BDNF genotype is associated with hippocampal volume in mild traumatic brain injury.

The negative long-term effects of mild traumatic brain injury (mTBI) have been a growing concern in recent years, with accumulating evidence suggesting that mTBI combined with additional vulnerability factors may induce neurodegenerative-type changes in the brain. However, the factors instantiating risk for neurodegenerative disease following mTBI are unknown. This study examined the link between mTBI and brain-derived neurotrophic factor (BDNF) genotype, which has previously been shown to regulate processes involved in neurodegeneration including synaptic plasticity and facilitation of neural survival through its expression. Specifically, we examined nine BDNF single-nucleotide polymorphisms (SNPs; rs908867, rs11030094, rs6265, rs10501087, rs1157659, rs1491850, rs11030107, rs7127507 and rs12273363) previously associated with brain atrophy or memory deficits in mTBI. Participants were 165 white, non-Hispanic Iraq and Afghanistan war veterans between the ages of 19 and 58, 110 of whom had at least one mTBI in their lifetime. Results showed that the BDNF SNP rs1157659 interacted with mTBI to predict hippocampal volume. Furthermore, exploratory analysis of functional resting state data showed that rs1157659 minor allele homozygotes with a history of mTBI had reduced functional connectivity in the default mode network compared to major allele homozygotes and heterozygotes. Apolipoprotein E (APOE) was not a significant predictor of hippocampal volume or functional connectivity. These results suggest that rs1157659 minor allele homozygotes may be at greater risk for neurodegeneration after exposure to mTBI and provide further evidence for a potential role for BDNF in regulating neural processes following mTBI.

CRP polymorphisms and DNA methylation of the AIM2 gene influence associations between trauma exposure, PTSD, and C-reactive protein.

BACKGROUND: Recent studies have implicated inflammatory processes in the pathophysiology of posttraumatic stress disorder (PTSD). C-reactive protein (CRP) is a widely-used measure of peripheral inflammation, but little is known about the genetic and epigenetic factors that influence blood levels of C-reactive protein (CRP) in individuals with PTSD. METHODS: Participants were 286 U.S. military veterans of post-9/11 conflicts (57% with current PTSD). Analyses focused on single nucleotide polymorphisms (SNPs) in the CRP gene and DNA methylation at cg10636246 in AIM2-a locus recently linked to CRP levels through results from a large-scale epigenome-wide association study. RESULTS: PTSD was positively correlated with serum CRP levels with PTSD cases more likely to have CRP levels in the clinically-elevated range compared to those without a PTSD diagnosis. Multivariate analyses that controlled for white blood cell proportions, genetic principal components, age and sex, showed this association to be mediated by methylation at the AIM2 locus. rs3091244, a functional SNP in the CRP promoter region, moderated the association between lifetime trauma exposure and current PTSD severity. Analyses also revealed that the top SNPs from the largest genome-wide association study of CRP conducted to date (rs1205 and rs2794520) significantly interacted with PTSD to influence CRP levels. CONCLUSIONS: These findings provide new insights into genetic and epigenetic mechanisms of inflammatory processes in the pathophysiology of PTSD and point to new directions for biomarker identification and treatment development for patients with PTSD.

SKA2 methylation is associated with decreased prefrontal cortical thickness and greater PTSD severity among trauma-exposed veterans.

Methylation of the SKA2 (spindle and kinetochore-associated complex subunit 2) gene has recently been identified as a promising biomarker of suicide risk. Based on this finding, we examined associations between SKA2 methylation, cortical thickness and psychiatric phenotypes linked to suicide in trauma-exposed veterans. About 200 trauma-exposed white non-Hispanic veterans of the recent conflicts in Iraq and Afghanistan (91% male) underwent clinical assessment and had blood drawn for genotyping and methylation analysis. Of all, 145 participants also had neuroimaging data available. Based on previous research, we examined DNA methylation at the cytosine-guanine locus cg13989295 as well as DNA methylation adjusted for genotype at the methylation-associated single nucleotide polymorphism (rs7208505) in relationship to whole-brain cortical thickness, posttraumatic stress disorder symptoms (PTSD) and depression symptoms. Whole-brain vertex-wise analyses identified three clusters in prefrontal cortex that were associated with genotype-adjusted SKA2 DNA methylation (methylation(adj)). Specifically, DNA methylation(adj) was associated with bilateral reductions of cortical thickness in frontal pole and superior frontal gyrus, and similar effects were found in the right orbitofrontal cortex and right inferior frontal gyrus. PTSD symptom severity was positively correlated with SKA2 DNA methylation(adj) and negatively correlated with cortical thickness in these regions. Mediation analyses showed a significant indirect effect of PTSD on cortical thickness via SKA2 methylation status. Results suggest that DNA methylation(adj) of SKA2 in blood indexes stress-related psychiatric phenotypes and neurobiology, pointing to its potential value as a biomarker of stress exposure and susceptibility.

