The impact of parent socio-economic status on executive functioning and cortical morphology in individuals with schizophrenia and healthy controls.

BACKGROUND: Relatively lower executive functioning is characteristic of individuals with schizophrenia. As low socio-economic status (SES) early in life (i.e. parent SES) has been linked with lower executive skills in healthy children, we hypothesized that parental SES (pSES) would be more strongly related to executive functioning in individuals with schizophrenia than in controls and have a greater impact on prefrontal cortical morphology. METHOD: Healthy controls (n = 125) and individuals with schizophrenia (n = 102) completed tests assessing executive functioning and intelligence. The groups were matched on pSES, which was evaluated with the Hollingshead-Redlich scale. A principal components analysis (PCA) was conducted on 10 variables from six executive tests, yielding three specific components (fluency, planning and response inhibition). Voxel-based morphometry (VBM) was used to evaluate effects of pSES on gray matter (GM) concentration. RESULTS: Lower pSES was associated with lower scores across the three executive functioning components, and a significant group by pSES interaction was observed such that low pSES, in particular, affected individuals with schizophrenia. These effects remained significant when intellectual ability, education and self-SES (sSES) were added as covariates. VBM revealed that lower pSES was associated with reduced GM volume in several anterior brain regions, especially the superior frontal gyrus, in patients but not in controls. CONCLUSIONS: These findings suggest that individuals with schizophrenia may be particularly vulnerable to the adverse impact of low pSES, in terms of both lower executive skills and reduced anterior GM volumes.

Alzheimer's disease and intelligence.

A significant body of evidence has accumulated suggesting that individual variation in intellectual ability, whether assessed directly by intelligence tests or indirectly through proxy measures, is related to risk of developing Alzheimer's disease (AD) in later life. Important questions remain unanswered, however, such as the specificity of risk for AD vs. other forms of dementia, and the specific links between premorbid intelligence and development of the neuropathology characteristic of AD. Lower premorbid intelligence has also emerged as a risk factor for greater mortality across myriad health and mental health diagnoses. Genetic covariance contributes importantly to these associations, and pleiotropic genetic effects may impact diverse organ systems through similar processes, including inefficient design and oxidative stress. Through such processes, the genetic underpinnings of intelligence, specifically, mutation load, may also increase the risk of developing AD. We discuss how specific neurobiologic features of relatively lower premorbid intelligence, including reduced metabolic efficiency, may facilitate the development of AD neuropathology. The cognitive reserve hypothesis, the most widely accepted account of the intelligence-AD association, is reviewed in the context of this larger literature.

A prospective diffusion tensor imaging study in mild traumatic brain injury.

OBJECTIVES: Only a handful of studies have investigated the nature, functional significance, and course of white matter abnormalities associated with mild traumatic brain injury (mTBI) during the semi-acute stage of injury. The present study used diffusion tensor imaging (DTI) to investigate white matter integrity and compared the accuracy of traditional anatomic scans, neuropsychological testing, and DTI for objectively classifying mTBI patients from controls. METHODS: Twenty-two patients with semi-acute mTBI (mean = 12 days postinjury), 21 matched healthy controls, and a larger sample (n = 32) of healthy controls were studied with an extensive imaging and clinical battery. A subset of participants was examined longitudinally 3-5 months after their initial visit. RESULTS: mTBI patients did not differ from controls on clinical imaging scans or neuropsychological performance, although effect sizes were consistent with literature values. In contrast, mTBI patients demonstrated significantly greater fractional anisotropy as a result of reduced radial diffusivity in the corpus callosum and several left hemisphere tracts. DTI measures were more accurate than traditional clinical measures in classifying patients from controls. Longitudinal data provided preliminary evidence of partial normalization of DTI values in several white matter tracts. CONCLUSIONS: Current findings of white matter abnormalities suggest that cytotoxic edema may be present during the semi-acute phase of mild traumatic brain injury (mTBI). Initial mechanical damage to axons disrupts ionic homeostasis and the ratio of intracellular and extracellular water, primarily affecting diffusion perpendicular to axons. Diffusion tensor imaging measurement may have utility for objectively classifying mTBI, and may serve as a potential biomarker of recovery.

