Translational validity of neuropsychological tasks of sustained attention between rodents and humans: A systematic review of three rodent tasks.

Atypical sustained attention is a symptom in a number of neurological and psychological conditions. Investigations into its neural underpinnings are required for improved management and treatment. Rodents are useful in investigating the neurobiology underlying atypical sustained attention and several rodent tasks have been developed for use in touchscreen testing platforms that mimic methodology used in human clinical attention assessment. This systematic review was conducted to assess how translatable these rodent tasks are to equivalent clinical human tasks. Studies using the rodent Continuous Performance Task (rCPT), Sustained Attention Task (SAT), and 5-choice CPT (5C-CPT) were sought and screened. Included in the review were 138 studies, using the rCPT (n = 21), SAT (n = 90), and 5C-CPT (n = 27). Translatability between rodent and human studies was assessed based on (1) methodological similarity, (2) performance similarity, and (3) replication of results. The 5C-CPT was found to be the most translatable cross-species paradigm with good utility, while the rCPT and SAT require adaptation and further development to meet these translatability benchmarks. With greater replication and more consistent results, greater confidence in the translation of sustained attention results between species will be engendered.

Daily arousal variation has little effect on sustained attention performance.

Sustaining attention is an important cognitive process for everyday functioning and arousal is thought to underpin its performance. Primate studies depict an inverted-u relation between sustained attention and arousal, in which sustained attention performance is most affected at the extreme levels of arousal and peak performance aligns with moderate arousal. Human research findings are, however, inconsistent. This study aimed to investigate the effects of arousal on sustained attention performance in humans using two approaches-a small-N study with an inbuilt replication to test within-participant variation, and a larger sample assessing between-participant variation. The Sustained Attention to Response Task (SART) was used to measure sustained attention performance and the Karolinska Sleepiness Scale (KSS) was used to measure arousal. In the small-N study five participants completed the SART and KSS once an hour between 7 a.m. and 7 p.m., repeated two weeks later. Significant, curvilinear variation in KSS across time-of-day was found. A linear association between SART response time variability (sigma) and KSS was noted, however no other consistent associations between the SART and KSS were found. In the large-N study, 161 participants completed the SART and KSS once, at a time of day of their choosing. There were no significant relations between SART measures and the KSS, indicating that subjective sleepiness was not related to sustained attention performance. Overall, the hypothesized inverted-u relation between arousal and sustained attention performance was not found. The results suggested that diurnal arousal variation does not modify sustained attention performance in adults.

Longitudinal maturation of resting state networks: Relevance to sustained attention and attention deficit/hyperactivity disorder.

The transition from childhood to adolescence involves important neural function, cognition, and behavior changes. However, the links between maturing brain function and sustained attention over this period could be better understood. This study examined typical changes in network functional connectivity over childhood to adolescence, developmental differences in attention deficit/hyperactivity disorder (ADHD), and how functional connectivity might underpin variability in sustained attention development in a longitudinal sample. A total of 398 resting state scans were collected from 173 children and adolescents (88 ADHD, 85 control) at up to three timepoints across ages 9-14 years. The effects of age, sex, and diagnostic group on changes in network functional connectivity were assessed, followed by relationships between functional connectivity and sustained attention development using linear mixed effects modelling. The ADHD group displayed greater decreases in functional connectivity between salience and visual networks compared with controls. Lower childhood functional connectivity between the frontoparietal and several brain networks was associated with more rapid sustained attention development, whereas frontoparietal to dorsal attention network connectivity related to attention trajectories in children with ADHD alone. Brain network segregation may increase into adolescence as predicted by key developmental theories; however, participants with ADHD demonstrated altered developmental trajectories between salience and visual networks. The segregation of the frontoparietal network from other brain networks may be a mechanism supporting sustained attention development. Frontoparietal to dorsal attention connectivity can be a focus for further work in ADHD.

Towards understanding neurocognitive mechanisms of parenting: Maternal behaviors and structural brain network organization in late childhood.

