Computerized Cognitive Training in Mild Cognitive Impairment: Findings in African Americans and Caucasians.

BACKGROUND: African Americans with MCI may be at increased risk for dementia compared to Caucasians. The effect of race on the efficacy of cognitive training in MCI is unclear. METHODS: We used data from a two-site, 78-week randomized trial of MCI comparing intensive, home-based, computerized training with Web-based cognitive games or Web-based crossword puzzles to examine the effect of race on outcomes. The study outcomes were changes from baseline in cognitive and functional scales as well as MRI-measured changes in hippocampal volume and cortical thickness. Analyses used linear models adjusted for baseline scores. This was an exploratory study. RESULTS: A total of 105 subjects were included comprising 81 whites (77.1%) and 24 African Americans (22.8%). The effect of race on the change from baseline in ADAS-Cog-11 was not significant. The effect of race on change from baseline to week 78 in the Functional Activities Questionnaire (FAQ) was significant with African American participants' FAQ scores showing greater improvements at weeks 52 and 78 (P = 0.009, P = 0.0002, respectively) than white subjects. Within the CCT cohort, FAQ scores for African American participants showed greater improvement between baseline and week 78, compared to white participants randomized to CCT (P = 0.006). There was no effect of race on the UPSA. There was no effect of race on hippocampal or cortical thickness outcomes. CONCLUSIONS: Our preliminary findings suggest that web-based cognitive training programs may benefit African Americans with MCI at least as much as Caucasians, and highlight the need to further study underrepresented minorities in AD prevention trials. (Supported by the National Institutes of Health, National Institute on Aging; ClinicalTrials.gov number, NCT03205709.).

Expectancy Does Not Predict 18-month Treatment Outcomes with Cognitive Training in Mild Cognitive Impairment.

BACKGROUND: Computerized cognitive training (CCT) has emerged as a potential treatment option for mild cognitive impairment (MCI). It remains unclear whether CCT's effect is driven in part by expectancy of improvement. OBJECTIVES: This study aimed to determine factors associated with therapeutic expectancy and the influence of therapeutic expectancy on treatment effects in a randomized clinical trial of CCT versus crossword puzzle training (CPT) for older adults with MCI. DESIGN: Randomized clinical trial of CCT vs CPT with 78-week follow-up. SETTING: Two-site study - New York State Psychiatric Institute and Duke University Medical Center. PARTICIPANTS: 107 patients with MCI. INTERVENTION: 12 weeks of intensive training with CCT or CPT with follow-up booster training over 78 weeks. MEASUREMENTS: Patients rated their expectancies for CCT and CPT prior to randomization. RESULTS: Patients reported greater expectancy for CCT than CPT. Lower patient expectancy was associated with lower global cognition at baseline and older age. Expectancy did not differ by sex or race. There was no association between expectancy and measures of everyday functioning, hippocampus volume, or apolipoprotein E genotype. Expectancy was not associated with change in measures of global cognition, everyday functioning, and hippocampus volume from baseline to week 78, nor did expectancy interact with treatment condition. CONCLUSIONS: While greater cognitive impairment and increased age was associated with low expectancy of improvement, expectancy was not associated with the likelihood of response to treatment with CPT or CCT.

Understanding pharmaceutical exposure and the potential for effects in marine biota: A survey of bonefish (Albula vulpes) across the Caribbean Basin.

Most research on pharmaceutical presence in the environment to date has focused on smaller scale assessments of freshwater and riverine systems, relying mainly on assays of water samples, while studies in marine ecosystems and of exposed biota are sparse. This study investigated the pharmaceutical burden in bonefish (Albula vulpes), an important recreational and artisanal fishery, to quantify pharmaceutical exposure throughout the Caribbean Basin. We sampled 74 bonefish from five regions, and analyzed them for 102 pharmaceuticals. We assessed the influence of sampling region on the number of pharmaceuticals, pharmaceutical assemblage, and risk of pharmacological effects. To evaluate the risk of pharmacological effects at the scale of the individual, we proposed a metric based on the human therapeutic plasma concentration (HTPC), comparing measured concentrations to a threshold of 1/3 the HTPC for each pharmaceutical. Every bonefish had at least one pharmaceutical, with an average of 4.9 and a maximum of 16 pharmaceuticals in one individual. At least one pharmaceutical was detected in exceedance of the 1/3 HTPC threshold in 39% of bonefish, with an average of 0.6 and a maximum of 11 pharmaceuticals exceeding in a Key West individual. The number of pharmaceuticals (49 detected in total) differed across regions, but the risk of pharmacological effects did not (23 pharmaceuticals exceeded the 1/3 HTPC threshold). The most common pharmaceuticals were venlafaxine (43 bonefish), atenolol (36), naloxone (27), codeine (27), and trimethoprim (24). Findings suggest that pharmaceutical detections and concentration may be independent, emphasizing the need to monitor risk to biota regardless of exposure diversity, and to focus on risk quantified at the individual level. This study supports the widespread presence of pharmaceuticals in marine systems and shows the utility of applying the HTPC to assess the potential for pharmacological effects, and thus quantify impact of exposure at large spatial scales.

