes may appear similar across types of insults, even when the sources of difficulties and their neural correlates are different. Comparisons of outcomes involving intellectual functions, memory and learning, reading, and language/discourse in children who sustain congenital injury (spina bifida meningomyelocele) and acquired injury (traumatic brain injury) illustrate these principles and the value of research on diffuse brain injury in children.     

Early Brain Injury in Children: Development and Reorganization of Cognitive Function

Children who sustain congenital or acquired brain injury typically experience a diffuse insult that impacts many areas of the brain. Yet research has only recently begun to examine the development of these children, who often provide excellent examples of the presence or absence of neural plasticity. Development and recovery after such injuries reflects both restoration and reorganization of cognitive functions. To understand these processes, research should focus on questions and assessment paradigms oriented toward the acquisition (rather than the recovery) of cognitive functions. Outcomes may appear similar across types of insults, even when the sources of difficulties and their neural correlates are different. Comparisons of outcomes involving intellectual functions, memory and learning, reading, and language/discourse in children who sustain congenital injury (spina bifida meningomyelocele) and acquired injury (traumatic brain injury) illustrate these principles and the value of research on diffuse brain injury in children.     

Association of KIBRA and memory

We report on the association of KIBRA with memory in two samples of older individuals assessed on either memory for semantically unrelated word stimuli (Rey Auditory Verbal Learning Test, n = 2091), or a measure of semantically related material (the WAIS Logical Memory Test of prose-passage recall, n = 542). SNP rs17070145 was associated with delayed recall of semantically unrelated items, but not with immediate recall for these stimuli, nor with either immediate or delayed recall for semantically related material. The pattern of results suggests a role for the T → C substitution in intron 9 of KIBRA in a component of episodic memory involved in long-term storage but independent of processes shared with immediate recall such as rehearsal involved in acquisition and rehearsal or processes.     

Quantitative and qualitative aspects of memory performance after minor head injury.

Neuropsychological investigation of minor head injury (MHI) has consistently corroborated patient subjective complaints of memory loss. An experimental group of 11 minor head-injured patients and a control group of age-matched normal volunteers were compared on the California Verbal Learning Test (CVLT) and on the Rey-Osterreith complex figure. Minor head-injured subjects were found to be impaired on measures of short-term and delayed free recall as well as on measures of organizational-semantic strategy in the retrieval phase. These findings are consistent with subjective reports from the patients and may in part explain reduced psychosocial and vocational adaptation following minor head injury.     

Voluntary exercise following traumatic brain injury: brain-derived neurotrophic factor upregulation and recovery of function

Voluntary exercise leads to an upregulation of brain-derived neurotrophic factor (BDNF) and associated proteins involved in synaptic function. Activity-induced enhancement of neuroplasticity may be considered for the treatment of traumatic brain injury (TBI). Given that during the first postinjury week the brain is undergoing dynamic restorative processes and energetic changes that may influence the outcome of exercise, we evaluated the effects of acute and delayed exercise following experimental TBI. Male Sprague-Dawley rats underwent either sham or lateral fluid-percussion injury (FPI) and were housed with or without access to a running wheel (RW) from postinjury days 0-6 (acute) or 14-20 (delayed). FPI alone resulted in significantly elevated levels of hippocampal phosphorylated synapsin I and phosphorylated cyclic AMP response element-binding-protein (CREB) at postinjury day 7, of which phosphorylated CREB remained elevated at postinjury day 21. Sham and delayed FPI-RW rats showed increased levels of BDNF, following exercise. Exercise also increased phosphorylated synapsin I and CREB in sham rats. In contrast to shams, the acutely exercised FPI rats failed to show activity-dependent BDNF upregulation and had significant decreases of phosphorylated synapsin I and total CREB. Additional rats were cognitively assessed (learning acquisition and memory) by utilizing the Morris water maze after acute or delayed RW exposure. Shams and delayed FPI-RW animals benefited from exercise, as indicated by a significant decrease in the number of trials to criterion (ability to locate the platform in 7 s or less for four consecutive trials), compared with the delayed FPI-sedentary rats. In contrast, cognitive performance in the acute FPI-RW rats was significantly impaired compared with all the other groups. These results suggest that voluntary exercise can endogenously upregulate BDNF and enhance recovery when it is delayed after TBI. However, when exercise is administered to soon after TBI, the molecular response to exercise is disrupted and recovery may be delayed.