Normal aging and cognition: the unacknowledged contribution of cerebrovascular risk factors.

Despite the widespread assumption that cognitive decline is an inherent part of the normal aging process, research suggests that part of the variance in age-related cognitive decline is attributable to modifiable factors common in geriatric populations such as cerebrovascular risk factors. We completed a literature search using Science Citation Index and evaluated the most cited articles from the last 10 years to determine the extent to which investigations of normal aging and cognition account for the influence of cerebrovascular risk factors. We found that the majority of the most frequently cited literature does not adequately account for the contribution of cerebrovascular risk factors and therefore, it is possible that many conclusions about normal aging and cognition are flawed or incomplete. Further investigation of the role of cerebrovascular risk factors in age-related cognitive decline is imperative to more accurately understand the effect of aging on cognition.

Triangular backgrounds shift the bias of line bisection performance in hemispatial neglect.

OBJECTIVE: Patients with left neglect on line bisection show normal implicit sensitivity to manipulations of both the stimulus and the visual background. Three experiments were designed to define this sensitivity more exactly. METHODS: Normal controls and patients with left neglect performed a series of horizontal line bisection tasks. Independent variables were the configurations of the backgrounds for the line-rectangle, square, circle, left and right pointing isosceles triangles-and whether the background was the shape of the piece of paper or an outline drawn on a standard piece of paper. In a separate experiment different components of the triangle were outlined on a piece of paper. Deviation from true midpoint was calculated. RESULTS: Simply placing the target lines in a symmetric background such as a square or circle did not reliably reduce neglect. A triangle asymmetric in the horizontal plane caused a shift in bisection away from the triangle's vertex. With right pointing triangles the perceived midpoint shifted to the left of true centre (crossed over). The effects of the triangles were comparable in the patients and the controls when controlled for baseline bisection bias. The critical components of the triangles were the angular legs. This effect of background was not influenced by lesion site or by hemianopia. CONCLUSIONS: Patients with left visual neglect remain sensitive to covert manipulations of the visual background that implicitly shift the perceived midpoint of a horizontal line. This effect is strong enough to eliminate neglect on a bisection task. The mechanism of this effect is expressed through preattentive visual capacities.

Stroke risk predicts verbal fluency decline in healthy older men: evidence from the normative aging study.

Risk factors for stroke cause ischemic changes in the cerebral white matter that may affect frontal lobe functions more than other brain functions. Therefore, stroke risk could specifically affect performance on behavioral indexes traditionally associated with frontal lobe function such as verbal fluency. The authors examined this hypothesis in 235 healthy older men (mean age = 66.41 years) who received concurrent medical and neuropsychological examinations twice at a 3-year interval. Relations between stroke risk and decline in verbal fluency, memory, and visuospatial performance were analyzed through regression, controlling for age and education. Age was associated with decline in all cognitive functions; stroke risk was associated with decline only on verbal fluency. The relation between stroke risk and fluency decline was 80% as large as that between age and fluency decline. These results suggest that stroke risk rivals the effects of aging on verbal fluency performance.

Preattentive and attentive visual search in individuals with hemispatial neglect.

Preattentive and attentive visual processing was examined in patients with hemispatial neglect, hemispatial neglect with hemianopia, and control participants. In the preattentive search task, targets possessed a unique feature that was not shared by distractors. In the attentive search task, targets lacked a feature that was present in the distractors. Preattentive search was normal in 3 neglect patients with cortical lesions but not in 2 neglect patients with hemianopia. A 4th neglect patient without hemianopia with a subcortical infarct abnormally used serial search mechanisms in the preattentive task. Neglect patients were characteristically impaired in the contralesional field in the attentive search task. This study demonstrates preserved explicit detection of visual features in cases of hemispatial neglect.

The mapping from sound structure to the lexicon in aphasia: evidence from rhyme and repetition priming.

