Ventral tegmental area amylin / calcitonin receptor signaling suppresses feeding and weight gain in female rats.

The pancreatic peptide amylin promotes negative energy balance in part through activation of amylin receptors (AmyRs) expressed in the ventral tegmental area (VTA), but studies have been limited to male rodents. We evaluated whether VTA amylin signaling governs feeding and body weight in female rats. Indeed, pharmacological VTA AmyR activation suppressed chow intake and body weight in females. Viral-mediated knockdown of VTA calcitonin receptor (GPCR of AmyR) supports the physiological relevance of VTA amylin signaling for energy balance control in females. Collectively, these data support the relevance of VTA amylin signaling for energy balance control in both sexes.

Cerebellar Neuromodulation Impacts Reading Fluency in Young Adults.

The cerebellum is traditionally associated with the control of coordinated movement, but ample evidence suggests that the cerebellum also supports cognitive processing. Consistent with this, right-lateralized posterolateral cerebellar regions are engaged during a range of reading and reading-related tasks, but the specific role of the cerebellum during reading tasks is not clear. Based on the cerebellar contribution to automatizing movement, it has been hypothesized that the cerebellum is specifically involved in rapid, fluent reading. We aimed to determine whether the right posterolateral cerebellum is a specific modulator of reading fluency or whether cerebellar modulation is broader, also impacting reading accuracy, rapid automatized naming, and general processing speed. To do this, we examined the effect of transcranial direct current stimulation (tDCS) targeting the right posterolateral cerebellum (lobules VI/VII) on single-word reading fluency, reading accuracy, rapid automatized naming, and processing speed. Young adults with typical reading development (n = 25; 15 female sex assigned at birth, 10 male sex assigned at birth, aged 18-28 years [M = 19.92 ± 2.04 years]) completed the reading and cognitive measures after 20 min of 2 mA anodal (excitatory), cathodal (inhibitory), or sham tDCS in a within-subjects design. Linear mixed effects models indicated that cathodal tDCS decreased single-word reading fluency scores (d = -0.36, p < 0.05) but did not significantly affect single-word reading accuracy, rapid automatized naming, or general processing speed measures. Our results suggest that the right posterolateral cerebellum is involved in reading fluency, consistent with a broader role of the cerebellum in fast, fluent cognition.

Processing Speed is Related to the General Psychopathology Factor in Youth.

The relationship between the p factor and cognition in youth has largely focused on general cognition (IQ) and executive functions (EF). Another cognitive construct, processing speed (PS), is dissociable from IQ and EF, but has received less research attention despite being related to many different mental health symptoms. The present sample included 795 youth, ages 11-16 from the Colorado Learning Disabilities Research Center (CLDRC) sample. Confirmatory factor analyses tested multiple p factor models, with the primary model being a second-order, multi-reporter p factor. We then tested the correlation between the p factor and a latent PS factor. There was a significant, negative correlation between the p factor and PS (r(87) = -0.42, p < .001), indicating that slower processing speed is associated with higher general mental health symptoms. This association is stronger than previously reported associations with IQ or EF. This finding was robust across models that used different raters (youth and caregiver) and modeling approaches (second-order vs. bifactor). Our findings indicate that PS is related to general psychopathology symptoms. This research points to processing speed as an important transdiagnostic construct that warrants further exploration across development.

Shared grey matter correlates of reading and attention.

Disorders of reading (developmental dyslexia) and attention (ADHD) have a high rate of comorbidity (25-40%), yet little is known about the neural underpinnings of this phenomenon. The current study investigated the shared and unique neural correlates of reading and attention in 330 typically developing children ages 8-18 from the Philadelphia Neurodevelopmental Cohort. Multiple regression analyses were used to identify regions of the brain where grey matter (GM) volume was associated with reading or attention scores (p < 0.001, cluster FDR p < 0.05). Better attention scores correlated with increased GM in the precuneus and higher reading scores were associated with greater thalamic GM. An exploratory conjunction analysis (p < 0.05, k > 239) found that GM in the caudate and precuneus correlated with both reading and attention scores. These results are consistent with a recent meta-analysis which identified GM reductions in the caudate in both dyslexia and ADHD and reveal potential shared neural correlates of reading and attention.

Compounding Effects of Domain-General Cognitive Weaknesses and Word Reading Difficulties on Anxiety Symptoms in Youth.

