Community versus orthopaedic controls in traumatic brain injury research: how comparable are they?

BACKGROUND: Community (CC) or orthopaedic/injury (OC) control groups are typically used to evaluate the consequences of traumatic brain injuries (TBIs). Whereas CCs match for demographic variables and are readily available, OCs may additionally control for other pre- and post-injury variables but are more costly to recruit. Together, they enable an evaluation of brain- vs general-injury effects. However, the comparability of these two groups and the increase in control over confounding variables when OCs are used has rarely been examined. METHOD: The current study compared samples of CCs (n = 71) and OCs (n = 69), aged between 18-80, on a range of demographic (age, gender, education, socio-economic status), background (medical history, handedness), psychosocial (alcohol use, fatigue, pain, depression, social support, community integration, 'post-concussion' symptoms) and cognitive (motor and processing speed, memory, intellectual ability) variables. RESULTS: The two groups were comparable on all variables, except alcohol use, with the OC group having higher levels of alcohol consumption. However, alcohol use did not correlate with any other variable, including commonly used measures of outcome following TBI. CONCLUSION: The current findings suggest that an orthopaedic injury control group does not have any clear advantages over a carefully recruited community control group.

Clinical Ratings of White Matter Hyperintensities, Hippocampal Ratings, and Neuropsychological Functioning from The Cache County Memory Study.

Objective: White matter burden and medial temporal atrophy are associated with cognitive health. A large epidemiological database, such as the Cache County Memory Study (CCMS), can provide additional insight into how visual clinical ratings of brain structural integrity predict cognition in older adults. Method: We used the Scheltens Ratings Scale to quantify white matter lesion burden and medial temporal atrophy in the CCMS sample to determine if these qualitative markers are predictive of memory function. We performed clinical ratings of MRI scans across two ascertainment periods among 187 community-dwelling older adults and correlated these ratings with MMSE, CERAD memory performance, and general cognitive ability. Results: Higher Scheltens ratings measuring white matter and basal ganglia hyperintensities were associated with lower memory performance (r = 0.21). The strongest correlations were observed between medial temporal atrophy and general cognition performance (r = 0.32). Conclusions: The current findings support previous research that the integrity of different regions of the brain correlate to function in a meaningful way.

White matter changes in patients with hypoxic amnesia.

A deficit of declarative memory is a common sequela after a hypoxic episode. While the role of gray matter changes (i.e., atrophy of hippocampal formation) as mainly responsible for memory loss has been emphasized, the role of the white matter damage has so far been neglected. The present study was aimed at evaluating whether white matter damage, within the neural circuitry responsible for declarative memory functioning, is present in anoxic patients. We assessed, by means of voxel-based morphometry, the integrity of white matter regions in five patients with hypoxic amnesia. When anoxic patients were compared to healthy controls, significantly less white matter density was detected in the fornix, anterior portion of the cingulum bundle and uncinate fasciculus bilaterally. We conclude that cerebral hypoxia may alter, together with the hippocampi, the integrity of white matter fibers throughout the memory-limbic system.

MRI Clinical Ratings and Cognitive Function in a Cross-Sectional Population Study of Dementia: The Cache County Memory Study.

BACKGROUND: White matter integrity in aging populations is associated with increased risk of cognitive decline, dementia diagnosis, and mortality. Population-based data can elucidate this association. OBJECTIVES: To examine the association between white matter integrity, as measured by a clinical rating scale of hyperintensities, and mental status in older adults including advanced aging. DESIGN: Scheltens Ratings Scale was used to qualitatively assess white matter (WM) hyperintensities in participants of the Cache County Memory Study (CCMS), an epidemiological study of Alzheimer's disease in an exceptionally long-lived population. Further, the relation between Mini-Mental State Exam (MMSE) and WM hyperintensities were explored. METHOD: Participants consisted of 415 individuals with dementia and 22 healthy controls. RESULTS: CCMS participants, including healthy controls, had high levels of WM pathology as measured by Scheltens Ratings Scale score. While age did not significantly relate to WM pathology, higher Scheltens Ratings Scale scores were associated with lower MMSE findings (correlation between -0.14 and -0.22; p < .05). CONCLUSIONS: WM pathology was common in this county-wide population sample of those ranging in age from 65 to 106. Increased WM burden was found to be significantly associated with decreased overall MMSE performance.

cerebellar atrophy after moderate-to-severe pediatric traumatic brain injury.

