Sex Differences Across Concussion Characteristics in US Service Academy Cadets: A CARE Consortium Study.

OBJECTIVE: To describe sex differences in concussion characteristics in US Service Academy cadets. DESIGN: Descriptive epidemiology study. SETTING: Four US service academies. PARTICIPANTS: 2209 cadets (n = 867 females, n = 1342 males). INDEPENDENT VARIABLE: Sex. OUTCOME MEASURES: Injury proportion ratios (IPR) compared the proportion of injuries by sex (females referent) for injury situation, certainty of diagnosis, prolonged recovery, recurrent injuries, mental status alterations, loss of consciousness (LOC), posttraumatic amnesia (PTA), retrograde amnesia (RGA), motor impairments, delayed symptom presentation, and immediate reporting. MAIN RESULTS: Concussions from varsity/intercollegiate sports [IPR of 1.73, 95% confidence interval (CI) 1.43-2.10] and intramurals (IPR of 1.53, 95% CI 1.02-2.32) accounted for a larger proportion in males, whereas concussions outside of sport and military activities accounted for a smaller proportion among males (IPR of 0.70, 95% CI 0.58-0.85). The proportion of concussions with prolonged recovery was lower among males (IPR of 0.69, 95% CI 0.60-0.78), while concussions with altered mental status (IPR of 1.23, 95% CI 1.09-1.38), LOC (IPR of 1.67, 95% CI 1.17-2.37), PTA (IPR of 1.94, 95% CI 1.43-2.62), and RGA (IPR of 2.14, 95% CI 1.38-3.31) accounted for a larger proportion among males. A larger proportion of concussions that were immediately reported was observed in males (IPR of 1.15, 95% CI 1.00-2.31). Proportions of other characteristics (e.g., recurrent injuries) were not different between sexes. CONCLUSIONS: A higher proportion of concussions occurred outside of sport and military training for female cadets, who also displayed proportionally longer recovery times than males, despite males demonstrating a higher proportion of LOC, PTA, and RGA. Possible factors may include different mechanisms of injury outside of sport and military training, different biopsychosocial states associated with sex or injury context, and delayed injury reporting when outside of an observed environment, possibly secondary to perceived stigma about reporting injuries.

Baseline concussion assessment performance by sex in military service academy rugby players: findings from the CARE Consortium.

BACKGROUND: Normative student-athlete concussion assessment data may not be appropriate for service academy members (SAMs), particularly rugby players, because of the uniqueness of their academic/military training environment. Having accurate baseline data for this population is important because of their high risk for concussion and frequent lack of assigned sports medicine professional. The primary purpose of this study was to characterise baseline performance on a concussion assessment battery, with secondary purpose to determine effect of sex and concussion history on these measures among SAM rugby players. METHODS: 601 rugby-playing SAMs (19.3±1.5 years, 37.9% female) completed baseline concussion assessments: the Sport Concussion Assessment Tool (SCAT) Symptom and Symptom Severity Checklist, Standard Assessment of Concussion (SAC) and a neuropsychological test (either ImPACT (Immediate Post Concussion Assessment and Cognitive Testing) or ANAM (Automated Neuropsychological Assessment Metrics)). Groups were compared using an independent samples t-test or Mann-Whitney U test. A 2 (sex) × 2 (concussion history) ANOVA was conducted to determine the effects of sex and concussion history on outcomes. RESULTS: Women reported greater SCAT total symptoms (3.3 vs 2.8, p<0.001, r=0.143) and symptom severities (5.7 vs 4.3, p<0.001, r=0.139), and performed worse on ImPACT Visual Memory (79.3 vs 82.6, p=0.002, r=0.144) than men. Women performed better than men on SAC (28.0 vs 27.7, p=0.03, r=0.088), ImPACT Reaction Time Composite (0.59 vs 0.61, p=0.04, r=0.092) and ANAM Code Substitution Delayed (64.3 vs 61.5, p=0.04, d=0.433). Individuals with a history of concussion reported lower ImPACT Symptom Severity (2.6 vs 4.2, p=0.02, r=0.110). There was no interaction between concussion history and sex on outcomes. CONCLUSIONS: These findings provide reference data for SAM rugby players on baseline assessments and to help in clinical decision-making when managing sports-related concussion in absence of baseline data.

Inter-site and inter-scanner diffusion MRI data harmonization.