This study examined whether domain-general cognitive weaknesses in processing speed (PS) or executive functioning (EF) moderate the relation between word reading scores and anxiety such that lower word reading scores in combination with lower cognitive scores are associated with higher anxiety symptoms. The sample consisted of 755 youth ages 8-16 who were recruited as part of the Colorado Learning Disabilities Research Center twins study. Lower scores on PS (R2 = .007, p = .014), EF (R2 = .009, p = .006), and word reading (R2 = .006-.008, p = .010-.032) were associated with higher anxiety scores. In addition, the word reading × cognitive interactions were significant such that lower scores on PS (R2 = .010, p = .005) or EF (R2 = .013, p = .010) combined with lower word reading were associated with higher-than-expected anxiety symptoms. Results suggest that weaknesses in PS, EF, and word reading are modestly associated with higher anxiety symptoms, and these anxiety symptoms may be compounded in youth with both PS or EF weaknesses and word reading difficulties. These findings can guide assessment approaches for identifying youth with word reading challenges who may be at increased risk for anxiety.

Using plain language to communicate with clinical trials participants: Comparison of readability calculators.

It is important that patient-facing clinical trial information is easily understood by potential trial participants, active trial participants, family members, friends and carers. The readability of a document refers to its typographic and linguistic characteristics that allow the text to be read and comprehended and it is recommended that healthcare providers aim that all information disseminated to the lay public be at a suitable readability level. Whilst there are established readability calculators for literature, there is no standard for health information. Several readability calculators are available that aid in the analysis of a text, URL or website's readability, however, to date there has been no head-to-head comparison of these. Five readability calculators were compared, including four online realtime calculators, (i) Readable (www.readable.com), (ii) www.webfx.com, (iii) www.datayze.com and (iv) www.online-utility.org, as well as the PC-based analyzer Microsoft Word (Microsoft Corp., USA). Three categories of text information were analysed, including (i) childrens' fairy tales (n = 20) (ii) scientific reports (n = 20) from BBC News websites and (iii) scientific abstracts (n = 20). This study demonstrated that varying scores were obtained by using different readability calculators. Based on these data in combination with issues including availability and ease-of-use, we advocate the use of Readable or Microsoft Word software to aid in the preparation of patient-facing clinical trial information. Clinical trial networks should now consider the need for standardisation of readability calculators and provide guidance to stakeholders so that readability of materials may be improved in a standardised and uniform manner.

Heritability and Clinical Characteristics of Neuropsychological Profiles in Youth With and Without Elevated ADHD Symptoms.

OBJECTIVE: In the last decade, there has been an increase in research that aims to parse heterogeneity in attention deficit hyperactivity disorder (ADHD). The current study tests heritability of latent class neuropsychological subtypes. METHOD: Latent class analysis was used to derive subtypes in a sample of school-age twins (N = 2,564) enriched for elevated ADHD symptoms. RESULTS: Five neuropsychological profiles replicated across twin 1 and twin 2 datasets. Latent class membership was heritable overall, but heritability varied by profile and was lower than heritability of ADHD status. Variability in neuropsychological performance across domains was the strongest predictor of elevated ADHD symptoms. Neuropsychological profiles showed distinct associations with age, psychiatric symptoms and reading ability. CONCLUSION: Neuropsychological profiles are associated with unique neurocognitive presentations, but are not strong candidate endophenotypes for ADHD diagnosis.

In Search of Cognitive Promotive and Protective Factors for Word Reading.

This study examined whether strong cognitive skills (i.e. vocabulary, rapid naming, verbal working memory [VWM], and processing speed [PS]) contributed to resilience in single-word reading skills in children at risk for reading difficulties because of low phonological awareness scores (PA). Promotive factors were identified by main effects and protective factors through PA x cognition interactions. This study included 1,807 children ages 8-16. As predicted, all cognitive skills were significantly related to reading, consistent with promotive effects. A significant, but small effect PA x vocabulary interaction (R2 change=.002, p=.00038) was detected but its form was not consistent with a classic protective effect. Rather, the PA x vocabulary interaction was consistent with a "skill-enhancement" pattern, such that children with strong PA and vocabulary skills had better than expected reading. This study provides a framework for reading resilience research and directs attention to promotive mechanisms underlying reading success.

Contextualizing genetic risk score for disease screening and rare variant discovery.