BACKGROUND AND PURPOSE: Although the cerebellum has not attracted the same degree of attention as cortical areas and the hippocampus in traumatic brain injury (TBI) literature, there is limited structural and functional imaging evidence that the cerebellum is also vulnerable to insult. The cerebellum is emerging as part of a frontocerebellar system that, when disrupted, results in significant cognitive and behavioral consequences. We hypothesized that cerebellar volume would be reduced in children following TBI and wished to examine the relation between the cerebellum and known sites of projection, including the prefrontal cortex, thalamus, and pons. MATERIALS AND METHODS: Quantitative MR imaging was used to measure cerebellar white and gray matter and lesion volumes 1-10 years following TBI in 16 children 9-16 years of age and 16 demographically matched typically developing children 9-16 years of age. Cerebellar volumes were also compared with volumetric data from other brain regions to which the cerebellum projects. RESULTS: A significant group difference was found in cerebellar white and gray matter volume, with children in the TBI group consistently exhibiting smaller volumes. Repeating the analysis after excluding children with focal cerebellar lesions revealed that significant group differences still remained for cerebellar white matter (WM). We also found a relation between the cerebellum and projection areas, including the dorsolateral prefrontal cortex, thalamus, and pons in 1 or both groups. CONCLUSION: Our finding of reduced cerebellar WM volume in children with TBI is consistent with evidence from experimental studies suggesting that the cerebellum and its related projection areas are highly vulnerable to fiber degeneration following traumatic insult.

Is performance on the Wechsler test of adult reading affected by traumatic brain injury?

OBJECTIVES: The validity of the National Adult Reading Test (NART) as a predictor of premorbid IQ when used with patients who have sustained a traumatic brain injury (TBI) has been questioned in recent years. This study examined whether performance on the Wechsler Test of Adult Reading (WTAR) is similarly affected by TBI in the first year after an injury. DESIGN AND METHOD: The WTAR scores of participants who had sustained a mild TBI (N=82), moderate TBI (N=73), severe TBI (N=61) or an orthopaedic injury (N=95) were compared (cross-sectional study). A subset of 21 mild TBI, 31 moderate TBI, 26 severe TBI and 21 control group participants were additionally reassessed 6 months later to assess the impact of recovery on WTAR scores (longitudinal study). RESULTS: The severe TBI group had significantly lower scores on the WTAR than the mild TBI, moderate TBI and control groups in the cross-sectional study, despite being matched demographically. The findings from the longitudinal study revealed a significant group difference and a small improvement in performance over time but the interaction between group and time was not significant, suggesting that the improvements in WTAR performance over time were not restricted to more severely injured individuals whose performance was temporarily suppressed. CONCLUSIONS: These findings suggest that reading performance may be affected by severe TBI and that the WTAR may underestimate premorbid IQ when used in this context, which may cause clinicians to underestimate the cognitive deficits experienced by these patients.

Multivariate characterization of white matter heterogeneity in autism spectrum disorder.

The complexity and heterogeneity of neuroimaging findings in individuals with autism spectrum disorder has suggested that many of the underlying alterations are subtle and involve many brain regions and networks. The ability to account for multivariate brain features and identify neuroimaging measures that can be used to characterize individual variation have thus become increasingly important for interpreting and understanding the neurobiological mechanisms of autism. In the present study, we utilize the Mahalanobis distance, a multidimensional counterpart of the Euclidean distance, as an informative index to characterize individual brain variation and deviation in autism. Longitudinal diffusion tensor imaging data from 149 participants (92 diagnosed with autism spectrum disorder and 57 typically developing controls) between 3.1 and 36.83 years of age were acquired over a roughly 10-year period and used to construct the Mahalanobis distance from regional measures of white matter microstructure. Mahalanobis distances were significantly greater and more variable in the autistic individuals as compared to control participants, demonstrating increased atypicalities and variation in the group of individuals diagnosed with autism spectrum disorder. Distributions of multivariate measures were also found to provide greater discrimination and more sensitive delineation between autistic and typically developing individuals than conventional univariate measures, while also being significantly associated with observed traits of the autism group. These results help substantiate autism as a truly heterogeneous neurodevelopmental disorder, while also suggesting that collectively considering neuroimaging measures from multiple brain regions provides improved insight into the diversity of brain measures in autism that is not observed when considering the same regions separately. Distinguishing multidimensional brain relationships may thus be informative for identifying neuroimaging-based phenotypes, as well as help elucidate underlying neural mechanisms of brain variation in autism spectrum disorders.