We propose a novel method to harmonize diffusion MRI data acquired from multiple sites and scanners, which is imperative for joint analysis of the data to significantly increase sample size and statistical power of neuroimaging studies. Our method incorporates the following main novelties: i) we take into account the scanner-dependent spatial variability of the diffusion signal in different parts of the brain; ii) our method is independent of compartmental modeling of diffusion (e.g., tensor, and intra/extra cellular compartments) and the acquired signal itself is corrected for scanner related differences; and iii) inter-subject variability as measured by the coefficient of variation is maintained at each site. We represent the signal in a basis of spherical harmonics and compute several rotation invariant spherical harmonic features to estimate a region and tissue specific linear mapping between the signal from different sites (and scanners). We validate our method on diffusion data acquired from seven different sites (including two GE, three Philips, and two Siemens scanners) on a group of age-matched healthy subjects. Since the extracted rotation invariant spherical harmonic features depend on the accuracy of the brain parcellation provided by Freesurfer, we propose a feature based refinement of the original parcellation such that it better characterizes the anatomy and provides robust linear mappings to harmonize the dMRI data. We demonstrate the efficacy of our method by statistically comparing diffusion measures such as fractional anisotropy, mean diffusivity and generalized fractional anisotropy across multiple sites before and after data harmonization. We also show results using tract-based spatial statistics before and after harmonization for independent validation of the proposed methodology. Our experimental results demonstrate that, for nearly identical acquisition protocol across sites, scanner-specific differences can be accurately removed using the proposed method.

Cognitive effects of one season of head impacts in a cohort of collegiate contact sport athletes.

OBJECTIVE: To determine whether exposure to repetitive head impacts over a single season negatively affects cognitive performance in collegiate contact sport athletes. METHODS: This is a prospective cohort study at 3 Division I National Collegiate Athletic Association athletic programs. Participants were 214 Division I college varsity football and ice hockey players who wore instrumented helmets that recorded the acceleration-time history of the head following impact, and 45 noncontact sport athletes. All athletes were assessed prior to and shortly after the season with a cognitive screening battery (ImPACT) and a subgroup of athletes also were assessed with 7 measures from a neuropsychological test battery. RESULTS: Few cognitive differences were found between the athlete groups at the preseason or postseason assessments. However, a higher percentage of the contact sport athletes performed more poorly than predicted postseason on a measure of new learning (California Verbal Learning Test) compared to the noncontact athletes (24% vs 3.6%; p < 0.006). On 2 postseason cognitive measures (ImPACT Reaction Time and Trails 4/B), poorer performance was significantly associated with higher scores on several head impact exposure metrics. CONCLUSION: Repetitive head impacts over the course of a single season may negatively impact learning in some collegiate athletes. Further work is needed to assess whether such effects are short term or persistent.

Regional brain atrophy in cognitively intact adults with a single APOE epsilon4 allele.

OBJECTIVE: To determine whether cognitively intact adults with the APOE epsilon3/epsilon4 genotype show reduced gray matter density on voxel-based morphometry (VBM) vs those homozygous for the epsilon3 allele. METHODS: Participants were healthy, cognitively intact, right-handed adults, age 19 to 80, who completed genotyping, neuropsychological testing, and MRI. Forty-nine participants had the epsilon3/epsilon3 genotype and 27 had the epsilon3/epsilon4 genotype. Gray matter data were analyzed using the general linear model as implemented in the Statistical Parametric Mapping package, adjusting for age and sex. RESULTS: The epsilon3/epsilon4 participants showed lower gray matter density than the epsilon3/epsilon3 participants in right medial temporal and bilateral frontotemporal regions as well as other areas. There were no regions in which epsilon3/epsilon4 participants showed higher gray matter density than epsilon3/epsilon3 participants. CONCLUSIONS: Regionally reduced gray matter density is detectable in cognitively intact adults with a single copy of the APOE epsilon4 allele.

Differential working memory load effects after mild traumatic brain injury.

The objective of this study was to explore the effects of increasing working memory (WM) processing load on previously observed abnormalities in activation of WM circuitry shortly after mild traumatic brain injury (MTBI). Brain activation patterns in response to increasing WM processing load (auditory n-back: 0-, 1-, 2-, and 3-back conditions) were assessed with fMRI in 18 MTBI patients within 1 month of their injury and in 12 healthy controls. Performance accuracy on these tasks was also measured. Brain activation patterns differed between MTBI patients and controls in response to increasing WM processing loads. Controls maintained their ability to increase activation in regions of WM circuitry with each increase in WM processing load. MTBI patients showed disproportionately increased activation during the moderate processing load condition, but very little increase in activation associated with the highest processing load condition. Task performance did not differ significantly between groups on any task condition. MTBI patients showed a different pattern of allocation of processing resources associated with a high processing load condition compared to healthy controls, despite similar task performance. This suggests that injury-related changes in ability to activate or modulate WM processing resources might underlie some of the memory complaints after MTBI.