Studies of the genetic basis of complex traits have demonstrated a substantial role for common, small-effect variant polygenic burden (PB) as well as large-effect variants (LEV, primarily rare). We identify sufficient conditions in which GWAS-derived PB may be used for well-powered rare pathogenic variant discovery or as a sample prioritization tool for whole-genome or exome sequencing. Through extensive simulations of genetic architectures and generative models of disease liability with parameters informed by empirical data, we quantify the power to detect, among cases, a lower PB in LEV carriers than in non-carriers. Furthermore, we uncover clinically useful conditions wherein the risk derived from the PB is comparable to the LEV-derived risk. The resulting summary-statistics-based methodology (with publicly available software, PB-LEV-SCAN) makes predictions on PB-based LEV screening for 36 complex traits, which we confirm in several disease datasets with available LEV information in the UK Biobank, with important implications on clinical decision-making.

The long-acting amylin/calcitonin receptor agonist ZP5461 suppresses food intake and body weight in male rats.

The peptide hormone amylin reduces food intake and body weight and is an attractive candidate target for novel pharmacotherapies to treat obesity. However, the short half-life of native amylin and amylin analogs like pramlintide limits these compounds' potential utility in promoting sustained negative energy balance. Here, we evaluate the ability of the novel long-acting amylin/calcitonin receptor agonist ZP5461 to reduce feeding and body weight in rats, and also test the role of calcitonin receptors (CTRs) in the dorsal vagal complex (DVC) of the hindbrain in the energy balance effects of chronic ZP5461 administration. Acute dose-response studies indicate that systemic ZP5461 (0.5-3 nmol/kg) robustly suppresses energy intake and body weight gain in chow- and high-fat diet (HFD)-fed rats. When HFD-fed rats received chronic systemic administration of ZP5461 (1-2 nmol/kg), the compound initially produced reductions in energy intake and weight gain but failed to produce sustained suppression of intake and body weight. Using virally mediated knockdown of DVC CTRs, the ability of chronic systemic ZP5461 to promote early reductions in intake and body weight gain was determined to be mediated in part by activation of DVC CTRs, implicating the DVC as a central site of action for ZP5461. Future studies should address other dosing regimens of ZP5461 to determine whether an alternative dose/frequency of administration would produce more sustained body weight suppression.

How Specific Are Learning Disabilities?

Despite historical emphasis on "specific" learning disabilities (SLDs), academic skills are strongly correlated across the curriculum. Thus, one can ask how specific SLDs truly are. To answer this question, we used bifactor models to identify variance shared across academic domains (academic g), as well as variance unique to reading, mathematics, and writing. Participants were 686 children ages 8 to 16. Although the sample was overselected for learning disabilities, we intentionally included children across the full range of individual differences in this study in response to growing recognition that a dimensional, quantitative view of SLD is more accurate than a categorical view. Confirmatory factor analysis identified five academic domains (basic reading, reading comprehension, basic math, math problem-solving, and written expression); spelling clustered with basic reading and not writing. In the bifactor model, all measures loaded significantly on academic g. Basic reading and mathematics maintained variance distinct from academic g, consistent with the notion of SLDs in these domains. Writing did not maintain specific variance apart from academic g, and evidence for reading comprehension-specific variance was mixed. Academic g was strongly correlated with cognitive g (r = .72) but not identical to it. Implications for SLD diagnosis are discussed.

The Multiple Deficit Model: Progress, Problems, and Prospects.

The multiple deficit model (MDM) was proposed because the prevailing single-deficit model provided an inadequate account of atypical neuropsychological development. Across methods and levels of analysis, there has been support for the two fundamental tenets of the MDM, that multiple predictors contribute probabilistically to neurodevelopmental disorders and shared risk factors contribute to comorbidity. Diagnostically, the multiplicity of factors means that no single cognitive deficit or combination of deficits can be used to rule in or out most neurodevelopmental disorders. Challenges for the MDM are that the theory is difficult to falsify and that current cross-sectional studies cannot establish causality. Prospects for further development of the MDM include incorporating an explicit focus on promotive and protective factors and pursuing mechanistic connections between multiple factors across levels of analysis.

A Review of Online Dyslexia Learning Modules.