A substantial body of knowledge suggests that exposure to adverse family environments - including violence and neglect - influences many aspects of brain development. Relatively less attention has been directed toward the influence of "normative" differences in parenting behaviors. Given the rapid brain reorganization during late childhood, parenting behaviors are particularly likely to impact the structure of the brain during this time. This study investigated associations between maternal parenting behaviors and the organization of structural brain networks in late childhood, as measured by structural covariance. One hundred and forty-five typically developing 8-year-olds and their mothers completed questionnaire measures and two observed interaction tasks; magnetic resonance imaging (MRI) scans were obtained from the children. Measures of maternal negative, positive, and communicative behavior were derived from the interaction tasks. Structural covariance networks based on partial correlations between cortical thickness estimates were constructed and estimates of modularity were obtained using graph theoretical analysis. High levels of negative maternal behavior were associated with low modularity. Minimal support was found for an association between positive maternal behaviors and modularity and between maternal communicative behaviors and modularity. Our findings suggest that variation in negative maternal behavior is associated with the structural organization of brain networks in children.

Human Colon Organoids and Other Laboratory Strategies to Enhance Patient Treatment Selection.

OPINION STATEMENT: Though many advancements in personalized medicine have been made, better methods are still needed to predict treatment benefit for patients with colorectal cancer. Patient-derived cancer organoids (PDCOs) are a major advance towards true personalization of treatment strategies. A growing body of literature is demonstrating the feasibility of PDCOs as an accurate and high-throughput preclinical tool for patient treatment selection. Many studies demonstrate that these cultures are readily generated and represent the tumors they were derived from phenotypically and based on their mutation profile. This includes maintenance of the driver muatations giving the cancer cells a selective growth advantage, and also heterogeneity, including molecular and metabolic heterogeneity. Additionally, PDCOs are now being utilized to develop patient biospecimen repositories, perform high to moderate-throughput drug screening, and to potentially predict treatment response for individual patients that are undergoing anti-cancer treatments. In order to develop PDCOs as a true clinical tool, further studies are required to determine the reproducibility and accuracy of these models to predict patient response.

Structural covariance networks in children and their associations with maternal behaviors.

There is a substantial body of research documenting the influence of early adverse experience on brain development. In contrast, relatively little attention has been directed toward the influence of 'normative' variation in parenting behaviors. This study investigated associations between parenting behaviors and structural brain networks, as measured by structural covariance, in a community sample of children. One hundred and forty-five typically developing 8-year-olds and their mothers completed questionnaire measures and two observed parent-child interaction tasks. Structural MRI scans were also obtained from the children. Structural covariance networks based on partial correlation between cortical thickness estimates were constructed, and estimates of efficiency were obtained using graph theoretical analysis. Associations between affective and communicative maternal behaviors and these network metrics were investigated. High levels of observed negative affective and communicative maternal behaviors were associated with decreased local efficiency, whereas high levels of positive affective maternal behaviors were associated with increased local efficiency. The regions implicated (including the cingulate cortex, temporal pole, and temporo-parietal junction) are thought to be involved in the processing of social information. Minimal support was found for an association between global efficiency and maternal behaviors. Our findings suggest that variations in parenting behaviors are associated with structural organization of socio-emotional brain networks in children.

A new look at the developmental profile of visual endogenous orienting.

There is a long-standing assumption that covert measurement of orienting, the shifting of the "mind's eye" independent of a saccade to a location in space, is a more "pure" measure of underlying attention than overt measurement of orienting. Testing attention covertly often relies on target detection tasks, which depend on making a decision about when and where a target has appeared and what is the appropriate action, all of which are potential confounds in measuring attention in children. This study cross-sectionally examined developmental profiles at ages 6-12  years of endogenous visual orienting. We used two tasks: one that measured orienting with a traditional covert attention button press response and one that measured orienting with eye tracking to measure overt saccades. The results obtained from the two orienting tasks demonstrate that each task measures distinct underlying processes with clear developmental profiles. Orienting, when measured by overt saccades, may be mature by 6 years of age, whereas the more complex manual response selection skills required in manual reaction time covert attention tasks continue to develop through middle childhood.

