Enhanced Learning through Multimodal Training: Evidence from a Comprehensive Cognitive, Physical Fitness, and Neuroscience Intervention.

The potential impact of brain training methods for enhancing human cognition in healthy and clinical populations has motivated increasing public interest and scientific scrutiny. At issue is the merits of intervention modalities, such as computer-based cognitive training, physical exercise training, and non-invasive brain stimulation, and whether such interventions synergistically enhance cognition. To investigate this issue, we conducted a comprehensive 4-month randomized controlled trial in which 318 healthy, young adults were enrolled in one of five interventions: (1) Computer-based cognitive training on six adaptive tests of executive function; (2) Cognitive and physical exercise training; (3) Cognitive training combined with non-invasive brain stimulation and physical exercise training; (4) Active control training in adaptive visual search and change detection tasks; and (5) Passive control. Our findings demonstrate that multimodal training significantly enhanced learning (relative to computer-based cognitive training alone) and provided an effective method to promote skill learning across multiple cognitive domains, spanning executive functions, working memory, and planning and problem solving. These results help to establish the beneficial effects of multimodal intervention and identify key areas for future research in the continued effort to improve human cognition.

Underlying sources of cognitive-anatomical variation in multi-modal neuroimaging and cognitive testing.

Healthy adults have robust individual differences in neuroanatomy and cognitive ability not captured by demographics or gross morphology (Luders, Narr, Thompson, & Toga, 2009). We used a hierarchical independent component analysis (hICA) to create novel characterizations of individual differences in our participants (N=190). These components fused data across multiple cognitive tests and neuroanatomical variables. The first level contained four independent, underlying sources of phenotypic variance that predominately modeled broad relationships within types of data (e.g., "white matter," or "subcortical gray matter"), but were not reflective of traditional individual difference measures such as sex, age, or intracranial volume. After accounting for the novel individual difference measures, a second level analysis identified two underlying sources of phenotypic variation. One of these made strong, joint contributions to both the anatomical structures associated with the core fronto-parietal "rich club" network (van den Heuvel & Sporns, 2011), and to cognitive factors. These findings suggest that a hierarchical, data-driven approach is able to identify underlying sources of individual difference that contribute to cognitive-anatomical variation in healthy young adults.

Cognitive and anatomical data in a healthy cohort of adults.

We present data from a sample of 190 healthy adults including assessments of 4 cognitive factor scores, 12 cognitive tests, and 115 MRI-assessed neuroanatomical variables (cortical thicknesses, cortical and sub-cortical volumes, fractional anisotropy, and radial diffusivity). These data were used in estimating underlying sources of individual variation via independent component analysis (Watson et al., In press) [25].

Intronic polymorphism in CYP3A4 affects hepatic expression and response to statin drugs.

Cytochrome P450 3A4 (CYP3A4) metabolizes ∼50% of all clinically used drugs. Although CYP3A4 expression varies widely between individuals, the contribution of genetic factors remains uncertain. In this study, we measured allelic CYP3A4 heteronuclear RNA (hnRNA) and mRNA expression in 76 human liver samples heterozygous for at least one of eight marker SNPs and found marked allelic expression imbalance (1.6-6.3-fold) in 10/76 liver samples (13%). This was fully accounted for by an intron 6 SNP (rs35599367, C>T), which also affected mRNA expression in cell culture on minigene transfections. CYP3A4 mRNA level and enzyme activity in livers with CC genotype were 1.7- and 2.5-fold, respectively, greater than in CT and TT carriers. In 235 patients taking stable doses of atorvastatin, simvastatin, or lovastatin for lipid control, carriers of the T allele required significantly lower statin doses (0.2-0.6-fold, P=0.019) than non-T carriers for optimal lipid control. These results indicate that intron 6 SNP rs35599367 markedly affects expression of CYP3A4 and could serve as a biomarker for predicting response to CYP3A4-metabolized drugs.

The PlA polymorphism of glycoprotein IIIa functions as a modifier for the effect of estrogen on platelet aggregation.

