Brenda Colella

Long-term cognitive outcome in moderate to severe traumatic brain injury: a meta-analysis examining timed and untimed tests at 1 and 4.5 or more years after injury.

OBJECTIVES To examine long-term outcome of moderate to severe traumatic brain injury (TBI) on timed and untimed cognitive tests using meta-analysis. DESIGN Meta-analysis examining outcome at 2 epochs, 6 to 18 months postinjury (epoch 1) and 4.5 to 11 years postinjury (epoch 2). SETTING Data source was published articles (1966-2007) identified through electronic and manual search. PARTICIPANTS A total of 1380 subjects with moderate to severe TBI participated in the 16 studies meeting inclusion criteria. INTERVENTIONS Not applicable. MAIN OUTCOME MEASURES Timed and untimed neuropsychologic tests with quantitative results (means, SDs, t, and df tests) from studies containing a healthy comparison group and a mean time since injury falling within 1 of the 2 epochs. RESULTS Patient versus control weighted effect sizes were medium to large at epoch 1 for both untimed tasks (r=-.46; confidence interval [CI], -.32 to -.65) and timed tasks (r=-.46; CI, -.35 to -.59). At epoch 2, effect sizes were slightly smaller for untimed tasks (r=-.38; CI, -.25 to -.60) and timed tasks (r=-.40; CI, -.32 to -.62). CONCLUSIONS Patients showed robust, persisting impairments on both timed and untimed tests at recovery plateau (ie, 6-18mo postinjury) and many years later. These findings converge with previous studies, though using an alternative approach that obviates some of the methodologic problems of longitudinal studies, such as selective attrition.

Magnetic Resonance Imaging Evidence of Progression of Subacute Brain Atrophy in Moderate to Severe Traumatic Brain Injury

OBJECTIVE To demonstrate subacute progression of brain atrophy (from 4.5-29mo postinjury) in moderate to severe traumatic brain injury (TBI) using structural magnetic resonance imaging (MRI). DESIGN Within-subjects, repeated-measures design. SETTING Inpatient neurorehabilitation program and teaching hospital (MRI department). PARTICIPANTS Adults (N=14) with moderate to severe TBI. INTERVENTIONS Not applicable. MAIN OUTCOME MEASURES Neuroradiologist readings and volumetric measurements (total brain cerebrospinal fluid and hippocampus) at 4.5 months and 2.5 years postinjury. RESULTS Ten of 14 patients showed visible atrophy progression. Significant increase in cerebrospinal fluid (CSF) volume (t(13)=-4.073, P<.001) and decrease in right and left hippocampal volumes (t(13)=4.221, P<.001 and t(13)=3.078, P<.005, respectively) were observed from 4.5 months to 2.5 years. Compared with published normative data, patients with TBI showed significantly more pathologic percent annual volume change for the hippocampi (t(26)=-3.864, P<.001, right; and t(26)=-2.737, P<.01, left), and a trend for CSF (t(26)=1.655, P=.059). CONCLUSIONS This study provides strong MRI evidence for subacute progression of atrophy, as distinct from early, acute neurologic changes observed.

Prediction of Return to Productivity After Severe Traumatic Brain Injury: Investigations of Optimal Neuropsychological Tests and Timing of Assessment

OBJECTIVES (1) To examine predictive validity of global neuropsychological performance, and performance on timed tests (controlling for manual motor function) and untimed tests, including attention, memory, executive function, on return to productivity at 1 year after traumatic brain injury (TBI). (2) To compare predictive validity at 8 weeks versus 5 months postinjury. (3) To examine predictive validity of early degree of recovery (8wk-5mo postinjury) for return to productivity. DESIGN Longitudinal, within subjects. SETTING Inpatient neurorehabilitation and community. PARTICIPANTS Patients (N=63) with moderate to severe TBI. INTERVENTIONS Not applicable. MAIN OUTCOME MEASURES PRIMARY OUTCOME return to productivity at 1 year postinjury. Primary predictors: neuropsychological composite scores. Control variables: posttraumatic amnesia, acute care length of stay (LOS), Glasgow Coma Scale score, age, and estimated premorbid intelligence quotient. RESULTS Return to productivity was significantly correlated with global neuropsychological performance at 5 months postinjury (P<.05) and showed a trend toward significance at 8 weeks. Performance on the untimed composite score, and more specifically executive and memory functions, mirrored this pattern. Logical Memory performance significantly predicted return to productivity, but not other memory tests. Timed tests showed no significance or trend at either time point. Early degree of recovery did not predict return to productivity. Among control variables, only acute care LOS was predictive of return to productivity. CONCLUSIONS Findings validate utility of early neuropsychological assessment for predicting later return to productivity. They also provide more precise information regarding the optimal timing and test type: results support testing at 5 months postinjury on untimed tests (memory and executive function), but not simple attention or speed of mental processing. Findings are discussed with reference to previous literature.