Measurement of cortisol, dehydroepiandrosterone, and testosterone in the hair of children: Preliminary results and promising indications.

Hormone analysis is a valuable tool for understanding how physiology and behavior interact. Cortisol in hair has recently been examined as a measure of longer-term hormone output. The aim of this study was to investigate the relationships between other androgens in hair and anthropometric measures. In a child sample (n = 114, mean age: 8.5 years, 66 females) levels of cortisol, dehydroepiandrosterone (DHEA) and testosterone were assayed in the 0-3 cm section proximal to scalp. The 3-6 cm segment within a subsample of female participants (n = 35) was examined and compared. Results showed that testosterone strongly correlated with DHEA, and moderately correlated with cortisol (0-3 cm only). Higher hormone concentrations were present in the 3-6 cm segment. Finally, there was a weak positive association between DHEA and height. The replication of previously identified associations between androgens, particularly testosterone-DHEA, and with developmental measures suggests hair may offer a valid method of hormone measurement for DHEA and testosterone.

Evidence of substantial development of inhibitory control and sustained attention between 6 and 8years of age on an unpredictable Go/No-Go task.

Inhibitory control and sustained attention are important cognitive abilities; however, their developmental trajectories remain unclear. In total, 35 6-year-olds, 32 8-year-olds, and 37 10-year-olds performed a Go/No-Go task; this required frequent responding to stimuli with infrequent inhibition to a target that appeared unpredictably. Children performed this task three times over 12months. Response time variability and accuracy measures, linked to inhibition and sustained attention, were assessed. Specifically, fast Fourier transform and ex-Gaussian analyses of response time data provided several measures of response time variability; these measures are thought to represent different components of sustained attention. The 6-year-olds performed less well than the older groups on most measures. The 8-year-olds exhibited greater momentary fluctuations in response time and made more long responses than the 10-year-olds; otherwise, there were few differences between the two older groups. Response inhibition and sustained attention developed significantly between 6 and 8years of age, with subtle changes in attentional control between 8 and 11years of age.

Response time variability under slow and fast-incentive conditions in children with ASD, ADHD and ASD+ADHD.

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) show significant behavioural and genetic overlap. Both ADHD and ASD are characterised by poor performance on a range of cognitive tasks. In particular, increased response time variability (RTV) is a promising indicator of risk for both ADHD and ASD. However, it is not clear whether different indices of RTV and changes to RTV according to task conditions are able to discriminate between the two disorders. METHODS: Children with ASD (n = 19), ADHD (n = 18), ASD + ADHD (n = 29) and typically developing controls (TDC; n = 26) performed a four-choice RT task with slow-baseline and fast-incentive conditions. Performance was characterised by mean RT (MRT), standard deviation of RT (SD-RT), coefficient of variation (CV) and ex-Gaussian distribution measures of Mu, Sigma and Tau. RESULTS: In the slow-baseline condition, categorical diagnoses and trait measures converged to indicate that children with ADHD-only and ASD + ADHD demonstrated increased MRT, SD-RT, CV and Tau compared to TDC and ASD-only. Importantly, greater improvement in MRT, SD-RT and Tau was demonstrated in ADHD and ASD + ADHD from slow-baseline to fast-incentive conditions compared to TDC and ASD-only. CONCLUSIONS: Slower and more variable RTs are markers of ADHD compared to ASD and typically developing controls during slow and less rewarding conditions. Energetic factors and rewards improve task performance to a greater extent in children with ADHD compared to children with ASD. These findings suggest that RTV can be distinguished in ASD, ADHD and ASD + ADHD based on the indices of variability used and the conditions in which they are elicited. Further work identifying neural processes underlying increased RTV is warranted, in order to elucidate disorder-specific and disorder-convergent aetiological pathways.