This paper presents a comprehensive review of publicly available online dyslexia learning modules with a particular focus on the extent to which modules address the prevalent myth that dyslexia is caused by "backwards reading." The authors conducted a systematic internet search to identify publicly available online dyslexia learning modules and coded the content across education, neurocognition, and policy disciplinary domains. We identified 18 topics across a small number (N = 14) of publicly available modules that focused on dyslexia, with only two modules directly addressing this dyslexia myth. While both identified this myth as false, neither provided information about the neurocognitive underpinnings of dyslexia to explain why this myth is false. This review will be useful for guiding further development of online dyslexia learning modules which are urgently needed due to persisting misinformation about this disorder. The coded content reviews of each module will also be beneficial for directing attention to existing resources for professional development on dyslexia.

Are there shared neural correlates between dyslexia and ADHD? A meta-analysis of voxel-based morphometry studies.

BACKGROUND: Dyslexia and Attention-deficit/hyperactivity disorder (ADHD) are highly comorbid neurodevelopmental disorders (estimates of 25-40% bidirectional comorbidity). Previous work has identified strong genetic and cognitive overlap between the disorders, but neural overlap is relatively unexplored. This study is a systematic meta-analysis of existing voxel-based morphometry studies to determine whether there is any overlap in the gray matter correlates of both disorders. METHODS: We conducted anatomic likelihood estimate (ALE) meta-analyses of voxel-based morphometry studies in which individuals with dyslexia (15 studies; 417 cases, 416 controls) or ADHD (22 studies; 898 cases, 763 controls) were compared to typically developing controls. We generated ALE maps for dyslexia vs. controls and ADHD vs. controls using more conservative (p < .001, k = 50) and more lenient (p < .005, k = 50) thresholds. To determine the overlap of gray matter correlates of dyslexia and ADHD, we examined the statistical conjunction between the ALE maps for dyslexia vs. controls and ADHD vs. controls (false discovery rate [FDR] p < .05, k = 50, 5000 permutations). RESULTS: Results showed largely distinct gray matter differences associated with dyslexia and ADHD. There was no evidence of statistically significant gray matter overlap at our conservative threshold, and only one region of overlap in the right caudate at our more lenient threshold. Reduced gray matter in the right caudate may be relevant to shared cognitive correlates in executive functioning and/or procedural learning. The more general finding of largely distinct regional differences in gray matter between dyslexia and ADHD suggests that other neuroimaging modalities may be more sensitive to overlapping neural correlates, and that current neuroimaging recruitment approaches may be hindering progress toward uncovering neural systems associated with comorbidity. CONCLUSIONS: The current study is the first to meta-analyze overlap between gray matter differences in dyslexia and ADHD, which is a critical step toward constructing a multi-level understanding of this comorbidity that spans the genetic, neural, and cognitive levels of analysis.

Combined Amylin/GLP-1 pharmacotherapy to promote and sustain long-lasting weight loss.

A growing appreciation of the overlapping neuroendocrine mechanisms controlling energy balance has highlighted combination therapies as a promising strategy to enhance sustained weight loss. Here, we investigated whether amylin- and glucagon-like-peptide-1 (GLP-1)-based combination therapies produce greater food intake- and body weight-suppressive effects compared to monotherapies in both lean and diet-induced obese (DIO) rats. In chow-maintained rats, systemic amylin and GLP-1 combine to reduce meal size. Furthermore, the amylin and GLP-1 analogs salmon calcitonin (sCT) and liraglutide produce synergistic-like reductions in 24 hours energy intake and body weight. The administration of sCT with liraglutide also led to a significant enhancement in cFos-activation in the dorsal-vagal-complex (DVC) compared to mono-therapy, suggesting an activation of distinct, yet overlapping neural substrates in this critical energy balance hub. In DIO animals, long-term daily administration of this combination therapy, specifically in a stepwise manner, results in reduced energy intake and greater body weight loss over time when compared to chronic mono- and combined-treated groups, without affecting GLP-1 receptor, preproglucagon or amylin-receptor gene expression in the DVC.

Understanding Comorbidity Between Specific Learning Disabilities.