Gerstmann syndrome in systemic lupus erythematosus: neuropsychological, neuroimaging and spectroscopic findings.

Gerstmann syndrome (GS) comprises four interlaced neuropsychological symptoms including finger agnosia, right-left confusion, agraphia, and acalculia. While GS is commonly associated with focal lesions to the region of the left angular gyrus, it has also been associated with numerous diffuse etiologies including atrophy, alcoholism, carbon monoxide poisoning, lead intoxication and anaphylactic shock. Thus, a vigorous debate has emerged as to whether GS represents a syndrome arising from general brain decline or a distinct and localizing lesion. We report a right-handed patient who developed neuropsychological dysfunction secondary to systemic lupus erythematosus (SLE). Neuropsychological evaluation found the patient to exhibit symptoms consistent with the GS tetrad, as well as general cognitive decline. Magnetic resonance imaging revealed a distinct focal lesion of the left parieto-occipital white matter underlying the angular gyrus as well as diffuse atrophy. (1)H-magnetic resonance spectroscopy revealed substantial metabolic derangement in a voxel placed within the visible lesion, although substantial metabolic derangement was observed in regions remote from the focal pathology. Thus, GS in this first case in SLE would appear to comprise a focal neurological tetrad of disorders within a more general pattern of cognitive decline and metabolic derangement.

Metabolic and cognitive response to human traumatic brain injury: a quantitative proton magnetic resonance study.

Proton magnetic resonance spectroscopy (1H-MRS) offers a unique insight into brain cellular metabolism following traumatic brain injury (TBI). The aim of the present study was to assess change in neurometabolite markers of brain injury during the recovery period following TBI. We studied 19 TBI patients at 1.5, 3, and 6 months postinjury and 28 controls. We used 1H-MRS to quantify N-acetylaspartate (NAA), creatine (Cre), choline (Cho), and myoinositol (mIns) in occipitoparietal gray matter (GM) and white matter (WM) remote from the primary injury focus. Neuropsychological testing quantified cognitive impairment and recovery. At 1.5 months, we found cognitive impairment (mean z score = -1.36 vs. 0.18,p < 0.01), lower NAA (GM: 12.42 mM vs. 13.03, p = 0.01; WM: 11.75 vs. 12.81, p < 0.01), and elevated Cho (GM: 1.51 vs. 1.25, p < 0.01; WM: 1.98 vs. 1.79, p < 0.01) in TBI patients compared with controls. GM NAA at 1.5 months predicted cognitive function at outcome (6 months postinjury; r = 0.63, p = 0.04). GM NAA continued to fall by 0.46 mM between 1.5 and 3 months (p = 0.02) indicating continuing neuronal loss, metabolic dysfunction, or both. Between 3 and 6 months, WM NAA increased by 0.55 mM (p = 0.06) suggesting metabolic recovery. Patients with poorer outcomes had elevated mean GM Cho at 3 months postinjury, suggesting active inflammation, as compared to patients with better outcomes (p = 0.002). 1H-MRS offers a noninvasive approach to assessing neuronal injury and inflammation following TBI, and may provide unique data for patient management and assessment of therapeutic efficacy.

Developmental instability and working memory ability in children: a magnetic resonance spectroscopy investigation.