Nitrogen uptake and macronutrients distribution in mango (Mangifera indica L. cv. Keitt) trees.

We assessed the effects of N fertigation regime on nutrient uptake and distribution in leaves and fruit of mango cv. Keitt grown in a lysimeter for four years. We applied three treatments: N1 - no N fertilization (less than 2 mg/L in the tap water); N2 - 10 mg/L N; and N3 - 20 mg/L N. Deficient N conditions (N1) resulted in low vegetation and fruit yield, high fruit:leaf ratio, high photosynthetic activity, high leaf P and K concentrations, as well as high sugar content and low acidity in the fruit. Excess N concentration (N3) enhanced vegetative growth and reduced fruit yield and gas exchange. The calculated annual nitrogen uptake heavily depended on the nitrogen supply, being highest for the N2 treatment (196 g/tree) as compared with the N1 (25 g/tree) or N3 (185 g/tree) treatments. Fruits were a major N sink being 82% (in N1), 26% (in N2), and 5% (in N3) of the total annual N supplied. The N accumulation rate in the fruit of the N1 and N2 treatment were above the N quantities supplied via fertigation, suggesting that N reserve in the vegetative tissues supplied the fruit's high N demand. These findings highlight the link between mango's N requirements and fruit yield, as well as the risks of excessive N fertilization.

Quantification of antimicrobial usage in adult cows and preweaned calves on 40 large Wisconsin dairy farms using dose-based and mass-based metrics.

Use of antimicrobials in animal agriculture is under increasing scrutiny, but the quantity of antimicrobials used on large US dairy farms has not been evaluated using data from large farms and different metrics. This study investigated total antimicrobial usage (AMU) in adult dairy cows and preweaned calves (PWC) and contrasted 2 metrics used for measurement of AMU. Wisconsin dairy farms were eligible if they had >250 lactating cows, maintained computerized animal health records, and were willing to allow researchers access to treatment records. Animal health data for a 1-yr period was retrospectively collected from computerized records, and a farm visit was performed to verify case definitions and recording accuracy. Both dose-based (animal daily doses; ADD) and mass-based (total mg of antimicrobials per kg of body weight; BW) metrics were calculated at the herd, cow, and PWC levels. Descriptive statistics for AMU were examined for both age groups. Mean AMU was compared among active ingredients and route of usage using ANOVA models that included farm as a random variable. At enrollment, farms (n = 40) contained approximately 52,639 cows (mean: 1,316 ± 169; 95% CI: 975, 1657) and 6,281 PWC (mean: 180 ± 33; 95% CI: 112, 247). When estimated using ADD, total herd AMU was 17.2 ADD per 1,000 animal-days (95% CI: 14.9, 19.5), with 83% of total herd-level AMU in adult cows. When estimated using the mass-based metric, total herd AMU was 13.6 mg of antimicrobial per kilogram of animal BW (95% CI: 10.3, 17.0), with 86% of total AMU used in adult cows. For cows, 78% of total ADD (15.8 ADD per 1,000 cow-d) was administered as intramammary (IMM) preparations. In contrast, when AMU was estimated using a mass-based metric, IMM preparations represented only 24% of total AMU (12.1 mg of antimicrobial/kg of cow BW). For cows, ceftiofur was the primary antimicrobial used and accounted for 53% of total ADD, with 80% attributed to IMM and 20% attributed to injectable treatments. When estimated using a mass-based metric, ampicillin was the predominant antimicrobial used in cows and accounted for 33% of total antimicrobial mass per kilogram of BW. When AMU was estimated for PWC using ADD, injectable antimicrobials represented 79% of total usage (28.3 ADD per 1,000 PWC-d). In contrast, when AMU was estimated for PWC using a mass-based metric, injectable products represented 42% of total AMU, even though more farms administered antimicrobials using this route. When AMU in PWC was summarized using ADD, penicillin represented 32% of AMU, and there were no significant differences in ADD among ampicillin, oxytetracycline or enrofloxacin. When a mass-based metric was used to estimate AMU in PWC, oral products (sulfadimethoxine and trimethoprim-sulfa) represented more than half of the total AMU given to this group. Overall, these results showed that choice of metric and inclusion of different age groups can substantially influence interpretation of AMU on dairy farms.