Social influences on eating and physical activity behaviours of urban, minority youths.

OBJECTIVE: Social relationships can impact youths' eating and physical activity behaviours; however, the best strategies for intervening in the social environment are unknown. The objectives of the present study were to provide in-depth information on the social roles that youths' parents and friends play related to eating and physical activity behaviours and to explore the impact of other social relationships on youths' eating and physical activity behaviours. DESIGN: Convergent parallel mixed-methods design. SETTING: Low-income, African American, food desert neighbourhoods in Baltimore City, MD, USA. SUBJECTS: Data were collected from 297 youths (53 % female, 91 % African American, mean age 12·3 (sd 1·5) years) using structured questionnaires and combined with in-depth interviews from thirty-eight youths (42 % female, 97 % African American, mean age 11·4 (sd 1·5) years) and ten parents (80 % female, 50 % single heads of house, 100 % African American). RESULTS: Combined interpretation of the results found that parents and caregivers have multiple, dynamic roles influencing youths' eating and physical activity behaviours, such as creating health-promoting rules, managing the home food environment and serving as a role model for physical activity. Other social relationships have specific, but limited roles. For example, friends served as partners for physical activity, aunts provided exposure to novel food experiences, and teachers and doctors provided information related to eating and physical activity. CONCLUSIONS: Obesity prevention programmes should consider minority youths' perceptions of social roles when designing interventions. Specifically, future research is needed to test the effectiveness of intervention strategies that enhance or expand the supportive roles played by social relationships.

Pragmatic language difficulties in children with hyperactivity and attention problems: an integrated review.

BACKGROUND: Diagnostic criteria for attention deficit hyperactivity disorder (ADHD) suggest a range of difficulties in the pragmatic aspects of language, including excessive talking and interrupting others. Such difficulties have been periodically reported over several decades in studies on the language abilities of children with features of ADHD, yet a comprehensive review of the literature has been lacking. AIMS: This review aims to integrate evidence from several lines of research from 1979 to the present on pragmatic language difficulties in children with ADHD or symptoms of ADHD. METHODS & PROCEDURES: A comprehensive search of empirical literature on pragmatic language in children with ADHD or symptoms of ADHD was conducted using PsycINFO and PubMed databases and through following up relevant references cited in articles. Literature was reviewed with respect to the nature and extent of pragmatic language difficulties in ADHD. OUTCOMES & RESULTS: Thirty studies met the review inclusion criteria, including recent questionnaire studies, observational studies of children's communication patterns, and studies of higher-level language comprehension and production. The studies indicate a consistent profile of pragmatic language impairments in children with features of ADHD, particularly in the areas of excessive talking, poor conversational turn-taking, and lack of coherence and organization in elicited speech. CONCLUSIONS & IMPLICATIONS: Pragmatic language difficulties are common in children with features of ADHD. These difficulties are consistent with deficits in executive function that are thought to characterize ADHD, thus providing some support for the theory that executive function contributes to pragmatic language competency. As yet there is very little empirical evidence of specific relationships between particular aspects of pragmatic language and particular domains of executive function. Given the importance of pragmatic language competency for children's social and academic functioning, pragmatic language abilities should be considered during clinical assessment for ADHD and targeted for intervention.

Quicker Exogenous Orienting and Slower Endogenous Orienting in Autistic People.

Research is equivocal on whether attention orienting is atypical in autism. This study investigated two types of attention orienting in autistic people and accounted for the potential confounders of alerting level, co-occurring symptoms of attention-deficit/hyperactivity disorder (ADHD) and anxiety, age, and sex. Twenty-seven autistic participants (14 males; 9-43 years) and 22 age- and sex-matched non-autistic participants (13 males; 9-42 years) completed the exogenous and endogenous Posner tasks. Response time and pupillometric data were recorded. Autistic participants were faster at orienting attention to valid cues in the exogenous task and slower at disengaging from invalid cues in the endogenous task compared to non-autistic participants. With increasing age, autistic participants showed faster exogenous and endogenous orienting, whereas non-autistic participants showed faster exogenous orienting but stable speed of endogenous orienting. Higher ADHD symptoms were associated with slower exogenous orienting in both groups, whereas higher anxiety symptoms were associated with faster exogenous orienting only in autistic participants. No group differences were noted for alerting levels, sex, or pupillary responses. This study provides new evidence of superior exogenous orienting and inefficient endogenous orienting in autistic people and suggests that age and co-occurring symptoms are important to consider when assessing attention orienting in autism.

