Working memory deficits after traumatic brain injury: catecholaminergic mechanisms and prospects for treatment -- a review

Primary objective: To review the neural circuitry and neurochemistry of working memory and outline the evidence for working memory deficits after traumatic brain injury, and the evidence for the use of catecholaminergic agents in the amelioration of these deficits. Current knowledge gaps and research needs are identified.

Main outcomes and results: Impairments in working memory are a core component of the cognitive deficits associated with traumatic brain injury. Recent progress in understanding the neural circuitry and neurochemistry of working memory suggests that catecholamines play a central role in the activation and regulation of working memory and thus lays a framework in which to consider the use of catecholaminergic agents (dopaminergic and alpha-2 adrenergic agonists) in the treatment of specific cognitive deficits after traumatic brain injury.

Conclusions: The combined methods of cognitive neuroscience, functional brain imaging and neuropharmacology are proposed as an excellent method for studying working memory deficits. A strong rationale exists for the targeted use of catecholaminergic agonists in the treatment of working memory deficits after traumatic brain injury.     

Cognitive deficits following traumatic brain injury produced by controlled cortical impact.

Traumatic brain injury produces significant cognitive deficits in humans. This experiment used a controlled cortical impact model of experimental brain injury to examine the effects of brain injury on spatial learning and memory using the Morris water maze task. Rats (n = 8) were injured at a moderate level of cortical impact injury (6 m/sec, 1.5-2.0 mm deformation). Eight additional rats served as a sham-injured control group. Morris water maze performance was assessed on days 11-15 and 30-34 following injury. Results revealed that brain-injured rats exhibited significant deficits (p less than 0.05) in maze performance at both testing intervals. Since the Morris water maze task is particularly sensitive to hippocampal dysfunction, the results of the present experiment support the hypothesis that the hippocampus is preferentially vulnerable to damage following traumatic brain injury. These results demonstrate that controlled cortical impact brain injury produces enduring cognitive deficits analogous to those observed after human brain injury.     

Study on cognition disorder and morphologic change of neurons in hippocampus area following traumatic brain injury in rats

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Cognitive interventions post acquired brain injury

Objective: Cognitive rehabilitation represents a substantial portion of rehabilitative efforts put forth in increasing independence following an acquired brain injury. Main outcomes and results: This review examined four major areas of cognitive therapy including: attention/concentration, learning and memory, executive functioning, and general cognitive rehabilitation approaches. In total, 64 studies were evaluated throughout the four major areas, which provided the evidence-base for 18 conclusions. The majority of the conclusions were based on moderate and limited evidence, however three strong and one conflicting conclusions were made.

Conclusions: Future research should explore functional outcome measures and long-term effects of treatment interventions through follow-up.     

Objective documentation of traumatic brain injury subsequent to mild head trauma: multimodal brain imaging with MEG, SPECT, and MRI

OBJECTIVE: To determine to what extent magnetic resonance imaging (MRI), single photon emission computed tomography (SPECT), and magnetoencephalography (MEG) can provide objective evidence of brain injury in adult patients with persistent (>1 year) postconcussive symptoms following mild blunt head trauma. DESIGN: A retrospective and blind review of imaging data with respect to the presence of specific somatic, psychiatric, and cognitive complaints. SETTING/PARTICIPANTS: Thirty complete data sets (with MRI, SPECT, MEG, and neuropsychological testing results) were collected between 1994 and 2000 from the MEG programs at the Albuquerque VAMC and the University of Utah. MAIN OUTCOME MEASURES: MRI data were evaluated for focal and diffuse structural abnormalities, SPECT data for regions of hypoperfusion, and resting MEG data for abnormal dipolar slow wave activity (DSWA) and epileptiform transients. RESULTS: Structural MRI was abnormal for 4 patients. SPECT showed regions of hypoperfusion in 12 patients, while MEG showed abnormal activity in 19 patients. None of the imaging methods produced findings statistically associated with postconcussive psychiatric symptoms. A significant association was found between basal ganglia hypoperfusion and postconcussive headaches. For patients with cognitive complaints, abnormalities were more likely to be detected by MEG (86%) than either SPECT (40%) or MRI (18%) (P<.01). MEG also revealed significant (P<.01) associations between temporal lobe DSWA and memory problems, parietal DSWA and attention problems, and frontal DSWA and problems in executive function. CONCLUSIONS: Functional brain imaging data collected in a resting state can provide objective evidence of brain injury in mild blunt head trauma patients with persistent postconcussive somatic and/or cognitive symptoms. MEG proved to be particularly informative for patients with cognitive symptoms.     