Motoric laterality and eye dominance suggest unique pattern of cerebral organization in schizophrenia.

The performance of 26 young patients with early-onset schizophrenia on motoric laterality and eye dominance was compared with that of 24 psychiatric inpatients suffering from an early and diffuse brain damage, 16 nonpsychotic non-brain-damaged psychiatric inpatients, and 36 university students. All subjects were in late adolescence. These schizophrenic patients showed more left-sidedness on all the laterality measures. Left eye dominance was highly prevalent in the schizophrenic group (about 75% of the subjects) and had high diagnostic usefulness. In addition, laterality measures of the schizophrenic patients were highly incongruous. Our results support the hypothesis of a specific left hemispheric dysfunction in schizophrenia that is neither shared by all psychiatric patients nor resembles a generalized insult to the brain. Although the left hemispheric dysfunction in schizophrenia is considered to be neurological, the etiological contributions of brain insults and of genetic and environmental factors are unclear.

Brainstem white matter integrity is related to loss of consciousness and postconcussive symptomatology in veterans with chronic mild to moderate traumatic brain injury.

We investigated associations between DTI indices of three brainstem white matter tracts, traumatic brain injury (TBI) injury characteristics, and postconcussive symptomatology (PCS) in a well-characterized sample of veterans with history of mild to moderate TBI (mTBI). 58 military veterans (mTBI: n = 38, mean age = 33.2, mean time since injury = 90.9 months; military controls [MC]; n = 20; mean age = 29.4) were administered 3T DTI scans as well as a comprehensive neuropsychiatric evaluation including evaluation of TBI injury characteristics and PCS symptoms (e.g., negative mood, dizziness, balance and coordination difficulties). Tractography was employed by seeding ROIs along 3 brainstem white matter tracts (i.e., medial lemniscus-central tegmentum tract [ML-CTT]; corticospinal tracts [CST], and pontine tegmentum [PT]), and mean DTI values were derived from fractional anisotropic (FA) maps. Results showed that there were no significant difference in FA between the MC and TBI groups across the 3 regions of interest; however, among the TBI group, CST FA was significantly negatively associated with LOC duration. Additionally, lower FA of certain tracts-most especially the PT-was significantly associated with increased PCS symptoms (i.e., more severe vestibular symptoms, poorer physical functioning, and greater levels of fatigue), even after adjusting for PTSD symptoms. Our findings show that, in our sample of veterans with mTBI, tractography-based DTI indices of brainstem white matter tracts of interest are related to the presence and severity of PCS symptoms. Findings are promising as they show linkages between brainstem white matter integrity and injury severity (LOC), and they raise the possibility that the pontine tegmentum in particular may be a useful marker of PCS symptoms. Collectively, these data point to important neurobiological substrates of the chronic and complex constellation of symptoms following the 'signature injury' of our combat-exposed veterans.

Apolipoprotein E epsilon 4 allele and hippocampal volume in twins with normal cognition.

We examined the relation of APOE-epsilon 4, hippocampal volume, and cognitive performance in ten pairs of cognitively normal twins who had a mean age of 62.5 years (SD = 7.8). There were no significant differences in neuropsychological measures of the groups categorized by the presence of an epsilon 4 allele. However, the mean normalized right and left hippocampal volumes were smaller in the epsilon 4 groups compared to the group without epsilon 4. Combined with prior reports, these findings suggest that epsilon 4 is associated with differences in brain morphology that may be evident when no symptoms of dementia are present.

White matter hyperintensities and neuropsychological outcome following carbon monoxide poisoning.