Faecal parasites increase with age but not reproductive effort in wild female chimpanzees.

Energy investment in reproduction is predicted to trade off against other necessary physiological functions like immunity, but it is unclear to what extent this impacts fitness in long-lived species. Among mammals, female primates, and especially apes, exhibit extensive periods of investment in each offspring. During this time, energy diverted to gestation and lactation is hypothesized to incur short and long-term deficits in maternal immunity and lead to accelerated ageing. We examined the relationship between reproduction and immunity, as measured by faecal parasite counts, in wild female chimpanzees (Pan troglodytes schweinfurthii) of Kibale National Park, Uganda. While we observed higher parasite shedding (counts of eggs, cysts and larvae) in pregnant chimpanzees relative to cycling females, parasites rapidly decreased during early lactation, the most energetically taxing phase of the reproductive cycle. Additionally, while our results indicate that parasite shedding increases with age, females with higher fertility for their age had lower faecal parasite counts. Such findings support the hypothesis that the relatively conservative rate of female reproduction in chimpanzees may be protective against the negative effects of reproductive effort on health. This article is part of the theme issue 'Evolution of the primate ageing process'.

Development of an UPSA Short Form for Use in Longitudinal Studies in the Early Alzheimer's Disease Spectrum.

BACKGROUND: In individuals with only mild or very mild cognitive attenuations (i.e., so-called pre-clinical AD), performance-based measures of function may be superior to informant-based measures because of increased sensitivity, greater reliability, and fewer ceiling effects. OBJECTIVE: We sought to determine if a performance-based measure of everyday function would demonstrate adequate psychometric properties and validity in the context of serial assessment over a one-year period in patients with Mild Cognitive Impairment (MCI) and early stage Alzheimer's disease (AD). DESIGN: Participants were assessed with the performance-based measure at baseline, six weeks, and one year. SETTING: A specialized center for the assessment and treatment of AD. PARTICIPANTS: Three groups of subjects participated: a healthy subjects (HS) older cognitively intact group (N=43), an MCI group (N=20), and an AD group (N=26). MEASUREMENTS: A three subtest short form of the UCSD Performance-Based Skills Assessment (UPSA) (called the UPSA-3) was the measure of interest. It consisted of the Communication, Planning, and Finance subtests. RESULTS: Mixed model repeated measures were used to assess performance over time. Large group effects were present (HS>MCI>AD). Additionally, the AD and MCI groups demonstrated declines over one year, while the HS group remained stable (group x time interaction p=.11). The MCI/AD group demonstrated adequate test-retest reliability and did not demonstrate ceiling or floor effects. CONCLUSION: Our data indicate that the UPSA-3 is suitable for clinical trials in that it has adequate ecological coverage and reasonable psychometric properties, and perhaps most importantly, demonstrates validity in serial assessments.

Independent and combined effects of improved water, sanitation, and hygiene (WASH) and improved complementary feeding on early neurodevelopment among children born to HIV-negative mothers in rural Zimbabwe: Substudy of a cluster-randomized trial.