Focal lesions in acute mild traumatic brain injury and neurocognitive outcome: CT versus 3T MRI

Abstract Mild traumatic brain injury (mTBI) is associated with long-term cognitive deficits. This study compared the detection rate of acute post-traumatic focal lesions on computed tomography (CT) and 3T (Tesla) magnetic resonance (MR) imaging with neurocognitive outcomes. Adults (n = 36; age range, 19-52 years) with a single episode of mTBI (Glasgow Coma Scale 13-15, as well as loss of consciousness and post-traumatic amnesia) were prospectively enrolled and had CT within 24 h of injury and 3T MR within 2 weeks of injury. The CT and MR scans were reviewed by two neuroradiologists who were blinded to clinical information. Twenty-eight of these mTBI subjects and 18 matched healthy volunteers also underwent serial neurocognitive testing. Of the 36 mTBI cases, intraparenchymal lesions were detected in 18 CT and 27 acute MR exams, consisting of hemorrhagic traumatic axonal injury (TAI) (eight CT, 17 MR), non-hemorrhagic TAI (zero CT, four MR), and cerebral contusions (13 CT, 21 MR). Mild TBI patients had significantly worse performance on working memory tasks than matched controls at the acute time point (<2 weeks), and at 1 month and at 1 year post-injury; yet there was no significant correlation of imaging findings with working memory impairment. In conclusion, 3T MR detected parenchymal lesions in 75% of this mTBI cohort with loss of consciousness and post-traumatic amnesia, a much higher rate than CT. However, the CT and 3T MR imaging findings did not account for cognitive impairment, suggesting that newer imaging techniques such as diffusion tensor imaging are needed to provide biomarkers for neurocognitive and functional outcome in mTBI.     

Enhanced hippocampal neurogenesis by intraventricular S100B infusion is associated with improved cognitive recovery after traumatic brain injury

Evidence of injury-induced neurogenesis in the adult hippocampus suggests that an endogenous repair mechanism exists for cognitive dysfunction following traumatic brain injury (TBI). One factor that may be associated with this restoration is S100B, a neurotrophic/mitogenic protein produced by astrocytes, which has been shown to improve memory function. Therefore, we examined whether an intraventricular S100B infusion enhances neurogenesis within the hippocampus following experimental TBI and whether the biological response can be associated with a measurable cognitive improvement. Following lateral fluid percussion or sham injury in male rats (n = 60), we infused S100B (50 ng/h) or vehicle into the lateral ventricle for 7 days using an osmotic micro-pump. Cell proliferation was assessed by injecting the mitotic marker bromodeoxyuridine (BrdU) on day 2 postinjury. Quantification of BrdU-immunoreactive cells in the dentate gyrus revealed an S100B-enhanced proliferation as assessed on day 5 post-injury (p < 0.05), persisting up to 5 weeks (p < 0.05). Using cell-specific markers, we determined the relative numbers of these progenitor cells that became neurons or glia and found that S100B profoundly increased hippocampal neurogenesis 5 weeks after TBI (p < 0.05). Furthermore, spatial learning ability, as assessed by the Morris water maze on day 30-34 post-injury, revealed an improved cognitive performance after S100B infusion (p < 0.05). Collectively, our findings indicate that an intraventricular S100B infusion induces neurogenesis within the hippocampus, which can be associated with an enhanced cognitive function following experimental TBI. These observations provide compelling evidence for the therapeutic potential of S100B in improving functional recovery following TBI.     