BACKGROUND: Carbon monoxide (CO) poisoning may result in white matter hyperintensities (WMH) and neurocognitive impairments. OBJECTIVE: To assess in a prospective study WMH in CO-poisoned patients and their relationship to cognitive functioning. METHODS: Seventy-three consecutive CO-poisoned patients were studied. MR scans and neurocognitive tests were administered on day 1 (within 36 hours after CO poisoning), 2 weeks, and 6 months. Age- and sex-matched control subjects for white matter analyses only were obtained from the authors' normative imaging database. MR scans were rated for WMH in the periventricular and centrum semiovale regions, using a 4-point rating scale. Two independent raters rated the scans, and a consensus was reached. RESULTS: Thirty percent of CO-poisoned patients had cognitive sequelae. Twelve percent of the CO-poisoned patients had WMH, with significantly more periventricular, but not centrum semiovale, WMH than control subjects. The WMH in CO-poisoned patients did not change from day 1 to 6 months. Centrum semiovale hyperintensities were related to worse cognitive performance. Duration of loss of consciousness correlated with cognitive impairment at all three times. Initial carboxyhemoglobin levels correlated with loss of consciousness but not with WMH or cognitive sequelae. CONCLUSIONS: CO poisoning can result in brain injury manifested by WMH and cognitive sequelae. The WMH were not related to CO poisoning severity. The WMH occurred in both the periventricular and the centrum semiovale regions; however, only those in the centrum semiovale were significantly associated with cognitive impairments.

Basic relations among lesion laterality, lesion volume and neuropsychological performance.

Although it is widely accepted that lesion size is an important determinant of severity of deficit, difficulties in the quantification of lesion size and the absence of a theoretical model of how lesion volume combines with lesion locus to produce deficits have inhibited the development of methodological and statistical procedures for studying naturally occurring lesions in humans. We propose such a unified model and apply it to the analysis of neuropsychological performance in a sample of patients with naturally occurring unilateral lesions. The analysis suggests that a statistical interaction between lesion size and laterality may be an important determinant of neuropsychological deficit.

Handedness and language among the mentally retarded: implications for the model of pathological left-handedness and gender differences in hemispheric specialization.

The relationship between handedness and language was examined among 238 mentally retarded subjects representing the four DSM III classification ranges of mental retardation. Language ability was found to be significantly related to handedness, with an increased prevalence of left-handedness among those individuals with language deficits. In addition, both expressive and receptive language ability interacted with gender, with the main effects of each language variable being stronger for females than males. Although no main effects were found for severity of retardation, a significant interaction was found between severity and gender. Results support the model of pathological left-handedness and are discussed within the context of this theory, as well as with regard to gender differences in cerebral lateralization of language and cognitive functioning.

Brain volume, intracranial volume, and dementia.

RATIONALE AND OBJECTIVES: Using a large magnetic resonance (MR) imaging data set (n = 532), we investigated the utility of total intracranial volume (TICV) as a correction factor for head size variability when assessing total brain volume (TBV) and the subcortical volumes of the temporal horn of the lateral ventricular system and the hippocampus. METHODS: A uniform tissue segmentation procedure (analyze) was used to calculate volumes. Total brain volume was compared with TICV in 357 control subjects and 175 patients with various dementing and neuropsychiatric disorders (mixed dementia/neuropsychiatric group). These MR-based TBV/TICV relationships were compared with actual postmortem (n = 87) values obtained from a study of neurologically healthy subjects at the time of death. Comparisons were also made in which temporal horn and hippocampal volumes were corrected by TICV and TBV. Lastly, the ability of corrected TBV and temporal horn and hippocampal volumes to distinguish subjects in the mixed dementia/neuropsychiatric group from controls was examined by logistic regression. RESULTS: In the control sample, brain volume averaged 9% of TICV, regardless of age. In contrast, TBV in the mixed dementia/neuropsychiatric subjects showed, on average, a 22% reduction compared with TICV. By plotting TBV/TICV curves, highly significant but different regression lines emerged, wherein a reduction in brain volume in conditions of mixed dementia/neuropsychiatric disorder showed a distinct separation from the norm. The TBV/TICV regression line generated from MR imaging in controls did not differ from the postmortem TBV/TICV regression line. Logistic regression showed a 96% correct classification of mixed dementia/neuropsychiatric subjects from controls by using the TBV/TICV ratio. This technique has the advantage that each subject serves as his or her own control. CONCLUSIONS: In cases of dementia and neuropsychiatric disorder in persons 65 and older, TBV corrected by TICV readily differentiated this clinical population from controls. This technique is easy and simple to use and has various clinical applications. For temporal horn and hippocampal volume, corrections with TBV rather than TICV may provide more clinically meaningful corrections.