BACKGROUND: Globally, nearly 250 million children (43% of all children under 5 years of age) are at risk of compromised neurodevelopment due to poverty, stunting, and lack of stimulation. We tested the independent and combined effects of improved water, sanitation, and hygiene (WASH) and improved infant and young child feeding (IYCF) on early child development (ECD) among children enrolled in the Sanitation Hygiene Infant Nutrition Efficacy (SHINE) trial in rural Zimbabwe. METHODS AND FINDINGS: SHINE was a cluster-randomized community-based 2×2 factorial trial. A total of 5,280 pregnant women were enrolled from 211 clusters (defined as the catchment area of 1-4 village health workers [VHWs] employed by the Zimbabwean Ministry of Health and Child Care). Clusters were randomly allocated to standard of care, IYCF (20 g of small-quantity lipid-based nutrient supplement per day from age 6 to 18 months plus complementary feeding counseling), WASH (ventilated improved pit latrine, handwashing stations, chlorine, liquid soap, and play yard), and WASH + IYCF. Primary outcomes were child length-for-age Z-score and hemoglobin concentration at 18 months of age. Children who completed the 18-month visit and turned 2 years (102-112 weeks) between March 1, 2016, and April 30, 2017, were eligible for the ECD substudy. We prespecified that primary inferences would be drawn from findings of children born to HIV-negative mothers; these results are presented in this paper. A total of 1,655 HIV-unexposed children (64% of those eligible) were recruited into the ECD substudy from 206 clusters and evaluated for ECD at 2 years of age using the Malawi Developmental Assessment Tool (MDAT) to assess gross motor, fine motor, language, and social skills; the MacArthur-Bates Communicative Development Inventories (CDI) to assess vocabulary and grammar; the A-not-B test to assess object permanence; and a self-control task. Outcomes were analyzed in the intention-to-treat population. For all ECD outcomes, there was not a statistical interaction between the IYCF and WASH interventions, so we estimated the effects of the interventions by comparing the 2 IYCF groups with the 2 non-IYCF groups and the 2 WASH groups with the 2 non-WASH groups. The mean (95% CI) total MDAT score was modestly higher in the IYCF groups compared to the non-IYCF groups in unadjusted analysis: 1.35 (0.24, 2.46; p = 0.017); this difference did not persist in adjusted analysis: 0.79 (-0.22, 1.68; p = 0.057). There was no evidence of impact of the IYCF intervention on the CDI, A-not-B, or self-control tests. Among children in the WASH groups compared to those in the non-WASH groups, mean scores were not different for the MDAT, A-not-B, or self-control tests; mean CDI score was not different in unadjusted analysis (0.99 [95% CI -1.18, 3.17]) but was higher in children in the WASH groups in adjusted analysis (1.81 [0.01, 3.61]). The main limitation of the study was the specific time window for substudy recruitment, meaning not all children from the main trial were enrolled. CONCLUSIONS: We found little evidence that the IYCF and WASH interventions implemented in SHINE caused clinically important improvements in child development at 2 years of age. Interventions that directly target neurodevelopment (e.g., early stimulation) or that more comprehensively address the multifactorial nature of neurodevelopment may be required to support healthy development of vulnerable children. TRIAL REGISTRATION: ClinicalTrials.gov NCT01824940.

Independent and combined effects of improved water, sanitation, and hygiene, and improved complementary feeding, on stunting and anaemia among HIV-exposed children in rural Zimbabwe: a cluster-randomised controlled trial.