Treatment with vitamin B3 improves functional recovery and reduces GFAP expression following traumatic brain injury in rats

Previous studies have shown that administration of vitamin B(3) (B(3)) in animal models of ischemia significantly reduced the size of infarction and improved functional recovery. The present study evaluated the effect of administration of B(3) on recovery of function following traumatic brain injury (TBI), incorporating the bilateral medial frontal cortex contusion injury model. Groups of rats were assigned to B(3) (500 mg/kg) or saline (1.0 ml/kg) treatment conditions and received contusion injuries or sham surgeries. Drug treatment was administered 15 min and 24 h following injury. Rats were examined on a variety of tests to measure sensorimotor performance (bilateral tactile adhesive removal), skilled forelimb use (staircase test), and cognitive ability (reference and working memory) in the Morris Water Maze. Administration of B(3) following injury significantly reduced the behavioral impairments observed on the bilateral tactile removal test, but not on skilled forelimb use. The acquisition of reference and working memory tests were also significantly improved compared to saline-treated rats. Examination of the brains revealed that administration of B(3) significantly reduced the size of the lesion compared to treatment with saline. In addition, examination of glial fibrillary acidic protein (GFAP) expression around the lesion revealed that B(3) significantly reduced the number of GFAP(+) astrocytes. These results indicate that B(3) administration significantly improved behavioral outcome following injury, reduced the size of the lesion, and reduced the expression of GFAP. The current findings suggest that B(3) may have therapeutic potential for the treatment of TBI.     

Administration of riboflavin improves behavioral outcome and reduces edema formation and glial fibrillary acidic protein expression after traumatic brain injury

Previous studies have shown that administration of riboflavin, vitamin B2, significantly reduced edema formation following experimental stroke. The present study evaluated the ability of B2 to improve behavioral function, reduce edema formation, and limit glial fibrillary acidic protein (GFAP) expression following frontal cortex contusion injury. Groups of rats were assigned to B2 (7.5 mg/kg) or saline (1.0 ml/kg) treatment conditions and received contusion injuries or sham procedures. Drug treatment was administered 15 min and 24 h following injury. Rats were examined on a variety of tests to measure sensorimotor performance (bilateral tactile removal test), and cognitive ability (acquisition of reference and working memory) in the Morris water maze. Administration of B2 following injury significantly reduced the behavioral impairments observed on the bilateral tactile removal test and improved the acquisition of both reference and working memory tests compared to saline-treated rats. The lesion analysis showed that B2 reduced the size of the lesion. Examination of GFAP expression around the lesion revealed that B2 significantly reduced the number of GFAP+ astrocytes. Edema formation following injury was also significantly reduced by B2 administration. These findings are the first to show that B2 administration significantly improved behavioral outcome and reduced lesion volume, edema formation, and the expression of GFAP following traumatic brain injury. These findings suggest that B2 may have therapeutic potential for the treatment of TBI.     

Evaluation of a novel calcium channel blocker, (S)-emopamil, on regional cerebral edema and neurobehavioral function after experimental brain injury.

The authors investigated the effects of a novel calcium channel blocker, (S)-emopamil, on cerebral edema and neurobehavioral and memory function following experimental fluid-percussion brain injury in the rat. Two independent experiments were performed to evaluate the effects of this compound on cardiovascular variables and postinjury cerebral edema (increases in tissue water content), and on cognitive deficits and neurological motor function following brain injury. Treatment with (S)-emopamil significantly reduced focal brain edema at 48 hours after brain injury. Profound memory dysfunction induced by brain injury was significantly attenuated following (S)-emopamil treatment. In addition, (S)-emopamil also attenuated the deficits in motor function that were observed over a 2-week period following brain injury. These results suggest that changes in calcium homeostasis may play an important role in the pathogenesis of trauma to the central nervous system and that the calcium channel blocker (S)-emopamil might be a useful compound for the treatment of traumatic brain injury.     