Lesion volume, injury severity, and thalamic integrity following head injury.

Magnetic resonance (MR) scans of 63 traumatic brain injury (TBI) patients were analyzed to examine the relationship between injury severity, lesion volume (nonthalamic cortical/subcortical lesions), ventricle-to-brain ratio (VBR), and thalamic volume. For comparison, 33 normal control subjects were used. Patients with visible nonthalamic structural lesions showed significantly smaller thalamic volumes than patients without visible lesions or control subjects. Results also indicated that patients with visible lesions had significantly more severe injuries than patients without lesions. Patients with moderate-severe injuries had significantly smaller thalamic volumes and greater VBRs than patients with mild-moderate injuries. Although several variables related to thalamic volume, the presence of nonthalamic lesions was sufficient to result in smaller thalamic volume. Decreased thalamic volume following head injury suggests that subcortical brain structures may be susceptible to transneuronal degeneration following cortical lesions, and that this can be detected by in vivo MR-based volumetric analysis.

Lesion volume, injury severity, and thalamic integrity following head injury.

Magnetic resonance scans of 63 TBI patients were analyzed to examine the relationship between injury severity, lesion volume (nonthalamic cortical/subcortical lesions), ventricle-to-brain ratio (VBR), and thalamic volume. For comparison, 33 normal control subjects were used. Patients with visible nonthalamic structural lesions showed significantly smaller thalamic volumes than patients without visible lesions or control subjects. Results also indicated that patients with visible lesions had significantly more severe injuries than patients without lesions. Patients with moderate-severe injuries had significantly smaller thalamic volumes and greater VBRs than patients with mild-moderate injuries. Although several variables related to thalamic volume, the presence of nonthalamic lesions was sufficient to result in smaller thalamic volume. Decreased thalamic volume following head injury suggests that subcortical brain structures may be susceptible to transneuronal degeneration following cortical lesions, and that this can be detected by in vivo MR-based volumetric analysis.

Trauma-induced degenerative changes in brain injury: a morphometric analysis of three patients with preinjury and postinjury MR scans.

Three patients with pretraumatic and posttraumatic brain injury (TBI) MR imaging of the brain are presented. Two patients had moderate to severe injury, whereas the third patient sustained a mild injury. Using imaging software to conduct morphometric analyses, quantitative neuropathologic change was ascertained in each TBI patient. Each case was compared quantitatively to preinjury scans as well as to an age-matched control group. For the moderately to severely injured patients, extensive degenerative changes were found throughout the various cortical structures and the cerebellum, whereas most midbrain and brainstem measures did not demonstrate significant change. For these two patients, the most significant changes occurred within the ventricular system, where generalized ventricular dilation was observed post-TBI. In the mild case, no significant anatomic changes were evident. These case studies demonstrate the use of quantitative methods for examining the structural basis of TBI sequelae.

Dementia, quantitative neuroimaging, and apolipoprotein E genotype.

