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.

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.

Differential effects of human and animal insulin on the responses to hypoglycemia in elderly patients with NIDDM.

Recent studies suggest that insulin-dependent diabetes mellitus patients switched from animal to human insulin may have decreased awareness of hypoglycemic warning symptoms. The risk of severe or fatal hypoglycemia associated with the treatment of diabetes increases with age. We conducted these studies to determine if awareness of hypoglycemic warning symptoms was greater with animal than with human insulin in elderly patients with diabetes. Nonobese elderly patients with non-insulin-dependent diabetes mellitus (NIDDM) (n = 13; age, 74 +/- 1 years; body mass index, 26.6 +/- 0.7 kg/m2) underwent paired hyperinsulinemic glucose clamp studies (insulin infusion rate 60 mU.m-2.min) in random order. In one study, regular human insulin was infused, and in the other study, regular beef/pork insulin was infused. In all studies, plasma glucose was decreased from fasting levels to 5 mmol/l during the first 60 min and was then allowed to fall to 4.4, 3.8, 3.3, and 2.8 mmol/l in each subsequent hour. Subjects were blinded as to which study they were undergoing. In each study, a hypoglycemic symptom checklist was administered, and counterregulatory hormones were measured every 15 min. Neuropsychological tests were performed every hour. Counterregulatory hormone responses to the two insulin preparations were similar. Autonomic (P < 0.05) and neuroglycopenic (P < 0.01) symptom scores were significantly higher during the beef/pork insulin studies. The responses on the neuropsychological tests were not significantly different. We conclude that beef/pork insulin results in greater awareness of hypoglycemic warning symptoms than does human insulin in elderly patients with NIDDM.

Dissociable cognitive and neural mechanisms of unilateral visual neglect.

We administered two experimental tasks to 16 patients with neglect following unilateral right hemisphere strokes, designed to probe processing of information in the neglected left visual field. A semantic priming/lexical decision task examined implicit processing of stimuli presented to the neglected field, and a discrimination task required explicit recognition of the same stimuli. We grouped patients according to three patterns of performance: (1) poor discrimination in the left visual field but intact priming, (2) normal priming and discrimination in both fields, and (3) normal priming but poor discrimination in both fields. Although patients in group 1 had posterior lesions, patients in groups 2 and 3 had extensive deep anterior lesions. These results suggest that the clinical phenomenon of unilateral visual neglect can be the surface manifestation of deficits in two different and interacting processes--attentional processes (group 1) and intentional processes (group 2)--or it may be a global attentional disturbance superimposed on these deficits (group 3).

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.

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.

The relationship among handedness, sighting dominance, and acuity dominance in elementary school children.

The present study was an attempt to clarify the relationship between handedness, sighting dominance, and eye-acuity in children. Ninety-four males and ninety-seven females between the ages of five and eleven were assessed on standardized measures of handedness, sighting dominance, and visual acuity. Right-handers were more likely to show right-sighting dominance, whereas left-handers had an equal chance of being right-sighted or left-sighted. Acuity dominance was not consistently associated with handedness or sighting dominance. No effects for sex or age were found. It is suggested that further clarification of the function of various lateralized sensorimotor measures is needed before an understanding of how these measures may be related to cortical dominance is possible.

Learning of a complex arithmetic skill in dementia: further evidence for a dissociation between compilation and production.

An amnesic Alzheimer's Disease patient was tested on his ability to learn an algorithm to square two-digit numbers. The results indicated a dissociation in the patient's ability to execute the individual steps of the algorithm and his ability to combine the steps of the algorithm, the former accounting for almost all of the improvement in response time. The results are discussed in conjunction with findings from Charness et al. (1988) and Milberg et al. (1988) and suggest that skill learning in Alzheimer's Disease may be compromised due to an inability to combine individual steps of a procedure.

Role of subvocal motor activity in dichotic speech perception and selective attention.