Vaccinia virus complement control protein enhances functional recovery after traumatic brain injury

Inflammation is a major contributor to the neuropathological consequences of traumatic brain injury (TBI). Previous studies have shown that proinflammatory complement activation fragments are present in the injured brain within the first 24 h after trauma. To investigate whether complement activation within the injured brain leads to the neuropathology and subsequent functional impairment associated with TBI, we examined what effect administration of a complement inhibitor, the vaccinia virus complement control protein (VCP), would have on spatial learning and memory in brain injured rats, as measured using the Morris Water Maze (MWM) procedure. Animals were subjected to a lateral fluid percussion brain injury of moderate severity and, 15 min later, received a 10-microL injection of either full-length VCP, a truncated version of VCP (VCPt), which lacks the complement inhibitory activity but retains the heparin binding activity of VCP, or saline directly into the cortex. Results of such intervention indicated that, at 2 weeks postinjury, both VCP and VCPt treatment attenuated impairments in spatial memory, but not neuropathological damage, as compared to the saline treated controls. These results were surprising and suggest that the neuroprotective effects following administration of VCP after acute brain injury are mediated by mechanisms other than complement inhibition. Potential mechanisms are discussed.     

Cognitive functions in relation to MRI findings 30 years after traumatic brain injury

OBJECTIVE: The aim of the study was to relate cognitive effects of a remote traumatic brain injury (TBI) to MRI findings and severity of injury. METHOD: Sixty-one patients were assessed on average 30 years after a TBI of variable severity. A comprehensive cognitive test battery was used to evaluate memory, executive functions and cognitive overall impairment. Multiple regression analyses were used to examine the relationships between cognitive variables and MRI volumetric findings (the volumes of the hippocampus and the lateral ventricles) and local contusions on MRI. Also, the effect of injury severity on cognitive outcome was evaluated. RESULTS: Reductions in hippocampal volumes and lateral ventricular enlargement were significantly associated with impaired memory functions, memory complaints and executive functions. Of the MRI parameters used, the best predictor for cognitive outcome was the volume of the lateral ventricle. There was only a modest relationship between severity of injury and cognitive performance. CONCLUSIONS: The results show that long-term memory impairments after TBI are associated with MRI volumetric measures. This suggests that the degree of diffuse injury leading to atrophic changes is prognostically more important than the initial severity of TBI.     

Monitoring emergence from coma following severe brain injury in an octogenarian using behavioural indicators, electrophysiological measures and metabolic studies: a demonstration of the potential for good recovery in older adults

This case study describes a multi-disciplinary investigation of the emergence from coma of an 80-year old female (KE) following severe traumatic brain injury. The relationship between cognitive/behavioural ability and the integrity of cerebral function was assessed using neuropsychological measures, positron emission tomography, electroencephalography, somatosensory evoked potentials and trans-cranial magnetic stimulation. These investigations were performed as KE was beginning to emerge from coma (4 weeks) and, again, ∼1 year following brain injury, when she was judged to have achieved her maximum level of recovery. Neuropsychological measures revealed improvement during the first year post-injury in KE's speed of information processing, memory and executive abilities. Electrophysiological and metabolic studies indicated a restoration of functional integrity that was consistent with the gradual recovery in higher brain function documented using behavioural procedures. This case study demonstrates the rehabilitation potential of pre-morbidly healthy older adults following severe traumatic brain injury.     