Specific frontal lobe subregions correlated with unawareness of illness in schizophrenia: a preliminary study.

The authors examined the relationship between unawareness of illness and eight frontal lobe subregions in 15 patients with schizophrenia. Significant inverse correlations were seen between unawareness and bilateral middle frontal gyrus volume and between symptom misattribution and superior frontal gyrus volume.

Brain activation on fMRI and verbal memory ability: functional neuroanatomic correlates of CVLT performance.

We have recently reported (Saykin et al., 1999b) selective activation of left medial temporal lobe structures during processing of novel compared to familiar words using functional magnetic resonance imaging (fMRI). The current study describes the relationship between a widely used clinical test of verbal learning, the California Verbal Learning Test (CVLT), and the previously reported fMRI activations. Thirteen right-handed healthy adult participants were studied with whole brain echo-planar fMRI while listening to novel and recently learned (familiar) words intermixed pseudorandomly in an event-related design. These participants were also tested with the CVLT. Scores for CVLT Trial 1 (immediate encoding of novel words) and recognition discriminability (recognition of familiar vs. novel words) were correlated with fMRI signal change during processing of novel versus familiar words using a covariance model implemented in SPM96. For the novel words analysis, voxels in the right anterior hippocampus correlated significantly with Trial 1 (r = .76 at the maxima). For the recognition analysis, a significant cluster of voxels was found in the right dorsolateral prefrontal cortex (r = .88 at the maxima). Our prior results of separable left medial temporal activation to novel and familiar words, together with results of the covariance analyses reported here, suggest that in addition to the left medial temporal lobe (MTL) regions that are engaged during novel and familiar word processing, the right hippocampus and right frontal lobe are also involved, particularly in those participants with better memory ability. This positive relationship between fMRI activation and CVLT performance suggests a role for these right hemisphere regions in successful memory processing of verbal material, perhaps reflecting more efficient encoding and retrieval strategies that facilitate memory.

Neuroimaging findings in mild traumatic brain injury.

The role of neuroimaging in the diagnosis and management of mild traumatic brain injury (TBI) is evolving. In general, the structural imaging techniques play a role in acute diagnosis and management, while the functional imaging techniques show promise for clarification of pathophysiology, symptom genesis, and mechanisms of recovery. A wide array of neuropathological processes are involved in mild TBI including changes in bone (e.g., a skull fracture), tissue density and water content (edema), blood flow, white matter integrity and pathway connectivity (diffuse axonal injury), and subtle changes in the neuronal and extracellular biochemical milieu. No single imaging technique is capable of addressing all these processes. It is, therefore, important to be aware of the advantages and limitations of the various available imaging modalities. This paper selectively reviews the pertinent literature on the structural and functional imaging in mild TBI.

Smaller brain size associated with unawareness of illness in patients with schizophrenia.

OBJECTIVE: Although several neuropsychological studies have supported the notion of frontal and parietal lobe involvement in unawareness of illness in schizophrenia, neuroanatomic differences have not been examined. METHOD: Thirty patients with schizophrenia spectrum disorder were rated by means of a structured interview assessing awareness of illness and performance on clinical rating scales. With 13 healthy comparison subjects, they underwent neuropsychological assessment and a scan using three-dimensional, spoiled gradient recall acquisition volumetric magnetic resonance imaging. RESULTS: Patients who were relatively unaware of their illness had smaller brain and intracranial volumes (brain tissue plus CSF) than either aware patients or normal comparison subjects, who did not differ significantly from each other. CONCLUSIONS: These findings suggest that unawareness of illness is an important phenomenological feature with neurological correlates that is seen in at least one subgroup of patients with schizophrenia.

The relationship between fMRI activation and cerebral atrophy: comparison of normal aging and alzheimer disease.