BACKGROUND: Children exposed to HIV have a high prevalence of stunting and anaemia. We aimed to test the effect of improved infant and young child feeding (IYCF) and improved water, sanitation, and hygiene (WASH) on child linear growth and haemoglobin concentrations. METHODS: We did a cluster randomised 2 × 2 factorial trial in two districts in rural Zimbabwe. Women were eligible for inclusion if they permanently lived in the trial clusters (ie, the catchment area of between one and four village health workers employed by the Zimbabwean Ministry of Health and Child Care) and were confirmed pregnant. Clusters were randomly allocated to standard of care (52 clusters); IYCF (20 g small-quantity lipid-based nutrient supplement daily for infants from 6 months to 18 months, complementary feeding counselling with context-specific messages, longitudinal delivery, and reinforcement; 53 clusters); WASH (ventilated, improved pit latrine, two hand-washing stations, liquid soap, chlorine, play space, and hygiene counselling; 53 clusters); or IYCF plus WASH (53 clusters). Participants and fieldworkers were not masked. Our co-primary outcomes were length for age Z score and haemoglobin in infants at 18 months of age. Here, we report these outcomes in the HIV-exposed children, analysed by intention to treat. We estimated the effects of the interventions by comparing the two IYCF groups with the two non-IYCF groups and the two WASH groups with the two non-WASH groups, except for outcomes with an important statistical interaction between the interventions. The trial is registered at ClinicalTrials.gov (NCT01824940) and is now complete. FINDINGS: Between Nov 22, 2012, and March 27, 2015, 726 HIV-positive pregnant women were included in the trial. 668 children were evaluated at 18 months (147 from 46 standard of care clusters; 147 from 48 IYCF clusters; 184 from 44 WASH clusters; 190 from 47 IYCF plus WASH clusters). Of the 668 children, 22 (3%) were HIV-positive, 594 (89%) HIV-exposed uninfected, and 52 (8%) HIV-unknown. The IYCF intervention increased mean length for age Z score by 0·26 (95% CI 0·09-0·43; p=0·003) and haemoglobin concentration by 2·9 g/L (95% CI 0·90-4·90; p=0·005). 165 (50%) of 329 children in the non-IYCF groups were stunted, compared with 136 (40%) of 336 in the IYCF groups (absolute difference 10%, 95% CI 2-17); and the prevalence of anaemia was also lower in the IYCF groups (45 [14%] of 319) than in the non-IYCF groups (24 [7%] of 329; absolute difference 7%, 95% CI 2-12). The WASH intervention had no effect on length or haemoglobin concentration. There were no trial-related adverse or serious adverse events. INTERPRETATION: Since HIV-exposed children are particularly vulnerable to undernutrition and responded well to improved complementary feeding, IYCF interventions could have considerable benefits in areas of high antenatal HIV prevalence. However, elementary WASH interventions did not lead to improvements in growth. FUNDING: Bill & Melinda Gates Foundation, UK Aid, Wellcome Trust, Swiss Development Cooperation, US National Institutes of Health, and UNICEF.

The impact of excess body fat on bone remodeling in adolescents.

The impact of excess body fat on bone remodeling was evaluated in overweight, obese, and extremely obese adolescents. In adolescents with excess weight, it was observed that the higher the bone mineral content and bone mineral density values, the lower the levels of the biomarkers. Nutritional imbalances by excess had a negative effect on bone formation in this stage of life. INTRODUCTION: The aim of this study was to investigate the impact of excess body fat on bone remodeling in adolescents. METHODS: Body weight, height, and body mass index were determined in 391 adolescents classified as normal weight, overweight, obese, and extremely obese. Bone age was obtained and bone mineral content and bone mineral density were evaluated in the lumbar spine, proximal femur, and total and subtotal body. Blood samples were collected for evaluation of the following bone biomarkers: osteocalcin, bone alkaline phosphatase (BAP), and serum carboxy-terminal telopeptide (S-CTx). The data were analyzed according to nutritional status and age. RESULTS: In girls with excess weight, the biomarkers were higher in the 10 to 13-year age group and no significant differences were observed between groups according to nutritional status. In boys, the levels were higher in those aged 13 to 15 years. According to nutritional status, significant differences were only observed in mean S-CTx for the age groups of 10-15 years, with higher levels between overweight and obese adolescents aged 10-12 years and between obese and extremely obese adolescents aged 13-15 years. In girls, significant negative correlations were observed between lean mass, fat mass, and fat percentage and each of the three bone markers studied. There was no correlation between lean mass or fat mass and the three biomarkers in boys. The biomarker trends demonstrated across the age groups follow the age trends for growth velocity. CONCLUSIONS: The higher the fat percentage and fat mass in girls, the lower the levels of the biomarkers, indicating that excess body fat has a negative effect on the evolution of these markers during adolescence.

Predicting West Nile Virus Infection Risk From the Synergistic Effects of Rainfall and Temperature.