Post-trauma administration of caffeine plus ethanol reduces contusion volume and improves working memory in rats

It has been demonstrated that ethanol exerts dose-dependent effects, both beneficial and detrimental, on the outcome of traumatic brain injury (TBI). Recently, it has been reported that co-administration of caffeine (10 mg/kg) and a low amount of alcohol (0.65 g/kg; caffeinol) reduces cortical infarct volume up to 80%, and improves motor coordination, following a rodent model of reversible common carotid/middle cerebral artery occlusion. However, the protective effects of caffeinol following other CNS insults, nor its influence on cognitive function, have been examined. Using a controlled cortical impact model of brain injury, the effect of caffeinol administration on TBI-associated motor and cognitive deficits was assessed. When given 15 min following injury, caffeinol reduced cortical tissue loss and improved working memory. However, no influence on motor skills, Morris water maze performance or associative learning and memory was observed. Delayed administration (6 h post-injury) of caffeinol containing a dose of ethanol (1 g/kg) previously demonstrated to improve motor performance eliminated the working memory benefit and cortical protection. These results indicate that early administration of caffeinol may be beneficial in lessening some of the deficits and cortical tissue loss associated with brain trauma.     

Perceived needs following traumatic brain injury

OBJECTIVES: (1) Provide population-based estimates of perceived needs following traumatic brain injury (TBI) and the prevalence of unmet needs 1 year postinjury; (2) identify relations among needs that define unique clusters of individuals; and (3) identify risk factors for experiencing selected needs. DESIGN: Telephone survey 1 year after injury of a prospective cohort of all people hospitalized with TBI in the state of Colorado during 2000. MEASURES: Self-reported need for assistance in 13 areas of functioning. RESULTS: A total of 58.8% of persons hospitalized with TBI experienced at least 1 need during the year following injury; 40.2% will experience at least 1 unmet need 1 year after injury. Most frequently experienced needs were "improving your memory, solving problems better" (34.1%), "managing stress, emotional upsets" (27.9%), and "managing your money, paying bills" (23.3%). Cluster analysis revealed 8 distinctive groupings of subjects. If a need existed, those least likely to be met involved cognitive abilities, employment, and alcohol and/or drug use. CONCLUSIONS: Results were consistent with findings from previous assessments of need for services based on surveys of convenience samples; however, the prevalence of unmet needs 1 year after injury may be higher than previously suspected. More post-hospital services addressing cognitive and emotional problems appear needed. Risk factors for experiencing needs suggest potential avenues for clinical intervention.     

Factors predicting return to work following mild traumatic brain injury: a discriminant analysis

Studies of mild traumatic brain injury (MTBI) suggest that most individuals recover rapidly and return to their everyday activities. However, a percentage of MTBI patients report persistent problems with cognitive, physical, and emotional symptoms. There is also evidence that some experience changes in occupational functioning following MTBI. The current study used a stepwise discriminant function analysis (DFA) to examine the role of injury severity variables, cognitive performance, and ratings of symptoms of TBI in predicting work status following MTBI. Subjects included 121 MTBI patients who were all active-duty military personnel. The stepwise DFA revealed that age and three cognitive variables (verbal memory, verbal fluency, and a speed test of planning and strategy) were predictive of work status 3-15 months following a documented MTBI, correctly classifying work status 68.8% of the time. A cross-validation DFA was conducted, with a 66.1% correct classification rate. These findings highlight the importance of cognitive impairments in identifying those at risk for occupational impairment following MTBI.     

Prospective and declarative memory problems following moderate and severe traumatic brain injury

PRIMARY OBJECTIVE: To examine prospective and declarative memory problems following moderate and severe traumatic brain injury (TBI) and the relationship between prospective memory (PM) and declarative memory and PM and other cognitive functions. RESEARCH DESIGN: The performance of persons who suffered a TBI (n = 25) was compared with that of a demographically matched control group (n = 25). METHODS AND PROCEDURES: Measures of time- and event-based PM, visual and verbal declarative memory, attention and executive functioning were administered to both groups. MAIN OUTCOME AND RESULTS: The group with a TBI performed more poorly on event- and time-based PM, verbal declarative memory, certain aspects of attention and executive functioning. The correlations between the measures of PM, declarative memory and the other cognitive tests were all non-significant. CONCLUSIONS: Problems with declarative memory, attention, and executive functioning do not adequately account for poorer PM performance following a TBI, suggesting that PM should also be assessed following TBI.     