This study of children (ages 7 through 12) wishes to determine (a) whether variation in frontal lobe brain chemistry, determined from proton magnetic resonance spectroscopy (1H-MRS), is related to performance on a working memory task in children, and (b) whether developmental instability (DI; the imprecise expression of the genetic plan for development due to several known genetic and environmental effects) underlies phenotypic variation in brain chemistry. 1H-MRS assessed neurometabolites in a right frontal white matter voxel. The Visual Two-Back test assessed working memory. A composite measure of DI was created from measures of minor physical anomalies, fluctuating asymmetry of body characteristics, and fluctuating asymmetry of dermatoglyphic features. Greater DI strongly predicted lower concentrations of creatine-phosphocreatine (Cre) and choline-containing compounds, whereas Cre and N-acetyl-aspartate positively correlated with working memory skills. Working memory skills thus seem related to frontal lobe energy metabolism, which in turn is related to DI.

Developmental instability predicts individual variation in verbal memory skill after caffeine ingestion.

OBJECTIVE: To determine the mediating effects of developmental instability on individual differences in response to caffeine. BACKGROUND: Individual variation of drug effects might reflect broad genomic factors as well as the direct effects of specific alleles. The current study tested the hypothesis that individual differences in developmental instability, in part determined by genomic characteristics, would predict individual variation in the magnitude of caffeine-induced verbal memory deficits. Minor physical anomalies and fluctuating asymmetry were used as measures of developmental instability. METHOD: One hundred participants were (1) administered one version of the Rey Auditory Verbal Learning Test; (2) given a dose of caffeine determined by body weight (3 mg/kg); (3) assessed for minor physical anomalies and fluctuating asymmetry; and (4) given an alternate randomized version of the Rey Auditory Verbal Learning Test. RESULTS: Consistent with predictions, a composite measure of developmental instability predicted the magnitude of caffeine-induced memory decrements. CONCLUSIONS: These results may have important implications for the genetic underpinnings of individual differences in drug effects.

Myths of neuropsychology: intelligence, neurometabolism, and cognitive ability.

Recently, Dodrill (1999) revised a previously described "Myth of neuropsychology" (1997) to state: "Just as below average performances on neuropsychological tests are found when intelligence is below average, to that same degree above average performances on neuropsychological tests are expected when intellectual abilities are above average." This study addresses the relationship between intellectual and neuropsychological performance in the context of Magnetic Resonance Spectroscopy (MRS) measurements of the neurometabolite N-acetylaspartate (NAA). When subjects were stratified by Full Scale IQ (Average, High Average, Superior) they differed significantly in terms of total neuropsychological performance [F(2,47) = 17.63; p <.001] and the neuronal marker NAA [F(2,47) = 3.25; p <.05]. Regression analysis across groups demonstrated that FSIQ and NAA were independently related to Total z-score [F(1,47) = 29.43; p <.0001] and accounted for over half the variance (r(2) of model =.56). The concurrent relationship of FSIQ and NAA to total neuropsychological performance suggests that the relationship between measures sensitive to intellectual ability and neuropsychological performance is real, and does not reflect arbitrary psychometric or scaling properties of the WAIS-III.

Biochemical markers of cognition: a proton MR spectroscopy study of normal human brain.

In the current study we explored the relationship between neurometabolites measured by proton magnetic resonance spectroscopy (1H-MRS) and cognitive ability assessed with a battery of neuropsychological tests. Forty-five participants were recruited from the local college community, and examined utilizing neuropsychological testing and 1H-MRS. Our central finding was that N-acetylaspartate (NAA) was associated with overall neuropsychological performance (F(1,42) = 23.16, p < 0.0001], r2 = 0.35. We found an even stronger association between timed neuropsychological measures and NAA (F(1,42) = 31.15, p < 0.0001], r = 0.43. These results reveal the specific relationship of NAA to neuropsychological functioning in normal human brain. The current observations in healthy individuals are consistent with the hypothesis that variability in NAA levels and neuropsychological performance may be related to mitochondrial function.

The evolutionary genetic underpinnings of schizophrenia: the developmental instability model.