Examining Moderators of Cognitive Recovery Trajectories After Moderate to Severe Traumatic Brain Injury

OBJECTIVES To examine the influence of cognitive reserve-related moderator variables on recovery trajectories during the first year after traumatic brain injury (TBI). Using mixed effects models, we measured (1) the level of cognitive function at 2 and 12 months postinjury and (2) the trajectories of cognitive recovery during the first 12 months postinjury. DESIGN Repeated-measures design with neuropsychological testing at 2, 5, and 12 months postinjury. SETTING Large, urban inpatient neurorehabilitation program. PARTICIPANTS Patients (N=75) with moderate-to-severe TBI. INTERVENTIONS Not applicable. MAIN OUTCOME MEASURES PRIMARY OUTCOMES neuropsychological composite scores including simple speed of processing, complex speed of processing, memory, untimed executive functions, and attention span. Primary predictors: age, estimated premorbid intelligence quotient (IQ), and years of education. RESULTS Only age significantly moderated trajectories. Decreasing age significantly enhanced recovery of speed of processing, both simple (2-12mo postinjury, P<.001) and complex (2-12mo postinjury, P<.05; 5-12mo postinjury, P<.005). Decreasing age and increasing estimated premorbid IQ were associated with higher performance at 2 and 12mo postinjury for simple speed of processing (premorbid IQ, 2 and 12mo), complex speed of processing (age, 2 and 12mo), untimed executive functions (premorbid IQ, 2 and 12mo), and memory (premorbid IQ, 2 and 12mo). CONCLUSIONS Recovery of speed of processing (both simple and complex) was favorably moderated by younger age. Older age is associated with more neuronal loss and less integrity of white matter, and speed of processing is associated with white matter networks. The recuperative effects of younger age may therefore be attributable to greater reserve capacity (as indexed by white matter integrity). Lower age and higher estimated premorbid IQ were associated with higher functioning on a variety of cognitive outcomes. This may reflect the buffering effects of reserve capacity or premorbid differences in age and IQ-related cognitive functioning. Implications for rehabilitation and recovery mechanisms are discussed.

Postrecovery Cognitive Decline in Adults With Traumatic Brain Injury

OBJECTIVE To assess prospectively the degree of postrecovery long-term cognitive decline after moderate to severe traumatic brain injury (TBI). DESIGN Observational cohort. SETTING Inpatient rehabilitation hospital. PARTICIPANTS Adults (N=33) with moderate and severe TBI from a well characterized sample with low attrition. INTERVENTIONS Not applicable. MAIN OUTCOME MEASURES Recovery of functioning was ascertained through repeat neuropsychological assessments over the first 5 years postinjury. Cognitive decline from a baseline of 12 months postinjury to a follow-up evaluation conducted on average +/- SD 2.1+/-0.99 years later. Change was calculated using the reliable change index (RCI) for 12 neuropsychological tests commonly used in the assessment of TBI. RESULTS At the group level, negligible changes in cognitive function were observed over time. However, application of the RCI using 90% confidence intervals showed statistically significant cognitive decline on at least 2 neuropsychological measures in 27.3% of study participants. Decline was most commonly observed on a test of verbal fluency and the delayed recall portion of a test of verbal list learning (Rey Auditory Verbal Learning Test), although substantial variability existed across patients. Decline was significantly correlated with hours of therapy received at 5 months postinjury (P<.02). CONCLUSIONS Consistent with a small number of previous studies, cognitive deterioration may follow an initial period of recovery. Overall, the pattern of decline across tests varied across individuals. Possible mechanisms of decline are discussed. Further research is needed to understand the stability of this finding and its functional implications.

Schema Representation in Patients with Ventromedial PFC Lesions

Human neuroimaging and animal studies have recently implicated the ventromedial prefrontal cortex (vmPFC) in memory schema, particularly in facilitating new encoding by existing schemas. In humans, the most conspicuous memory disorder following vmPFC damage is confabulation; strategic retrieval models suggest that aberrant schema activation or reinstatement plays a role in confabulation. This raises the possibility that beyond its role in schema-supported memory encoding, the vmPFC is also implicated in schema reinstatement itself. If that is the case, vmPFC lesions should lead to impaired schema-based operations, even on tasks that do not involve memory acquisition. To test this prediction, ten patients with vmPFC damage, four with present or prior confabulation, and a group of twelve matched healthy controls made speeded yes/no decisions as to whether words were closely related to a schema (a visit to the doctor). Ten minutes later, they repeated the task for a new schema (going to bed) with some words related to the first schema included as lures. Last, they rated the degree to which stimuli were related to the second schema. All four vmPFC patients with present or prior confabulation were impaired in rejecting lures and in classifying stimulus belongingness to the schema, even when they were not lures. Nonconfabulating patients performed comparably to healthy adults with high accuracy, comparable reaction times, and similar ratings. These results show for the first time that damage to the human vmPFC, when associated with confabulation, leads to deficient schema reinstatement, which is likely a prerequisite for schema-mediated memory integration.

Scale and pattern of atrophy in the chronic stages of moderate-severe TBI.

