Visuospatial working memory, auditory discrimination, and attention.

The present study examined the degree to which tests of visuospatial storage capacity tap into domain-general storage and attention processes. This was done by comparing performance of visuospatial memory tasks with performance on sound-based sensory discrimination tasks. We found that memory task- and discrimination task performance both tapped into a cross-modality factor (visual and auditory). We further examined the degree to which this common variance could be explained by attention control and sustained attention. These attention factors accounted for roughly 60% of the variance in memory. This indicates that tests of visuospatial memory capacity reflect more than modality-specific memory.

Amygdala-liver signaling orchestrates rapid glycemic responses to stress and drives stress-induced metabolic dysfunction.

Behavioral adaptations to environmental threats are crucial for survival and necessitate rapid deployment of energy reserves. The amygdala coordinates behavioral adaptations to threats, but little is known about its involvement in underpinning metabolic adaptations. Here, we show that acute stress activates medial amygdala (MeA) neurons that innervate the ventromedial hypothalamus (MeAVMH neurons), which precipitates hyperglycemia and hypophagia. The glycemic actions of MeAVMH neurons occur independent of adrenal or pancreatic glucoregulatory hormones. Instead, using whole-body virus tracing, we identify a polysynaptic connection from MeA to the liver, which promotes the rapid synthesis of glucose by hepatic gluconeogenesis. Repeated stress exposure disrupts MeA control of blood glucose and appetite, resulting in diabetes-like dysregulation of glucose homeostasis and weight gain. Our findings reveal a novel amygdala-liver axis that regulates rapid glycemic adaptations to stress and links recurrent stress to metabolic dysfunction.

A toolbox approach to improving the measurement of attention control.

Cognitive tasks that produce reliable and robust effects at the group level often fail to yield reliable and valid individual differences. An ongoing debate among attention researchers is whether conflict resolution mechanisms are task-specific or domain-general, and the lack of correlation between most attention measures seems to favor the view that attention control is not a unitary concept. We have argued that the use of difference scores, particularly in reaction time (RT), is the primary cause of null and conflicting results at the individual differences level, and that methodological issues with existing tasks preclude making strong theoretical conclusions. The present article is an empirical test of this view in which we used a toolbox approach to develop and validate new tasks hypothesized to reflect attention processes. Here, we administered existing, modified, and new attention tasks to over 400 participants (final N = 396). Compared with the traditional Stroop and flanker tasks, performance on the accuracy-based measures was more reliable, had stronger intercorrelations, formed a more coherent latent factor, and had stronger associations to measures of working memory capacity and fluid intelligence. Further, attention control fully accounted for the relationship between working memory capacity and fluid intelligence. These results show that accuracy-based measures can be better suited to individual differences investigations than traditional RT tasks, particularly when the goal is to maximize prediction. We conclude that attention control is a unitary concept. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

The visual arrays task: Visual storage capacity or attention control?

Extant literature suggests that performance on visual arrays tasks reflects limited-capacity storage of visual information. However, there is also evidence to suggest that visual arrays task performance reflects individual differences in controlled processing. The purpose of this study is to empirically evaluate the degree to which visual arrays tasks are more closely related to memory storage capacity or measures of attention control. To this end, we conducted new analyses on a series of large data sets that incorporate various versions of a visual arrays task. Based on these analyses, we suggest that the degree to which the visual arrays is related to memory storage ability or effortful attention control may be task-dependent. Specifically, when versions of the task require participants to ignore elements of the target display, individual differences in controlled attention reliably provide unique predictive value. Therefore, at least some versions of the visual arrays tasks can be used as valid indicators of individual differences in attention control. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Toxicity in ALS: TDP-43 modifiers and C9orf72.

Amyotrophic Lateral Sclerosis (ALS) is a devastating and fatal neurodegenerative disease affecting approximately 30,000 individuals in the United States. The average age of onset is 55 years and progression of the disease is rapid with most patients dying of respiratory failure within 3-5 years. Currently available therapeutics have modest effects on patient survival, underscoring the immediate need for more effective medicines. Recent technological advances in next generation sequencing have led to a substantial uptick in the discovery of genes linked to ALS. Since 90 % of ALS cases are sporadic, risk genes identified in familial cases provide invaluable insights into the molecular pathogenesis of the disease. Most notably, TDP-43-expressing neuronal inclusions and C9orf72 mutations have emerged as the key pathological and genetic hallmarks, respectively, of ALS. In this review, we will discuss recent advances in modifiers of TDP-43 toxicity, with an emphasis on Ataxin-2, one of the most well-characterized TDP-43 modifiers. An understanding of Ataxin-2 function and related biological pathways could provide a framework for the discovery of other novel modifiers of TDP-43. We will also describe the pathogenic mechanisms underlying C9orf72 toxicity and how these impact the disease process. Finally, we will explore emerging therapeutic strategies for dampening TDP-43 and C9orf72 toxicity and, ultimately, slowing or halting the progression of ALS.