Functional MRI has recently been used to examine activation associated with aging and dementia, yet little is known regarding the effect of cerebral atrophy on fMRI signal. The purpose of this study was to examine the relationship between measures of global and regionally specific atrophy and fMRI activation in normal aging and in Alzheimer disease (AD). Two groups of subjects were studied with echoplanar imaging and quantitative structural volumetry: healthy controls spanning a broad age and atrophy range (n = 16) and patients with mild AD (n = 8). Results from a semantic task previously found to activate left inferior frontal (LIFG) and left superior temporal (LSTG) gyri were analyzed. The correlations between clusters of activation in the LIFG and LSTG and measures of local atrophy in the LIFG and LSTG regions were evaluated. For control subjects, there was no significant correlation between activation and regional or total brain atrophy (for LIFG r = -0.03, NS; for LSTG r = 0.20, NS). In contrast, for AD patients, there was a significant positive correlation between atrophy and activation in LIFG (r = 0.70, P = 0.05) but not LSTG (r = 0.00, NS). These results suggest that activation of language regions and atrophy within those regions may be independent among healthy adults spanning a broad age and atrophy range. However, in AD, a relationship exists in the LIFG that may reflect compensatory recruitment of cortical units or disease-specific changes in the hemodynamic response.

Apathy.

Deficits in motivated behavior are a very common sequela of most neuropsychiatric disorders, a source of significant disability to the individual, and a source of great frustration to their caregivers. Well-intentioned attempts to encourage certain activities in the apathetic patient often precipitate aggressive, dyscontrolled behavior. The psychopharmacologic approach to motivated behavior deficits is informed by the study of the components, circuitry, and neurochemistry of motivated behavior in animals and humans. This article selectively reviews this literature. The circuitry of motivated behavior involves a combination of behavior specific regions in the hypothalamus as well as a general reward system running from midbrain to forebrain and including important components of several frontal-subcortical circuits. Catecholaminergic systems, particularly the mesolimbic dopaminergic system, are key modulators of motivated behaviors. Treatment thus involves the use of catecholaminergic agents.

Brain activation during working memory 1 month after mild traumatic brain injury: a functional MRI study.

OBJECTIVE: To assess patterns of regional brain activation in response to varying working memory loads shortly after mild traumatic brain injury (MTBI). BACKGROUND: Many individuals complain of memory difficulty shortly after MTBI. Memory performance in these individuals can be normal despite these complaints. METHODS: Brain activation patterns in response to a working memory task (auditory n-back) were assessed with functional MRI in 12 MTBI patients within 1 month of their injury and in 11 healthy control subjects. RESULTS: Brain activation patterns differed between MTBI patients and control subjects in response to increasing working memory processing loads. Maximum intensity projections of statistical parametric maps in control subjects showed bifrontal and biparietal activation in response to a low processing load, with little additional increase in activation associated with the high load task. MTBI patients showed some activation during the low processing load task but significantly increased activation during the high load condition, particularly in the right parietal and right dorsolateral frontal regions. Task performance did not differ significantly between groups. CONCLUSION: MTBI patients differed from control subjects in activation pattern of working memory circuitry in response to different processing loads, despite similar task performance. This suggests that injury-related changes in ability to activate or to modulate working memory processing resources may underlie some of the memory complaints after MTBI.

Functional differentiation of medial temporal and frontal regions involved in processing novel and familiar words: an fMRI study.

Results of recent functional magnetic resonance imaging (fMRI) studies of memory are not entirely consistent with lesion studies. Furthermore, although imaging probes have identified neural systems associated with processing novel visual episodic information, auditory verbal memory using a novel/familiar paradigm has not yet been examined. To address this gap, fMRI was used to compare the haemodynamic response when listening to recently learned and novel words. Sixteen healthy adults (6 male, 10 female) learned a 10-item word list to 100% criterion, approximately 1 h before functional scanning. During echo-planar imaging, subjects passively listened to a string of words presented at 6-s intervals. Previously learned words were interspersed pseudo-randomly between novel words. Mean scans corresponding to each word type were analysed with a random-effects model using statistical parametric mapping (SPM96). Familiar (learned) words activated the right prefrontal cortex, posterior left parahippocampal gyrus, left medial parietal cortex and right superior temporal gyrus. Novel words activated the anterior left hippocampal region. The results for the familiar words were similar to those found in other functional imaging studies of recognition and retrieval and implicate the right dorsolateral prefrontal and left posterior medial temporal lobe (MTL) regions. The results for novel words require replication, but are consistent with the substantial lesion and PET literature implicating the anterior MTL as a critical site for processing novel episodic information, presumably to permit encoding. Together, these results provide evidence for an anterior-posterior functional differentiation within the MTL in processing novel and familiar verbal information. The differentiation of MTL functions that was obtained is consistent with a large body of PET activation studies but is unique among fMRI studies, which to date have differed from results with PET. Further, the finding of left MTL lateralization is consistent with lesion-based material-specific models of memory.