Mosquito-based surveillance is a practical way to estimate the risk of transmission of West Nile virus (WNV) to people. Variations in temperature and precipitation play a role in driving mosquito infection rates and transmission of WNV, motivating efforts to predict infection rates based on prior weather conditions. Weather conditions and sequential patterns of meteorological events can have particularly important, but regionally distinctive, consequences for WNV transmission, with high temperatures and low precipitation often increasing WNV mosquito infection. Predictive models that incorporate weather can thus be used to provide early indications of the risk of WNV infection. The purpose of this study was first, to assess the ability of a previously published model of WNV mosquito infection to predict infection for an area within the region for which it was developed, and second, to improve the predictive ability of this model by incorporating new weather factors that may affect mosquito development. The legacy model captured the primary trends in mosquito infection, but it was improved considerably when calibrated with local mosquito infection rates. The use of interaction terms between precipitation and temperature improved model performance. Specifically, temperature had a stronger influence than rainfall, so that lower than average temperature greatly reduced the effect of low rainfall on increased infection rates. When rainfall was lower, high temperature had an even stronger positive impact on infection rates. The final model is practical, stable, and operationally valid for predicting West Nile virus infection rates in future weeks when calibrated with local data.

APOE2 enhances neuroprotection against Alzheimer's disease through multiple molecular mechanisms.

The common APOE2 gene variant is neuroprotective against Alzheimer's disease (AD) and reduces risk by nearly 50%. However, the mechanisms by which APOE2 confers neuroprotection are largely unknown. Here we showed that ApoE protein abundance in human postmortem cortex follows an isoform-dependent pattern (E2>E3>E4). We also identified a unique downstream transcriptional profile determined by microarray and characterized by downregulation of long-term potentiation (LTP) related transcripts and upregulation of extracellular matrix (ECM)/integrin-related transcripts in E2 cases and corroborated this finding at the protein level by demonstrating increases in ECM collagens and laminins. In vivo studies of healthy older individuals demonstrated a unique and advantageous biomarker signature in E2 carriers. APOE2 also reduced the risk of mild cognitive impairment to AD conversion by half. Our findings suggest that ApoE2 protein abundance, coupled with its inability to bind to LDLRs, may act to increase amyloid-beta (Ab) clearance. In addition, increased ECM and reduced LTP-related expression results in diminished activity-dependent Ab secretion and/or excitotoxicity, and thus also promotes neuroprotection.

Molecular signatures in post-mortem brain tissue of younger individuals at high risk for Alzheimer's disease as based on APOE genotype.

Alzheimer's disease (AD) is a neurodegenerative condition characterized histopathologically by neuritic plaques and neurofibrillary tangles. The objective of this transcriptional profiling study was to identify both neurosusceptibility and intrinsic neuroprotective factors at the molecular level, not confounded by the downstream consequences of pathology. We thus studied post-mortem cortical tissue in 28 cases that were non-APOE4 carriers (called the APOE3 group) and 13 cases that were APOE4 carriers. As APOE genotype is the major genetic risk factor for late-onset AD, the former group was at low risk for development of the disease and the latter group was at high risk for the disease. Mean age at death was 42 years and none of the brains had histopathology diagnostic of AD at the time of death. We first derived interregional difference scores in expression between cortical tissue from a region relatively invulnerable to AD (primary somatosensory cortex, BA 1/2/3) and an area known to be susceptible to AD pathology (middle temporal gyrus, BA 21). We then contrasted the magnitude of these interregional differences in between-group comparisons of the APOE3 (low risk) and APOE4 (high risk) genotype groups. We identified 70 transcripts that differed significantly between the groups. These included EGFR, CNTFR, CASP6, GRIA2, CTNNB1, FKBPL, LGALS1 and PSMC5. Using real-time quantitative PCR, we validated these findings. In addition, we found regional differences in the expression of APOE itself. We also identified multiple Kyoto pathways that were disrupted in the APOE4 group, including those involved in mitochondrial function, calcium regulation and cell-cycle reentry. To determine the functional significance of our transcriptional findings, we used bioinformatics pathway analyses to demonstrate that the molecules listed above comprised a network of connections with each other, APOE, and APP and MAPT. Overall, our results indicated that the abnormalities that we observed in single transcripts and in signaling pathways were not the consequences of diagnostic plaque and tangle pathology, but preceded it and thus may be a causative link in the long molecular prodrome that results in clinical AD.

Genetic variation in MAOA modulates ventromedial prefrontal circuitry mediating individual differences in human personality.