Outcome following traumatic brain injury in the elderly: a critical review

Background: The elderly are at risk for traumatic brain injury (TBI), but their outcome following these injuries remains unclear. Objective: This paper critically reviews research done to date on cognitive and functional outcome following TBI in the elderly. Methods: MEDLINE and PSYCHLIT databases going back to 1965 were searched. Results: Studies suggest that TBI results in adverse cognitive and functional outcomes in the elderly. There is uncertainty as to whether TBI is a significant risk factor for Alzheimer's disease (AD). Methodological problems in these studies include selection bias, small samples, retrospective analyses, and, particularly, the failure to address the role of pre-morbid functioning. These problems limit the strength of the outcome studies, and may account for the equivocal findings on AD risk. Conclusions: It is premature to conclude from the published research to date that the elderly have a uniformly poor outcome following TBI. Directions for further research are suggested.     

Cyclosporin A improves brain tissue oxygen consumption and learning/memory performance after lateral fluid percussion injury in rats

Traumatic brain injury (TBI) triggers a complex pathophysiological cascade, leading to cell death. A major factor in the pathogenesis of TBI is neuronal overloading with calcium, causing the opening of mitochondrial permeability transition pores (MPTP), which consequently inhibit normal mitochondrial function. The immunosuppressant Cyclosporin A (CsA) has been shown to block MPTPs, and to be neuroprotective in ischemia and TBI. However, the translation of these effects on mitochondrial function, into behavioral endpoints has not been investigated thoroughly. Therefore, we tested the effect of a low, clinically evaluated, CsA dose of 0.125 mg/kg (infused for 3 h) and a higher "known" neuroprotective dose of 18.75 mg/kg on brain tissue O(2) consumption, and on motor and cognitive performance following lateral fluid percussion injury (FPI) in rats. CsA at both concentrations abolished the 25% decrease in O(2) consumption (VO(2)), seen in saline-treated animals at 5 h post-FPI. Furthermore, the lower dose of CsA also ameliorated acute motor deficits (days 1-5 post-FPI) and learning and memory impairments in a Morris water maze test on days 11-15 post-FPI. Although, the higher dose of CsA improved cognitive performance, it worsened acute motor functional recovery. These results suggest, that the CsA-induced preservation of mitochondrial function, as assessed by tissue O(2) consumption, directly translated into improvements in motor and cognitive behavior.     

Neuroplasticity following non-penetrating traumatic brain injury

The primary objective of this review is to examine the methodology and evidence for neuroplasticity operating in recovery from traumatic brain injury (TBI), as compared with previous findings in patients sustaining perinatal and infantile focal vascular lesions. The evidence to date indicates that the traditional view of enhanced reorganization of function after early focal brain lesions might apply to early focal brain lesions, but does not conform with studies of early severe diffuse brain injury. In contrast to early focal vascular lesions, young age confers no advantage in the outcome of severe diffuse brain injury. Disruption of myelination could potentially alter connectivity, a suggestion which could be confirmed through diffusion tensor imaging (DTI). Initial reports of DTI in TBI patients support the possibility that this technique can demonstrate alterations in white matter connections which are not seen on conventional magnetic resonance imaging (MRI) and might change over time or with interventions. Preliminary functional MRI studies of TBI patients indicate alterations in the pattern of brain activation, suggesting recruitment of more extensive cortical regions to perform tasks which stress computational resources. Functional MRI, coupled with DTI and possibly other imaging modalities holds the promise of elucidating mechanisms of neuroplasticity and repair following TBI.