Evaluation of brain injury related behavioral disturbances in community mental health centers.

As a result of improved emergency trauma services, more individuals suffering a traumatic brain injury are surviving. Unfortunately, most of these survivors suffer chronic neuropsychiatric sequelae related to both the brain damage and the psychosocial impact of the injury on self-esteem, self-image, primary role, and vocational function. Current community supports are often inadequate to deal with the complex array of neurologic and psychiatric difficulties. This article outlines common features of brain injury, explores the link between these features and the common neuropsychiatric sequelae of brain injury, and suggests some principles helpful in the evaluation of the behaviorally challenged brain injured patient.

Treatment of organic bipolar mood disorders in Parkinson's disease.

Two patients with long-standing idiopathic Parkinson's disease (PD), without individual or family histories of affective disorders, developed bipolar mood disorders. Both were treated with lithium and clozapine, and one responded favorably. These may be the first reported cases in which mania was treated with clozapine in PD patients.

Ultra-rapid cycling bipolar affective disorder following a closed-head injury.

A young adult with no prior history of affective disease suffered the onset of a rapid cycling bipolar illness, marginally responsive to psychotropic medications, following a mild closed-head injury, and persisting after the cognitive effects of the injury had resolved. A concurrence of findings on the neurological examination, neurobehavioural examination, SPECT scan, EEG and neuropsychological test battery suggested the presence of a diffuse cerebral injury with a predominance of left frontotemporal findings. This case demonstrates that a severe and disabling mood disorder may follow a mild head injury, and that its course may be independent of cognitive impairment and recovery.

Mixed neurologic and psychiatric disorders: pharmacological issues.

The number of patients with mixed neurologic and psychiatric disturbances is large. The psychiatric disturbances are often atypical in presentation and fit poorly into standard psychiatric nomenclature. They can be difficult to treat using standard psychopharmacologic approaches. This report reviews the impact of brain dysfunction on the use of conventional and nonconventional psychotropic agents in this mixed population.

Neuropsychiatric sequelae of head injuries.

Based on the above review several general points can be highlighted: Head injuries are extremely common, affecting probably close to 2,000,000 people in this country each year. The most common are nonmissile, closed-head injuries, the majority of which occur in association with motor vehicle accidents. Virtually all studies of head injury suggest a peak incidence in the 15 to 24 years of age group. Coarse measures of outcome suggest that the very young and the elderly have poorer outcomes. Because of improved acute care, however, a large number of young, otherwise healthy patients are surviving head injuries with a variety of profound neuropsychiatric sequelae. Because of the mechanics of brain injury in acceleration-deceleration injuries, certain brain injury profiles are common including orbitofrontal, anterior and inferior temporal contusions, and diffuse axonal injury. The latter particularly affects the corpus callosum, superior cerebellar peduncle, basal ganglia, and periventricular white matter. The neuropsychiatric sequelae follow from the above injury profiles. Cognitive impairment is often diffuse with more prominent deficits in rate of information processing, attention, memory, cognitive flexibility, and problem solving. Prominent impulsivity, affective instability, and disinhibition are seen frequently, secondary to injury to frontal, temporal, and limbic areas. In association with the typical cognitive deficits, these sequelae characterize the frequently noted "personality changes" in TBI patients. In addition, these changes can exacerbate premorbid problems with impulse control. Marked difficulties with substance use, sexual expression, and aggression often result. The constellation of symptoms, which make up the postconcussive syndrome, are seen across the whole spectrum of brain injury severity. Even in so-called mild or minor head injury, these symptoms are likely to have an underlying neuropathologic, neurochemical, or neurophysiologic cause. Higher than expected rates of certain psychopathologic disorders occur in the TBI population, including psychotic syndromes and depressive syndromes. Manic syndromes also are associated with TBI; however, the incidence has not been established. Assessment and treatment of the neuropsychiatric sequelae is a complex and challenging process. The mixture of diffuse and focal injuries, the combination of cognitive, language, somatic, and behavioral difficulties do not fit easily into current diagnostic categories.