Little is known about neural mechanisms underlying human personality and temperament, despite their considerable importance as highly heritable risk mediators for somatic and psychiatric disorders. To identify these circuits, we used a combined genetic and imaging approach focused on Monoamine Oxidase A (MAOA), encoding a key enzyme for monoamine metabolism previously associated with temperament and antisocial behavior. Male carriers of a low-expressing genetic variant exhibited dysregulated amygdala activation and increased functional coupling with ventromedial prefrontal cortex (vmPFC). Stronger coupling predicted increased harm avoidance and decreased reward dependence scores, suggesting that this circuitry mediates a part of the association of MAOA with these traits. We utilized path analysis to parse the effective connectivity within this system, and provide evidence that vmPFC regulates amygdala indirectly by influencing rostral cingulate cortex function. Our data implicate a neural circuit for variation in human personality under genetic control, provide an anatomically consistent mechanism for vmPFC-amygdala interactions underlying this variation, and suggest a role for vmPFC as a superordinate regulatory area for emotional arousal and social behavior.

Allelic variation in GAD1 (GAD67) is associated with schizophrenia and influences cortical function and gene expression.

Cortical GABAergic dysfunction has been implicated as a key component of the pathophysiology of schizophrenia and decreased expression of the gamma-aminobutyric acid (GABA) synthetic enzyme glutamic acid decarboxylase 67 (GAD(67)), encoded by GAD1, is found in schizophrenic post-mortem brain. We report evidence of distorted transmission of single-nucleotide polymorphism (SNP) alleles in two independent schizophrenia family-based samples. In both samples, allelic association was dependent on the gender of the affected offspring, and in the Clinical Brain Disorders Branch/National Institute of Mental Health (CBDB/NIMH) sample it was also dependent on catechol-O-methyltransferase (COMT) Val158Met genotype. Quantitative transmission disequilibrium test analyses revealed that variation in GAD1 influenced multiple domains of cognition, including declarative memory, attention and working memory. A 5' flanking SNP affecting cognition in the families was also associated in unrelated healthy individuals with inefficient BOLD functional magnetic resonance imaging activation of dorsal prefrontal cortex (PFC) during a working memory task, a physiologic phenotype associated with schizophrenia and altered cortical inhibition. In addition, a SNP in the 5' untranslated (and predicted promoter) region that also influenced cognition was associated with decreased expression of GAD1 mRNA in the PFC of schizophrenic brain. Finally, we observed evidence of statistical epistasis between two SNPs in COMT and SNPs in GAD1, suggesting a potential biological synergism leading to increased risk. These coincident results implicate GAD1 in the etiology of schizophrenia and suggest that the mechanism involves altered cortical GABA inhibitory activity, perhaps modulated by dopaminergic function.

Duration judgements in patients with schizophrenia.

BACKGROUND: The ability to encode time cues underlies many cognitive processes. In the light of schizophrenic patients' compromised cognitive abilities in a variety of domains, it is noteworthy that there are numerous reports of these patients displaying impaired timing abilities. However, the timing intervals that patients have been evaluated on in prior studies vary considerably in magnitude (e.g. 1 s, 1 min, 1 h etc.). METHOD: In order to obviate differences in abilities in chronometric counting and place minimal demands on cognitive processing, we chose tasks that involve making judgements about brief durations of time (< 1 s). RESULTS: On a temporal generalization task, patients were less accurate than controls at recognizing a standard duration. The performance of patients was also significantly different from controls on a temporal bisection task, in which participants categorized durations as short or long. Although time estimation may be closely intertwined with working memory, patients' working memory as measured by the digit span task did not correlate significantly with their performance on the duration judgement tasks. Moreover, lowered intelligence scores could not completely account for the findings. CONCLUSIONS: We take these results to suggest that patients with schizophrenia are less accurate at estimating brief time periods. These deficits may reflect dysfunction of biopsychological timing processes.

Open-set speech perception in adult cochlear implant users with ossified cochleae.

This study describes open-set speech recognition in cochlear implant subjects with ossified cochleae and compares it to a control group with open cochleae. Twenty-one postlingually deafened adults with a Med-El Combi 40/40+GB split- electrode implant were matched to patients using a Med-El cochlear implant with a standard electrode. Speech recognition was assessed over an 18-month period. Split- electrode patients improved significantly over time, but their scores were significantly lower and increased significantly slower than those of controls. Of 14 patients with a duration of deafness less than 20 years, average sentence test scores were 50%, and average monosyllabic word test scores were 31%. This study provides evidence that cochlear implantation is beneficial to patients with ossified cochleae, but early implantation is advisable.