BACKGROUND AND PURPOSE: Quantitative MR imaging differences in an elderly population of subjects with various clinical disorders (including dementia, particularly Alzheimer's disease and vascular dementia) and disorders of mild cognitive impairment were examined. Potential quantitative MR differences were assessed by presence or absence of the apolipoprotein E (APOE) epsilon4 allele and by level of cognitive deficit. METHODS: One hundred eighty subjects with a diagnosis of dementia or other clinical disorders were identified from an eligible population of 5,677 elderly individuals. Age, duration of disease, and head size (where appropriate) were considered as covariates. APOE genotype was determined by polymerase chain reaction using buccal material. Axial and coronal intermediate- and T2-weighted MR images were quantified using a multispectral segmentation algorithm. Cognitive status was assessed by means of a modified Mini-Mental Status Examination. RESULTS: All types of dementing illness showed significant volume reductions in the majority of structures examined, particularly in the total brain, hippocampus, and white and gray matter, and increased CSF and ventricular volumes. Subjects with mild cognitive impairment showed fewer atrophic changes but were still distinguishable from the 24 control subjects. Presence of an epsilon4 allele was associated with smaller hippocampal volume in subjects with Alzheimer's disease and vascular dementia within just 1 year of disease onset. For other analyses, atrophy related to the presence of the epsilon4 allele disappeared after controlling for age and length of disease. CONCLUSION: The effects of the epsilon4 allele on brain morphology may be subtly expressed early in the development of dementia, but do not specifically affect cerebral atrophy thereafter. Cognitive impairment is associated with atrophy irrespective of diagnosis and presence of epsilon4.

Hippocampal volume in normal aging and traumatic brain injury.

PURPOSE: To present a normative database of hippocampal and temporal horn volume and to clarify the relationship between these measures and cognitive outcome in patients with traumatic brain injury. METHODS: Ninety-six healthy volunteers and 94 patients with traumatic brain injury were examined with coronal intermediate and T2-weighted MR imaging. Multispectral segmentation and volume analyses were performed. The volumetry of the hippocampus and temporal horn was characterized in the control subjects. Volumetric measures in a group of patients with traumatic brain injury who had received MR imaging 3 months or less after injury were compared with measurements in other patients in the chronic phase of recovery. The relationship between neuropsychological testing and volumetric measures was analyzed with particular emphasis on the correlation between cognitive outcome and hippocampal and temporal horn volumes. RESULTS: No significant age group differences were found in the normative group from age 16 to 65. Left and right hippocampal volumes were interrelated and did not differ from each other. This was also true for the temporal horns. Hippocampal and temporal horn volumes were not significantly related. Women had larger hippocampi relative to cranial volume. Comparisons between patients with traumatic brain injury and control subjects showed significant yet modest bilateral atrophic changes in hippocampal and temporal horn enlargement in the patients with brain injury. Hippocampal and temporal horn volumes correlated significantly with each other in the group with traumatic brain injury. Cognitive outcome was modestly related to hippocampal and temporal horn volumes. However, in a specific subgroup whose images were acquired between 71 and 210 days after injury, strong correlations were noted in which temporal horn volume correlated highly with IQ and hippocampal volume correlated with verbal memory function. CONCLUSION: Hippocampal and temporal horn volumes appear to be independent variables in healthy control subjects. Traumatic brain injury results in significant hippocampal atrophy and temporal horn enlargement. The hippocampus and temporal horn volumes were inversely correlated in the group with traumatic brain injury, suggesting a differential relationship of these structures in patients with brain injury as compared with control subjects. In the subacute phase, the volume of the temporal horn may be indicative of intellectual outcome and that of the hippocampus appears to be indicative of verbal memory function.

Quantitative volumetric analysis of brain MR: normative database spanning 5 decades of life.

PURPOSE: To present a normative volumetric database, spanning 5 decades of life, of cerebrospinal fluid, subarachnoid cerebrospinal fluid, total brain volume, total ventricular volume (component ventricular volumes of lateral, temporal horn, and third and fourth ventricles) and estimates of white and gray matter, based on a multispectral segmentation of brain MR. This database is presented as a reference for future studies comparing pathologic states. METHOD: One hundred ninety-four healthy subjects, ranging in age from 16 to 65 years, received standard axial intermediate- and T2-weighted spin-echo MR images. Multispectral segmentation and volume analysis were performed using ANALYZE. RESULTS: Normative volumetric estimates, both uncorrected and corrected for differences in total intracranial volume, were obtained for all subjects and presented by decade and sex. Age-related cerebrospinal fluid changes were evident for both male and female subjects. Most gender differences were eliminated by correction for differences in total intracranial volume. Standard and fast spin-echo acquisition methods gave comparable volume estimates. Total brain volume measurements from MR compare favorably with data from large autopsy series. CONCLUSION: Although there may be limitations to generalizations, these normative data tables can provide a comparison index for contrasting pathologic groups with a normative sample.