The importance of genes in the etiology of schizophrenia is well known, but the manner in which the relevant genomic factors influence neural development and the nature of selection forces operating on these factors are poorly understood. In several prominent papers, Crow has provided a unique and comprehensive theory that attempts to deal with these issues. A central aspect of his theory is that a single gene leads to reduced cerebral lateralization, increased ventricular size, and risk for developing schizophrenia. He relies greatly on Annett's right shift theory of individual variation in handedness. An alternative approach, based on the construct of developmental instability, provides a different way to conceptualize genetic influences, selection forces, and atypical lateralization in schizophrenia. We suggest that the developmental instability model has stronger empirical support and is better grounded in contemporary evolutionary genetics.

Biochemical markers of intelligence: a proton MR spectroscopy study of normal human brain.

Proton magnetic resonance spectroscopy (1H-MRS) offers a unique non-invasive approach to measurement of N-acetylaspartate (NAA) and choline (Cho), putative markers of neuronal and glial integrity. Previous studies revealed that these neurochemicals predict cognitive impairment in diseased subjects, although little is known about their relationship to cognitive functioning in healthy people. We measured the concentrations of NAA and Cho in the left occipitoparietal white matter of 26 healthy adults and compared them with intellectual performance assessed by the Wechsler Adult Intelligence Scale-3. We found that NAA (b = 0.6, p < 0.01) and Cho (b = -0.42, p < 0.01) were independently associated with the Full-Scale Intelligence Quotient. Together, these metabolites accounted for a large proportion of the variance in intelligence (r2 = 0.45). Possible mechanisms underlying these correlations, such as mitochondrial function and myelin turnover, are discussed. 1H-MRS is a sensitive new tool to assess the neuronal underpinnings of cognitive function non-invasively.

Quantitative proton MRS predicts outcome after traumatic brain injury.

OBJECTIVE: To determine whether proton MRS (1H-MRS) neurochemical measurements predict neuropsychological outcome of patients with traumatic brain injury (TBI). BACKGROUND: Although clinical indices and conventional imaging techniques provide critical information for TBI patient triage and acute care, none accurately predicts individual patient outcome. METHODS: The authors studied 14 patients with TBI soon after injury (45+/-21 days postinjury) and again at 6 months (172+/-43 days) and 14 age-, sex-, and education-matched control subjects. N-acetylaspartate (NAA), creatine, and choline were measured in normal-appearing occipitoparietal white and gray matter using quantitative 1H-MRS. Outcome was assessed with the Glasgow Outcome Scale (GOS) and a battery of neuropsychological tests. A composite measure of neuropsychological function was calculated from individual test z-scores probing the major functional domains commonly impaired after head trauma. RESULTS: Early NAA concentrations in gray matter predicted overall neuropsychological performance (r = 0.74, p = 0.01) and GOS (F = 11.93, p = 0.007). Other metabolite measures were not related to behavioral function at outcome. CONCLUSION: 1H-MRS provides a rapid, noninvasive tool to assess the extent of diffuse injury after head trauma, a component of injury that may be the most critical factor in evaluating resultant neuropsychological dysfunction. 1H-MRS can be added to conventional MR examinations with minimal additional time, and may prove useful in assessing injury severity, guiding patient care, and predicting patient outcome.

Frontal lobe of children with schizophrenia spectrum disorders: a proton magnetic resonance spectroscopic study.

BACKGROUND: Schizophrenia is commonly considered a neurodevelopmental disorder. Our aim was to determine whether the proton magnetic resonance spectroscopic (1H-MRS) changes seen in adults with schizophrenia are displayed in children at risk for developing schizophrenia. METHODS: Children with symptoms of schizophrenia-spectrum disorders (n = 16; mean age = 132 months) and a comparison group (n = 12; mean age 130 months) took part in a 1H-MRS study of the left frontal lobe. Areas of peaks from N-acetylaspartate (NAA), choline (Cho), and creatine (Cre) were determined and ratios of NAA/Cre and Cho/Cre calculated and compared between groups. RESULTS: The mean ratio of NAA/Cre was significantly lower in schizophrenia-spectrum subjects than the comparison group (1.67 vs. 1.92; p < .05). Medication status did not affect results in schizophrenia-spectrum subjects. CONCLUSIONS: Our findings suggest that the metabolic changes associated with adult schizophrenia are observed in children with some or all of the symptoms of schizophrenia, supporting a neurodevelopmental theory for schizophrenia.