BACKGROUND: Although estrogen has been shown to contribute to retardation of the development of coronary heart disease in premenopausal women, the efficacy of hormone replacement therapy for coronary heart disease prevention in women with established coronary heart disease remains controversial. Hence, additional research is needed to clarify the effects of hormone replacement therapy on the cardiovascular and clotting systems. We investigated the effect of estrogen on platelet aggregation induced by standard agonists (epinephrine and adenosine diphosphate), with and without the platelet antagonist aspirin. Furthermore, we analyzed our data according to the presence or absence of a prevalent polymorphism of the glycoprotein (GP) IIIa subunit of the platelet fibrinogen receptor GPIIb-IIIa, PlA2. METHODS AND RESULTS: The effect of estrogen on aggregation of platelets was studied in healthy men (n = 20, 10 PlA1/A1 and 10 PlA1/A2) and premenopausal healthy women (n = 10, 5 PlA1/A1 and 5 PlA1/A2). The PlA1/A1 and PlA1/A2 individuals were matched for age and race. Platelet response to agonists was investigated in the presence of (1) estrogen (10(-11) to 10(-8) mol/L), (2) aspirin (0.056 to 56 micromol/L), (3) estrogen plus aspirin, and (4) estrogen plus ICI 182 780 (ICI, 10(-9) mol/L, an inhibitor of the estrogen receptor). We found that physiologic concentrations of estrogen strongly and significantly inhibited the aggregation of PlA1/A2 platelets (P<.005 for epinephrine and P<.05 for adenosine diphosphate, induced aggregation, respectively) in both men and women. Concentrations of estrogen that were 1000-fold greater were required to observe the same level of inhibition with PlA1/A1 platelets. In the presence of aspirin, estrogen failed to provide additional inhibitory effect on aggregation of both PlA1/A1 and PlA1/A2 platelets. The estrogen-specific inhibitor ICI blocked the effect of estrogen on aggregation, suggesting that this effect is mediated by the estrogen receptor. CONCLUSIONS: Estrogen inhibits the aggregation of platelets, but such inhibition is highly dependent on the presence or absence of the PlA2 polymorphism of GPIIIa. However, in the presence of aspirin, the inhibitory effect of estrogen on aggregation was no longer detectable.

Plasma atherogenic markers in congestive heart failure and posttransplant (heart) patients.

OBJECTIVES: We hypothesized that plasma factors important for the development of atherosclerosis play a major role in the occurrence of cardiac allograft vasculopathy (CAV). BACKGROUND: Cardiac allograft vasculopathy is a major cause of death among heart transplant recipients, has a poorly understood pathogenesis and has similarities to atherosclerotic coronary disease. METHODS: The study population consisted of 93 postcardiac transplant recipients. Thirty-one patients with congestive heart failure (CHF) and 18 healthy individuals served as control subjects. Posttransplant coronary anatomy was evaluated by angiography and intravascular ultrasound. Laboratory analyses of lipids, homocysteine, vitamin B12 and folate, fibrinogen, von Willebrand factor antigen (vWFAg) and renin were obtained on all participants. RESULTS: Posttransplant patients were found to have elevated serum triglycerides, total cholesterol/ high-density lipoprotein cholesterol ratio, lipoprotein (a), homocysteine, vWFAg, fibrinogen and renin and lower high-density lipoprotein cholesterol. Most of these laboratory atherogenic factors were also elevated to a similar degree in the CHF control population. Although most atherogenic markers were elevated, there was little correlation with CAV severity. Cardiac allograft vasculopathy severity varied with time after transplantation, 3-hydroxy-methyl-glutaryl-coenzyme A reductase inhibitor use and prior cytomegalovirus infection. Even within the normal range, lower RBC folate levels were associated with increased severity of CAV. CONCLUSIONS: The posttransplant course is associated with increased clinical and laboratory atherogenic factors, some of which likely contribute to the severity of coronary vasculopathy. Compared with normal control subjects, many of these markers are already increased in pretransplant CHF patients with or without occlusive coronary artery disease.

Sample size to test for interaction between a specific exposure and a second risk factor in a pair-matched case-control study.

We discuss a sample size calculation for a pair-matched case-control study to test for interaction between a specific exposure and a second risk factor. The second risk factor could be either binary or continuous. An algorithm for the calculation of sample size is suggested which is based on a logistic regression model that relates the logarithm of the disease-exposure odds ratio to the second risk factor. This problem is motivated by a study comparing the prevalence of GP-IIIa Pl(A2) polymorphism (the exposure) in individuals with and without myocardial infarction (case-control). One of the hypotheses in this study is whether or not there is an interaction between the prevalence of GP-IIIa Pl(A2) polymorphism and a second risk factor such as smoking status and homocysteine level. We introduce the algorithm in detail with several numerical examples.