Two studies were conducted to explore the hypothesis that Broca's and Wernicke's aphasics have deficits arising from the processes involved in activating the lexicon from phonological form. The first study explored whether phonologically similar lexical entries differing only in their initial consonants show "rhyme priming." Results revealed that Broca's aphasics failed to show facilitation when the target was identical to the prime (i.e. identity priming) and they showed significant inhibition when targets were preceded by rhyming words. Wernicke's aphasics showed a pattern of results similar to that of normal subjects, i.e., identity priming and rhyme priming as well as significantly slower reaction-times in the rhyming condition compared to the identity condition. The second study investigated form-based repetition priming in aphasic patients at a number of intervals including when no other stimuli intervened between repeated stimuli (0 lag) or when 4, 8, or 12 stimuli intervened. Results showed that, unlike old normal subjects who showed repetition priming for both words and nonwords, both Broca's and Wernicke's aphasics showed repetition priming for word targets only. Moreover, in contrast to old normal subjects who showed a greater magnitude of priming at 0 lag for word targets, neither Broca's aphasics or Wernicke's aphasics showed priming at 0 lag. Implications of these findings are considered with respect to the hypotheses that Broca's and Wernicke's aphasics have deficits in the nature of the activation patterns within the lexicon itself and in auditory (working) memory.

Alterations in the dynamics of semantic activation in Alzheimer's disease: evidence for the Gain/Decay hypothesis of a disorder of semantic memory.

While it has been commonly assumed that a deficit in semantic memory underlies many of the clinical and cognitive features of early Alzheimer's disease (AD), there has been little agreement on what constitutes a proper theoretical description of this impaired system. Currently, most theories of this disorder fall into two categories: those that posit degraded semantic representations, and those that posit impaired retrieval operations with relatively intact semantic representations. It is argued that each position has both empirical and logical disadvantages that have prevented the development of a consensus on how to describe the pathology of semantic memory in AD. In this paper we present the details and supportive evidence for an alternative account of the semantic memory deficit of AD: the Gain/Decay hypothesis. The core claim of the Gain/Decay hypothesis is that a reduction in the time constant of spreading activation in AD produces dynamic changes in the availability of semantic representations that depend on the time frame in which this information must be accessed. The implications of this hypothesis for a range of experimental and clinical phenomena are discussed, as are possible biological correlates of the hypothesized alterations in the modulation of activation.

The effects of focal and diffuse brain damage on strategy application: evidence from focal lesions, traumatic brain injury and normal aging.

A new test of strategy application was designed to be relatively free of the constraints that limit the standard neuropsychological assessment of supervisory abilities. The validity of the test was assessed in 3 samples of participants with varying degrees of supervisory deficits and frontal systems dysfunction: focal frontal lesions, traumatic brain injury (TBI), and normal aging. Inefficient strategy application varied systematically across the 3 groups and was not due to extraneous factors such as forgetting the test instructions. Previous case studies have emphasized strategy application deficits in the face of normal neuropsychological test performance. In this study, it was shown that strategically impaired participants from a consecutive series can include those both with and without deficient neuropsychological test performance. When neuropsychological impairment was present, it was greatest on executive functioning tasks. Among participants with nonstrategic performance, there was evidence for a dissociation of knowledge from action. This finding was not specific to focal frontal lesions. A number of supervisory processes contributing to strategy application were identified. Exploratory analyses indicated differential effects of lesion location on these processes, especially inferior medial frontal and right hemisphere lesions. Overall, the results supported the use of unstructured tasks in the assessment of supervisory abilities.

Effects of aging on conditional associative learning: process analyses and comparison with focal frontal lesions.

Conditional associative learning (CAL), a measure validated in studies of frontal lesions, was used to evaluate the hypothesis that age-related cognitive decline is related to frontal dysfunction. Older adults and focal frontal participants showed impaired CAL performance, but the deficit was greater in the latter group, where it was specific to participants with dorsolateral prefrontal cortical (DLPFC) lesions. The deficits were attributable to strategic rather than basic associative processes. Error scores described ways in which past information failed to guide behavior, and they were related to lesion location. Congruence between older adults and DLPFC participants on a measure of defective inhibition suggests that age-related decline in inhibitory processes is due to DLPFC dysfunction.

Repetition priming in an auditory lexical decision task: effects of lexical status.

The effect of lexical status on the time course of repetition priming was examined in an auditory lexical decision task. Words and nonwords were repeated at lags of 0, 1, 4, and 8 items (Experiment 1A) and 0, 2, 4, and 8 items (Experiment 1B). The pattern of repetition effects differed for words and nonwords in that repetition priming for nonwords at lag 0 was significantly greater than for words. The magnitude of this effect decreased when one or more items intervened. A second experiment, replicating Experiment 1A with visual presentation, clarified that the greater magnitude of repetition priming for nonwords at lag 0 is unique to the auditory modality. This finding suggests that in the course of forming a stable perceptual representation, the details of the acoustic/phonological information of an auditory stimulus are more readily available for nonwords than for words. The capacity to carry this phonological information is limited, however, and can only be maintained until another stimulus is encountered.

Preserved semantic priming effect in alexia.