Proton MR spectroscopic findings correspond to neuropsychological function in traumatic brain injury.

BACKGROUND AND PURPOSE: Traumatic brain injury (TBI) causes substantial irreversible damage to neurons. Our aim was to investigate whether proton MR spectroscopic measures of diffuse cellular integrity were related to neuropsychological dysfunction after TBI. METHODS: Twelve patients with TBI (mean, 53 +/- 23 days postinjury) and 14 control subjects were included in the study using paired MR spectroscopy and neuropsychological assessment. N-acetylaspartate (NAA), creatine, and choline were measured in normal-appearing occipitoparietal white and occipital gray matter using short-echo quantitative spectroscopy. A composite measure of neuropsychological function was calculated from z-scored individual tests probing the major functional domains commonly impaired after head trauma. RESULTS: Patients with TBI displayed reduced NAA in white matter and elevated choline in gray matter, suggestive of neuronal injury and inflammation, respectively. NAA and creatine in white and gray matter were significantly associated with composite neuropsychological function and many individual neuropsychological tests. Gray matter choline, although abnormal, was not related to neuropsychological function. CONCLUSION: The concordance between neurometabolic levels and behavioral function supports the hypothesis that diffuse axonal injury is an important contributor to brain dysfunction after TBI.

Developmental instability and cerebral lateralization.

On the basis of prior studies of handedness, it was predicted that variations from modal asymmetry scores on cognitive tasks, in either direction from the mean, would be associated with an elevated incidence of classic markers of developmental instability (minor physical anomalies and fluctuating anatomic asymmetries). University students (N = 146) were administered 4 tasks that typically reveal functional asymmetries: the fused rhymed words dichotic listening task, the line bisection task, the chimeric faces task, and the cartoon faces task. A composite measure of developmental instability was computed from minor physical anomalies and fluctuating asymmetries. Participants with greater evidence of developmental instability had more atypical lateralization scores, deviating more from the sample mean, in either direction. Directional asymmetries were unrelated to developmental instability. These results suggest that developmental instability influences variation in the lateralization of cognitive skills as well as handedness.

Brain abnormalities in schizophrenia-spectrum children: implications for a neurodevelopmental perspective.

Children with symptoms of schizophrenia-spectrum disorder (N = 20) were compared to controls (N = 20) matched for age and socioeconomic status. Structural brain abnormalities were assessed with magnetic resonance imaging and functional brain abnormalities with neuropsychological tests. Children with schizophrenia-spectrum disorder had smaller amygdala and temporal cortex volumes, along with reduced callosal areas and an unusual pattern of neuroanatomic asymmetries. No differences were noted in overall brain volume, ventricular volume, hippocampal volume, or frontal area. Schizophrenia-spectrum children were also characterized by deficits in all neuropsychological functions examined. Some types of verbal memory and frontal lobe skills were especially deficient. These results support the hypothesis that children with schizophrenia-spectrum disorder have significant brain abnormalities, similar in some ways to those seen in adult schizophrenics. In conjunction with recent primate studies, the current results draw attention to the role of the amygdala as one relevant factor in the pathogenesis of schizophrenia.

Behavioral genetic variation, adaptation and maladaptation: an evolutionary perspective.