Higher prevalence of GPIIIa PlA2 polymorphism in siblings of patients with premature coronary heart disease.

BACKGROUND: The Pl(A2) polymorphism of GPIIIa has been associated with unstable coronary syndromes in some studies, but the association has remained debated. None of the previous studies have focused on families at high risk. Risk factors tend to cluster within kindreds with high prevalence of premature coronary heart disease (CHD). Therefore, a heightened prevalence of the Pl(A2) polymorphism among siblings of patients with CHD would support the hypothesis that Pl(A2) is linked, directly or indirectly, to CHD. OBJECTIVES: To measure the prevalence of the Pl(A2) polymorphism among siblings of patients with CHD before the age of 60 years and to seek an association between the Pl(A2) polymorphism and established atherosclerotic and thrombogenic risk factors. METHODS: From January 1994 to April 1996, we genotyped 116 asymptomatic siblings (60 Caucasians, 56 Afro-Caribbeans) of patients with CHD manifestations before the age of 60 years for the Pl(A) polymorphism (also called HPA-1). A control cohort was used for comparison, consisting of individuals that were matched for race and geographic area but were free of CHD (n = 268, 168 Caucasians and 100 Afro-Caribbeans). In addition, we have characterized the sibling cohort for other atherogenic and thrombogenic risk factors. RESULTS: The prevalence of Pl(A2)-positive individuals (Pl(A2)[+], Pl(A1/A2) heterozygotes plus Pl(A2/A2) homozygotes) in the sibling cohort was high: 41.4%. When analyzed separately, the prevalence of Pl(A2)(+) siblings was 53.3% among Caucasians and 28.6% among Afro-Caribbeans. There was no association between Pl(A2) and other established atherogenic or thrombogenic risk factors. Interestingly, the clustering of other risk factors was lesser among Pl(A2)(+) siblings than their Pl(A1) counterparts. CONCLUSIONS: This study supports the hypothesis that the prevalence of Pl(A2)(+) individuals is high in kindreds with premature CHD. Hence, like the established risk factors that tend to cluster in families with premature CHD and contribute strongly to the accelerated atherosclerotic process affecting these individuals, the Pl(A2) polymorphism of GPIIIa may represent an inherited risk that promotes the thromboembolic complications of CHD. That these asymptomatic Pl(A2)(+) siblings had overall less established risk factors than their Pl(A1) counterparts might represent an explanation for why they remained asymptomatic despite their Pl(A2) positivity.

Priming of platelet alphaIIbbeta3 by oxidants is associated with tyrosine phosphorylation of beta3.

Reactive oxygen species play an important role at the site of vascular injuries and arterial thromboses. We studied the mechanism mediating platelet aggregation induced by H2O2, a major cellular oxidant. Exposure to H2O2 triggered platelet aggregation, but only when the platelets were stirred. Strong platelet aggregation induced99032416 required the presence of the tyrosine phosphatase inhibitor sodium orthovanadate (NaVO4) and was dependent on the participation of integrin alphaIIbbeta3 (glycoprotein IIb-IIIa). A specific inhibitor of alphaIIbbeta3 blocked platelet aggregation induced by H2O2 and NaVO4, thus confirming that aggregation requires this receptor. In the presence of H2O2 and NaVO4, multiple platelet substrates were phosphorylated on tyrosine. Such tyrosine kinase response was necessary but not sufficient to activate alphaIIbbeta3, as detected by binding of soluble fibrinogen to platelets. Stirring of the platelets exposed to H2O2 and NaVO4 was also needed to allow for binding of fibrinogen to alphaIIbbeta3. The tyrosine kinase inhibitor genistein was able to block platelet aggregation induced by H2O2 and NaVO4, thus confirming that tyrosine kinase activity was needed to trigger alphaIIbbeta3 activation on stirring. N-Acetyl-L-cysteine, a cell-permeant antioxidant, blocked the tyrosine phosphorylation of platelet substrates and also the platelet aggregation induced by H2O2 and NaVO4. We found that beta3 was phosphorylated on tyrosine in platelets exposed to H2O2 and NaVO4, even in the absence of aggregation. Hence, tyrosine phosphorylation of beta3 might contribute to the "priming" of alphaIIbbeta3 induced by H2O2 and NaVO4, whereby the receptor can become activated on stirring of the platelets.