Twenty right-handed male and female subjects were asked for ear-by-ear recall of dichotically presented consonant--vowel syllables. Stimuli within each dichotic pair were contrasted on the features on voicing and/or place, or were differentiated by manner of production. While listening to the stimuli, the subjects were required to concurrently reduce the electromyographic subvocal activity recorded from the lips and throat or from a control site, the frontalis muscle. A right-ear advantage was observed during the control condition, the largest advantage occurring when the pairs were contrasted on both voicing and place. In contrast, a left-ear advantage was observed when subvocal articulatory activity was voluntarily reduced. These results suggest that subvocal articulatory activity contributes to the observed right-ear advantage for speech by affecting attentional bias and not phonetic processing. Possible underlying mechanisms for this effect are discussed.

Syntactic priming effects in aphasia: an investigation of local syntactic dependencies.

This study explored on-line processing of local syntactic dependencies in normal subjects and in Broca's and Wernicke's aphasics using a lexical decision paradigm. In addition, subjects performed a grammatically judgement task on the real word pairs used in the lexical decision tasks. Results of two experiments for normal subjects indicated different syntactic priming effects as a function of the type of local syntactic dependency. Word pairs that formed a single constituent phrase, i.e., a verb phrase, showed both facilitory and inhibitory effects, whereas word pairs that reflected local syntactic dependencies across a phrase boundary, i.e., pronoun verb, showed only inhibitory effects. Broca's aphasics failed to show facilitory effects when presented with word pairs forming a single constituent phrase but, similar to normals, did show inhibition when presented with word pairs that reflected local syntactic dependencies across a phrase boundary. In contrast, Wernicke's aphasics failed to show inhibitory effects in both experiments. The implications of these results for theories of language processing deficits in aphasia are considered.

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.

Age differences in depicting and perceiving tridimensionality in simple line drawings.

Twelve young adults (M = 21 years) and twelve elderly adults (M = 67 years) were asked to draw a solid cube. The depictions produced by elderly adults were rated by judges as less accurate than the depictions produced by young adults. Both age groups were also asked to evaluate cube drawings that were deliberately distorted in ways characteristic of the depictions produced by older adults. Compared to younger participants, the elderly were more likely to accept distorted drawings as accurate. Control tasks demonstrated that older adults were able to draw and evaluate simpler two-dimensional patterns on par with younger adults. Apparently the mental representation of tridimensional information deteriorates with age leading to deficits in both production and recognition.

Concept generation: validation of a test of executive functioning in a normal aging population.

A new test, Concept Generation, was designed to fractionate the processes that underlie sorting performance in an efficient paper-and-pencil format. The test was administered to 60 subjects, aged 18-79. Results indicated age-related deficits for self-initiated concept formation, shifting set, output monitoring, and perseverative tendencies. When cuing was introduced to increase structure, age group differences were attenuated or eliminated. Within the older group, subgroups were identified based upon the nature of their repetitions. The hypothesis that sorting behavior is mediated by executive functions led to correlational analyses between Concept Generation scores and other measures of executive functioning. The pattern of correlations supported the construct validity of the Concept Generation test. In addition to providing preliminary evidence for the usefulness of Concept Generation in executive functioning assessment, the results replicated and extended previous work on executive functioning in older individuals.

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.

Priming of spatial configurations in alcoholic Korsakoff's amnesia.

To examine priming for novel, nonverbal patterns, a modification of the paradigm used by Gabrieli et al. (1990, Neuropsychologia, 28, 417-427) was administered to a group of Korsakoff patients, a group of alcoholic controls, and a group of normal controls. Subjects were asked to connect five-dot configurations into the first pattern that came to mind. Priming was than assessed by having the subjects copy experimenter-provided interpretations for each configuration and examining the effect of this manipulation on the subjects' subsequent interpretation of the same configurations. For the Korsakoff patients, the copied prime replaced their initial perceptual interpretation less frequently than it did for normal controls. Instead, the prime had its effect by combining with the baseline percept. These findings suggest that priming for novel, nonverbal material is weaker and less direct for Korsakoff patients than it is for controls.

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.

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.