Evolutionary psychology seeks to understand the adaptive, evolved nature of humans by considering the forces of natural selection that gave rise to it. Individual humans also exhibit maladaptation, however, and some of the variation in maladaptive conditions is heritable. An evolutionary perspective can shed light on these phenomena too. Recent work suggests that developmental imprecision importantly affects the fitness of organisms and some of the genetic influences have been identified. Both theory and evidence that developmental imprecision underlies human cognitive maladaptation has begun to accumulate, although the manner in which the developing brain is affected remains largely unknown.

Lateralization of perceptual closure ability.

The present study investigated lateralization of perceptual closure ability. A zero-power, partially occluded, soft contact-lens system was used to lateralize visual input. This technique has been shown to create reliable artificial visual-field deficits when used in situations offering unlimited duration of stimulus exposure. The Street Gestalt Completion Test was administered to 18 right-handed men with no history of head trauma, neurological disorders, or familial sinistrality. Using repeated-measures analyses, and controlling for age, we found no significant hemispheric advantage for either speed or accuracy of performance.

Neuropsychophysiological study of children at risk for schizophrenia: a preliminary report.

OBJECTIVE: This initial report, from an ongoing study, examines whether children who have symptoms of schizophrenia spectrum disorder display neuropsychological or neuroanatomic abnormalities similar to those seen in adults with schizophrenia. METHOD: Experimental subjects were 12 children between 8 and 12 years of age who displayed symptoms of early-onset schizophrenia or schizotypal personality disorder, as assessed through the Schedule for Affective Disorders and Schizophrenia for School-Age Children. The experimental subjects were compared with 13 controls on neuropsychological test performance, magnetic resonance imaging measurements, and proton magnetic resonance spectroscopy results. RESULTS: Findings from the first phase of this project reveal significant overall group differences for several morphometric magnetic resonance imaging measurements and all neuropsychological measures. Differences between the groups were found for amygdala volume, mesial temporal volume, callosal area, and anatomic asymmetry. Magnetic resonance spectroscopy data showed a trend toward group differences. CONCLUSIONS: These findings support a neurodevelopmental model of schizophrenia which postulates that environmentally or genetically programmed events in utero disrupt the establishment of fundamental aspects of brain structure and function.

Adaptation in brain glucose uptake following recurrent hypoglycemia.

Brain glucose metabolism is impaired during hypoglycemia, but, if sustained, brain metabolism reverts to normal in animal models--data in man are lacking. We tested the hypothesis that adaptations occur to allow maintenance of normal rates of brain glucose uptake (BGU) following recurrent hypoglycemia in man. Twelve normal humans were studied over 4 days. On the initial day, arterial plasma glucose concentrations were decreased from 4.72 to 2.50 mmol/liter in five 0.56 mmol/liter steps. Cerebral blood flow, brain arteriovenous glucose difference, BGU, and cognitive function were quantitated at each step. BGU was initially impaired at the 3.61 mmol/liter glucose step (P = 0.04) and was antedated by increments in epinephrine that began at 4.16 mmol/liter (P = 0.03). The onset of hypoglycemic symptoms occurred during the 3.61 mmol/liter glucose step (P = 0.02), whereas tests of cognitive function generally deteriorated at the 3.05 mmol/liter step (P < 0.05). During the next 56 hr, mean glucose concentrations were kept at 2.9 +/- 0.1 mmol/liter and reached normal only during meals. The stepped clamp protocol was repeated beginning at 4.16 mmol/liter on the last day. No decrement in BGU was observed at any step; cognitive function was preserved until significantly lower glucose concentrations on the final day relative to the first (P = 0.04). Subjects remained asymptomatic of hypoglycemia until they reached a glucose concentration of 2.50 mmol/liter (P < 0.001 vs. day 1), while initial increments in all counterregulatory hormones were forestalled to lower glucose steps than on day 1. Therefore, adaptations occur that allow normal BGU and cerebral function to be maintained during recurrent systemic hypoglycemia. Counterregulatory events that should result in symptoms of hypoglycemia and increments in endogenous glucose production are prevented until extremely subnormal glucose concentrations.