Background: Moderate-severe traumatic brain injury (TBI) is increasingly being understood as a progressive disorder, with growing evidence of reduced brain volume and white matter (WM) integrity as well as lesion expansion in the chronic phases of injury. The scale of these losses has yet to be investigated, and pattern of change across structures has received limited attention. Objectives: (1) To measure the percentage of patients in our TBI sample showing atrophy from 5 to 20 months post-injury in the whole brain and in structures with known vulnerability to acute TBI, and (2) To examine relative vulnerability and patterns of volume loss across structures. Methods: Fifty-six TBI patients [complicated mild to severe, with mean Glasgow Coma Scale (GCS) in severe range] underwent MRI at, on average, 5 and 20 months post-injury; 12 healthy controls underwent MRI twice, with a mean gap between scans of 25.4 months. Mean monthly percent volume change was computed for whole brain (ventricle-to-brain ratio; VBR), corpus callosum (CC), and right and left hippocampi (HPC). Results: (1) Using a threshold of 2 z-scores below controls, 96% of patients showed atrophy across time points in at least one region; 75% showed atrophy in at least 3 of the 4 regions measured. (2) There were no significant differences in the proportion of patients who showed atrophy across structures. For those showing decline in VBR, there was a significant association with both the CC and the right HPC (P < 0.05 for both comparisons). There were also significant associations between those showing decline in (i) right and left HPC (P < 0.05); (ii) all combinations of genu, body and splenium of the CC (P < 0.05), and (iii) head and tail of the right HPC (P < 0.05 all sub-structure comparisons). Conclusions: Atrophy in chronic TBI is robust, and the CC, right HPC and left HPC appear equally vulnerable. Significant associations between the right and left HPC, and within substructures of the CC and right HPC, raise the possibility of common mechanisms for these regions, including transneuronal degeneration. Given the 96% incidence rate of atrophy, a genetic explanation is unlikely to explain all findings. Multiple and possibly synergistic mechanisms may explain findings. Atrophy has been associated with poorer functional outcomes, but recent findings suggest there is potential to offset this. A better, understanding of the underlying mechanisms could permit targeted therapy enabling better long-term outcomes.

Environmental enrichment may protect against hippocampal atrophy in the chronic stages of traumatic brain injury

Objective: To examine the relationship between environmental enrichment (EE) and hippocampal atrophy in the chronic stages of moderate to severe traumatic brain injury (TBI). Design: Retrospective analysis of prospectively collected data; observational, within-subjects. Participants: Patients (N = 25) with moderate to severe TBI. Measures: Primary predictors: (1) An aggregate of self-report rating of EE (comprising hours of cognitive, physical, and social activities) at 5 months post-injury; (2) pre-injury years of education as a proxy for pre-morbid EE (or cognitive reserve). Primary outcome: bilateral hippocampal volume change from 5 to 28 months post-injury. Results: As predicted, self-reported EE was significantly negatively correlated with bilateral hippocampal atrophy (p < 0.05), with greater EE associated with less atrophy from 5 to 28 months. Contrary to prediction, years of education (a proxy for cognitive reserve) was not significantly associated with atrophy. Conclusion: Post-injury EE may serve as a buffer against hippocampal atrophy in the chronic stages of moderate-severe TBI. Clinical application of EE should be considered for optimal maintenance of neurological functioning in the chronic stages of moderate-severe TBI.

Moderate–severe traumatic brain injury causes delayed loss of white matter integrity: Evidence of fornix deterioration in the chronic stage of injury

Abstract Objectives: To examine structural integrity loss in the fornix from 5–30 months after moderate and severe traumatic brain injury (TBI) using diffusion tensor imaging. Methods: MRIs were prospectively undertaken in 29 adults with moderate and severe TBI at two time points. Fractional anisotropy (FA) was calculated for the fornix (column/body, right crux and left crux) at 5 and 30 months post-injury. Results: Paired t-tests revealed significant FA reductions with large effect sizes across time in the column/body, p < 0.001, right crux, p < 0.001 and left crux, p < 0.001. Conclusions: These data contribute to the growing body of evidence that loss of white matter continues in moderate and severe TBI even after the acute neurological effects of TBI have resolved. As the fornix plays a critical role in memory, this may be a contributing factor to the poor clinical outcomes observed in these patients.

Negative neuroplasticity in chronic traumatic brain injury and implications for neurorehabilitation.

Based on growing findings of brain volume loss and deleterious white matter alterations during the chronic stages of injury, researchers posit that moderate-severe traumatic brain injury (TBI) may act to “age” the brain by reducing reserve capacity and inducing neurodegeneration. Evidence that these changes correlate with poorer cognitive and functional outcomes corroborates this progressive characterization of chronic TBI. Borrowing from a framework developed to explain cognitive aging (Mahncke et al., Progress in Brain Research, 157, 81–109, 2006a; Mahncke et al., Proceedings of the National Academy of Sciences of the United States of America, 103(33), 12523–12528, 2006b), we suggest here that environmental factors (specifically environmental impoverishment and cognitive disuse) contribute to a downward spiral of negative neuroplastic change that may modulate the brain changes described above. In this context, we review new literature supporting the original aging framework, and its extrapolation to chronic TBI. We conclude that negative neuroplasticity may be one of the mechanisms underlying cognitive and neural decline in chronic TBI, but that there are a number of points of intervention that would permit mitigation of this decline and better long-term clinical outcomes.