Attention control: The missing link between sensory discrimination and intelligence.

Intelligence is correlated with the ability to make fine sensory discriminations. Although this relationship has been known since the beginning of intelligence testing, the mechanisms underlying this relationship are still unknown. In two large-scale structural equation-modelling studies, we investigated whether individual differences in attention control abilities can explain the relationship between sensory discrimination and intelligence. Across these two studies, we replicated the finding that attention control fully mediated the relationships of intelligence/working-memory capacity to sensory discrimination. Our findings show that attention control plays a prominent role in relating sensory discrimination to higher-order cognitive abilities.

The role of maintenance and disengagement in predicting reading comprehension and vocabulary learning.

This study uses a novel framework based on work by Shipstead, Harrison, and Engle (2016) that includes measures of both working memory capacity and fluid intelligence in an attempt to better understand the processes that influence successful reading comprehension at the latent level. Further, we extend this framework to a second educationally relevant ability: second-language vocabulary learning. A large sample of young adults received a battery of working memory, fluid intelligence, language comprehension, and memory updating tasks. The results indicate that individual differences in reading comprehension and vocabulary learning benefit from the ability to maintain active information, as well as to disengage from no longer relevant information. Subsequently, we provide an interpretation of our results based on the maintenance and disengagement framework proposed by Shipstead et al. (2016). (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Reaction time in differential and developmental research: A review and commentary on the problems and alternatives.

Reaction time is believed to be a good indicator of the speed and efficiency of mental processes and is a ubiquitous variable in the behavioral sciences. Despite this popularity, there are numerous issues associated with using reaction time (RT), specifically in differential and developmental research. Here, we identify and focus on two main problems-unreliability and sensitivity to speed-accuracy interactions. The use of difference scores is a primary factor that leads to many RT measures having demonstrably low reliability, and RT measures in general often do not properly account for speed-accuracy interactions. Both factors jeopardize the validity and interpretability of results based on RT. Here, we evaluate conceptually and empirically how these issues affect individual differences research. Although the empirical evidence we provide are primarily within the domains of attention control and task switching, we highlight examples from various other areas of psychological inquiry. We also discuss many of the statistical and methodological alternatives available to researchers conducting correlational studies. Ultimately, we encourage researchers comparing individuals of differing cognitive and developmental levels to strongly consider using these alternatives in lieu of RT, specifically RT difference scores. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Technical Limitations of the C1q Single-Antigen Bead Assay to Detect Complement Binding HLA-Specific Antibodies.

BACKGROUND: Solid-phase assays to distinguish complement binding from noncomplement binding HLA-specific antibodies have been introduced, but technical limitations may compromise their interpretation. We have examined the extent to which C1q-binding to HLA-class I single-antigen beads (SAB) is influenced by denatured HLA on SAB, antibody titre, and complement interference that causes a misleading low assessment of HLA-specific antibody levels. METHODS: Sera from 25 highly sensitized patients were tested using Luminex IgG-SAB and C1q-SAB assays. Sera were tested undiluted, at 1:20 dilution to detect high-level IgG, and after ethylene diamine tetraacetic acid treatment to obviate complement interference. Conformational HLA and denatured HLA protein levels on SAB were determined using W6/32 and HC-10 monoclonal antibodies, respectively. Denatured HLA was expressed as HC-10 binding to untreated SAB as a percentage of maximal binding to acid-treated SAB. RESULTS: For undiluted sera, Luminex mean fluorescence intensity (MFI) values for IgG-SAB and C1q-SAB correlated poorly (r = 0.42). ethylene diamine tetraacetic acid and serum dilution improved the correlation (r = 0.57 and 0.77, respectively). Increasing levels of denatured HLA interfered with the detection of C1q binding. Consequently, the correlation between IgG-SAB MFI and C1q-SAB MFI was lowest using undiluted sera and SAB with greater than 30% denatured HLA (r = 0.40) and highest using diluted sera and SAB with 30% or less denatured HLA (r = 0.86). CONCLUSIONS: Antibody level, complement interference, and denatured HLA class I on SAB may all affect the clinical interpretation of the C1q-SAB assay. The C1q-SAB assay represents a substantial additional cost for routine clinical use, and we question its justification given the potential uncertainty about its interpretation.

Chocolate, Air Pollution and Children's Neuroprotection: What Cognition Tools should be at Hand to Evaluate Interventions?