BH, a left-handed patient with alexia and nonfluent aphasia, was presented with a lexical-decision task in which words and pronounceable pseudowords were preceded by semantically related or unrelated picture primes (Experiment 1). In Experiment 2, BH was given an explicit reading task using the word lists from Experiment 1. Performance on Experiment 2 disclosed severe reading deficits in both oral reading and semantic matching of the words to pictures. However, in Experiment 1, BH demonstrated a significant semantic priming effect, responding more accurately and more quickly to words preceded by related primes than by unrelated primes. The present results suggest that even in a patient with severe alexia, implicit access to semantic information can be preserved in the absence of explicit identification. The possibility of categorical gradient in implicit activation (living vs. nonliving) in BH was also discussed, which, however, needs to be clarified in the further investigation.

Assessment of neglect reveals dissociable behavioral but not neuroanatomical subtypes.

In the current study, we investigated whether standard assessment techniques of visuospatial neglect are sensitive to detecting dissociable subtypes. We administered a battery of tasks commonly used to detect the presence of visuospatial neglect to 120 patients with unilateral right hemisphere infarcts and, in most cases, performed a systematic analysis of their lesions to quantify and localize brain damage. Using a factor analysis, we discovered seven relatively independent constructs, three of which were specifically related to the presence of left hemispatial neglect: Left Attentional Processing, Line Bisection, and Word Reading. Impairments in two of these factors, Left Attentional Processing and Line Bisection, occurred together in most cases but also occurred independently in 38 cases. There were no cases in whom Word Reading was present without concomitant deficits in one or the other two factors. These three factors could not be distinguished neuroanatomically; that is, lesions were equally likely in the temporal/parietal cortex, dorsolateral frontal cortex, or in deep frontal structures. These data confirm the notion that hemispatial neglect is a complex and multifaceted disorder composed of cognitively independent processes. These processes, however, cannot be dissociated neuroanatomically based on currently available assessment techniques.

False recognition and the right frontal lobe: a case study.

We described a patient, BG, who exhibited a striking pattern of false recognition after an infarction of the right frontal lobe. Seven experiments document the existence of the phenomenon, explore its characteristics, and demonstrate how it can be eliminated. BG showed pathologically high false alarm rates when stimuli were visual words (experiments 1 and 4), auditory words (experiment 2), environmental sounds (experiment 3), pseudowords (experiment 5), and pictures (experiment 7). His false alarms were not merely attributable to the semantic or physical similarity of studied and non-studied items (experiments 4 and 5). However, BG's false recognitions were virtually eliminated by presenting him with categorized stimuli and testing him with new stimuli from non-studied categories (experiments 6 and 7). The results suggest that BG's false alarms may be attributable to an over-reliance on memory for general characteristics of the study episode, along with impaired memory for specific items. The damaged right frontal lobe mechanisms may normally support the monitoring and/or retrieval processes that are necessary for item-specific recognition.

Issues in the assessment of cognitive function in dementia.

The increasing prevalence of elderly patients presenting with disorders of cognitive functioning suggestive of dementia, coupled with limits in resources available to address these problems, is going to necessitate the development of new technologies to be used for assessment. These measures should be efficient, designed to reflect both the current knowledge of brain function and the developmental characteristics of older patients. Though few current measures of cognitive function meet these goals, neuropsychological "microbatteries" such as the DRS and NCSE may serve as models for a new generation of cognitively specific assessment instruments.

Semantic processing and orthographic specificity in hemispatial neglect.

Two sets of experiments, each consisting of a semantic priming task and a discrimination task, investigated the proceedings of lexical information in the neglected visual field. In the semantic priming task, subjects made lexical decisions to target words preceded by lateralized word primes; in the discrimination task, they indicated which of two words corresponded to a target word presented to the left visual field (LVF) or right visual field (RVF). The first set of experiments indicated that although patients were unable to discriminate words presented in the LVF, they showed significant priming when LVF primes were followed by semantically related targets compared to unrelated targets. The second set of experiments further examined the nature of this priming effect by comparing priming in a condition in which primes were semantically related to the target word (e.g., TEA-CUP) and a condition in which primes were unrelated to the target word, but orthographically similar to a related prime (e.g., PEA-CUP). This experiment replicated the previously established semantic priming effects and demonstrated significant negative priming for targets preceded by LVF primes that were orthographically similar to a semantically related word. Again, patients performed at chance in the forced-choice discrimination task when targets were presented in the LVF These findings indicate that semantic processing of neglected lexical information is based on fully specified perceptual and orthographic information. A lateral inhibitory mechanism is proposed that maximizes the probability, albeit unsuccessfully, that neglected orthographic information will reach awareness.