Current definitions of specific learning disability (SLD) identify a heterogeneous population that includes individuals with weaknesses in reading, math, or writing, and these academic difficulties often co-occur in many of the same individuals. The Colorado Learning Disabilities Research Center (CLDRC) is an interdisciplinary, multisite research program that uses converging levels of analysis to understand the genetic and environmental etiology, neuropsychology, and developmental outcomes of SLDs in reading (RD), math (MD), and writing (WD), along with the comorbidity between these SLDs and other developmental disorders. The latest results from the CLDRC twin study suggest that shared genetic influences contribute to the significant covariance between all aspects of reading (word reading, reading fluency, and reading comprehension) and math (calculations, math fluency, and word problems), and distinct genetic or environmental influences also contribute to weaknesses in each specific academic domain. RD and MD are associated with a range of negative outcomes on both concurrent measures and measures of functional outcomes completed 5 years after the twins were first assessed. Over the next several years the CLDRC will continue to expand on this work by administering a comprehensive test battery that includes measures of all dimensions of academic achievement that are described in current definitions of SLD and incorporating these measures in new neuroimaging and molecular genetic studies.

A vitamin B12 conjugate of exendin-4 improves glucose tolerance without associated nausea or hypophagia in rodents.

AIMS: While pharmacological glucagon-like peptide-1 receptor (GLP-1R) agonists are FDA-approved for treating type 2 diabetes mellitus (T2DM) and obesity, a major side effect is nausea/malaise. We recently developed a conjugate of vitamin B12 (B12) bound to the GLP-1R agonist exendin-4 (Ex4), which displays enhanced proteolytic stability and retention of GLP-1R agonism. Here, we evaluate whether the conjugate (B12-Ex4) can improve glucose tolerance without producing anorexia and malaise. MATERIALS AND METHODS: We evaluated the effects of systemic B12-Ex4 and unconjugated Ex4 on food intake and body weight change, oral glucose tolerance and nausea/malaise in male rats, and on intraperitoneal glucose tolerance in mice. To evaluate whether differences in the profile of effects of B12-Ex4 vs unconjugated Ex4 are the result of altered CNS penetrance, rats received systemic injections of fluorescein-Ex4 (Flex), Cy5-B12 or Cy5-B12-Ex4 and brain penetrance was evaluated using confocal microscopy. Uptake of systemically administered Cy5-B12-Ex4 in insulin-containing pancreatic beta cells was also examined. RESULTS: B12-Ex4 conjugate improves glucose tolerance, but does not elicit the malaise and anorexia produced by unconjugated Ex4. While Flex robustly penetrates into the brain (dorsal vagal complex, paraventricular hypothalamus), Cy5-B12 and Cy5-B12-Ex4 fluorescence were not observed centrally, supporting an absence of CNS penetrance, in line with observed reduction in CNS-associated Ex4 side effects. Cy5-B12-Ex4 colocalizes with insulin in the pancreas, suggesting direct pancreatic action as a potential mechanism underlying the hypoglycaemic effects of B12-Ex4. CONCLUSION: These novel findings highlight the potential clinical utility of B12-Ex4 conjugates as possible future T2DM therapeutics with reduced incidence of adverse effects.

Glucagon-Like Peptide-1 Receptor Signaling in the Lateral Dorsal Tegmental Nucleus Regulates Energy Balance.

The neurobiological substrates that mediate the anorectic effects of both endogenous glucagon-like peptide-1 (GLP-1) and exogenous GLP-1 receptor (GLP-1R) agonists are an active area of investigation. As the lateral dorsal tegmental nucleus (LDTg) expresses the GLP-1R and represents a potential neuroanatomical hub connecting the nucleus tractus solitarius (NTS), the major central source of GLP-1, with the other nuclei in the midbrain and forebrain, we tested the hypothesis that GLP-1R signaling in the LDTg controls food intake. Direct activation of LDTg GLP-1R suppresses food intake through a reduction in average meal size and independent of nausea/malaise. Immunohistochemical data show that GLP-1-producing neurons in the NTS project to the LDTg, providing anatomical evidence of endogenous central GLP-1 in the LDTg. Pharmacological blockade of LDTg GLP-1Rs with exendin-(9-39) dose-dependently increases food intake and attenuates the hypophagic effects of gastric distension. As GLP-1 mimetics are administered systemically in humans, we evaluated whether peripherally administered GLP-1R agonists access the LDTg to affect feeding. Immunohistochemical data show that a systemically administered fluorescent GLP-1R agonist accesses the LDTg and is juxtaposed with neurons. Additionally, blockade of LDTg GLP-1Rs attenuates the hypophagic effects of a systemic GLP-1R agonist. Together, these data indicate that LDTg GLP-1R signaling controls energy balance and underscores the role of the LDTg in integrating energy balance-relevant signals to modulate feeding.