Millions of children across the world are exposed to multiple sources of indoor and outdoor air pollutants, including high concentrations of fine particulate matter (PM2.5) and ozone (O3). The established link between exposure to PM2.5, brain structural, volumetric and metabolic changes, severe cognitive deficits (1.5-2 SD from average IQ) in APOE 4 heterozygous females with >75 - < 94% BMI percentiles, and the presence of Alzheimer's disease (AD) hallmarks in urban children and young adults necessitates exploration of ways to protect these individuals from the deleterious neural effects of pollution exposure. Emerging research suggests that cocoa interventions may be a viable option for neuroprotection, with evidence suggesting that early cocoa interventions could limit the risk of cognitive and developmental concerns including: endothelial dysfunction, cerebral hypoperfusion, neuroinflammation, and metabolic detrimental brain effects. Currently, however, it is not clear how early we should implement consumption of cocoa to optimize its neuroprotective effects. Moreover, we have yet to identify suitable instruments for evaluating cognitive responses to these interventions in clinically healthy children, teens, and young adults. An approach to guide the selection of cognitive tools should take into account neuropsychological markers of cognitive declines in patients with Alzheimer's neuropathology, the distinct patterns of memory impairment between early and late onset AD, and the key literature associating white matter integrity and poor memory binding performance in cases of asymptomatic familial AD. We highlight potential systemic and neural benefits of cocoa consumption. We also highlight Working Memory Capacity (WMC) and attention control tasks as opened avenues for exploration in the air pollution scenario. Exposures to air pollutants during brain development have serious brain consequences in the short and long term and reliable cognition tools should be at hand to evaluate interventions.

Dopaminergic neuron loss and up-regulation of chaperone protein mRNA induced by targeted over-expression of alpha-synuclein in mouse substantia nigra.

Several transgenic mouse lines with altered alpha-synuclein expression have been developed that show a variety of Parkinson's disease-like symptoms without specific loss of dopaminergic neurons. Targeted over-expression of human alpha-synuclein using viral-vector mediated gene delivery into the substantia nigra of rats and non-human primates leads to dopaminergic cell loss and the formation of alpha-synuclein aggregates reminiscent of Lewy bodies. In the context of these recent findings, we used adeno-associated virus (AAV) to over-express wild type human alpha-synuclein in the substantia nigra of mice. We hypothesized that this over-expression would recapitulate pathological hallmarks of Parkinson's disease, creating a mouse model to further characterize the disease pathogenesis. Recombinant AAV expressing alpha-synuclein was stereotaxically injected into the substantia nigra of mice, leading to a 25% reduction of dopaminergic neurons after 24 weeks of transduction. Furthermore, examination of mRNA levels of stress-related proteins using laser capture microdissection and quantitative PCR revealed a positive correlation of Hsp27 expression with the extent of viral transduction at 4 weeks and a positive correlation of Hsp40, Hsp70 and caspase 9 with the extent of viral transduction at 24 weeks. Taken together, our findings suggest that targeted over-expression of alpha-synuclein can induce pathology at the gross anatomical and molecular level in the substantia nigra, providing a mouse model in which upstream changes in Parkinson's disease pathogenesis can be further elucidated.

Role of NMDA and AMPA glutamate receptors in the induction and the expression of dopamine-mediated sensitization in 6-hydroxydopamine-lesioned rats.

Rats with unilateral 6-hydroxydopamine (6-OHDA) lesions exhibit behavioral sensitization following repeated treatment with dopamine agonists, a phenomenon called "priming." Priming has two distinct phases: induction and expression. Priming induction using three injections with D1/D2 agonist apomorphine (0.5 mg/kg) or D1 agonist SKF38393 (10 mg/kg) allows priming expression, robust contralateral rotational behavior and striatal Fos expression, following a challenge with the D2 agonist quinpirole (0.25 mg/kg). We examined the roles of N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA) glutamate receptors on dopamine agonist priming. Administration of the NMDA antagonist (+)5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5,10-imine maleate (MK801) (0.5 mg/kg) blocked apomorphine-priming of quinpirole-mediated responses, while MK801 dose-dependently attenuated SKF38393-priming of quinpirole-mediated striatal Fos expression and had no effect on SKF38393-priming of quinpirole-mediated rotational behavior. In contrast, administration of the AMPA antagonist 2,3-dihydroxy-6-nitro-7sulfamoyl-benzo[f]quinoxaline (NBQX) (5 or 10 mg/kg) potentiated apomorphine- and SKF38393-priming of quinpirole-mediated striatal Fos expression, but had no effect on their priming of quinpirole-mediated rotational behavior. In SKF38393-primed 6-OHDA rats, administration of MK801 (0.5 mg/kg) blocked the expression of quinpirole-mediated responses, while administration of NBQX (10 mg/kg) or the noncompetitive AMPA antagonist 4-(8-methyl-9H-1,3-dioxolo[4,5-h][2,3]benzodiazepin-5-yl)-benzenamine dihydrochloride (GYKI52466) (5 or 15 mg/kg) had no effect. These results suggest that NMDA and AMPA glutamate receptors have differing roles in dopamine agonist priming-with NMDA receptors required for D1/D2 priming induction and D2-mediated priming expression, and AMPA receptors inhibiting priming induction of D2-mediated immediate early gene expression in the striatum, but not affecting priming induction of D2-mediated rotational behavior or the expression of D2-mediated responses.