Mice with an autism-associated R451C mutation in neuroligin-3 show intact attention orienting but atypical responses to methylphenidate and atomoxetine in the mouse-Posner task.

RATIONALE: Atypical attention orienting has been associated with some autistic symptoms, but the neural mechanisms remain unclear. The human Posner task, a classic attention orienting paradigm, was recently adapted for use with mice, supporting the investigation of the neurobiological underpinnings of atypical attention orienting in preclinical mouse models. OBJECTIVE: The current study tested mice expressing the autism-associated R451C gene mutation in neuroligin-3 (NL3) on the mouse-Posner (mPosner) task. METHODS: NL3R451C and wild-type (WT) mice were trained to respond to a validly or invalidly cued target on a touchscreen. The cue was a peripheral non-predictive flash in the exogenous task and a central spatially predictive image in the endogenous task. The effects of dopaminergic- and noradrenergic-modulating drugs, methylphenidate and atomoxetine, on task performance were assessed. RESULTS: In both tasks, mice were quicker and more accurate in the validly versus invalidly cued trials, consistent with results in the human Posner task. NL3R451C and WT mice showed similar response times and accuracy but responded differently when treated with methylphenidate and atomoxetine. Methylphenidate impaired exogenous attention disengagement in NL3R451C mice but did not significantly affect WT mice. Atomoxetine impaired endogenous orienting in WT mice but did not significantly affect NL3R451C mice. CONCLUSIONS: NL3R451C mice demonstrated intact attention orienting but altered responses to the pharmacological manipulation of the dopaminergic and noradrenergic networks. These findings expand our understanding of the NL3R451C mutation by suggesting that this mutation may lead to selective alterations in attentional processes.

Effects of iron supplementation on neural indices of habituation in Bangladeshi children.

BACKGROUND: Iron deficiency and anemia have been associated with poor cognition in children, yet the effects of iron supplementation on neurocognition remain unclear. OBJECTIVE: We aimed to examine the effects of supplementation with iron on neural indices of habituation using auditory event-related brain potentials (ERPs). METHODS: This substudy was nested within a 3-arm, double-blind, double-dummy, individual randomized trial in Bangladesh, in which 3300 8-mo-old children were randomly selected to receive 3 mo of daily iron syrup (12.5 mg iron), multiple micronutrient powders (MNPs) (including 12.5 mg iron), or placebo. Children were assessed after 3 mo of intervention (mo 3) and 9 mo thereafter (mo 12). The neurocognitive substudy comprised a randomly selected subset of children from the main trial. Brain activity elicited during an auditory roving oddball task was recorded using electroencephalography to provide an index of habituation. The differential response to a novel (deviant) compared with a repeated (standard) sound was examined. The primary outcome was the amplitude of the mismatch response (deviant minusstandard tone waveforms) at mo 3. Secondary outcomes included the deviant and standard tone-evoked amplitudes, N2 amplitude differences, and differences in mean amplitudes evoked by deviant tones presented in the second compared with first half of the oddball sequence at mo 3 and 12. RESULTS: Data were analyzed from 329 children at month 3 and 363 at mo 12. Analyses indicated no treatment effects of iron interventions compared with placebo on the amplitude of the mismatch response (iron syrup compared with placebo: mean difference (MD) = 0.07µV [95% CI: -1.22, 1.37]; MNPs compared with placebo: MD = 0.58µV [95% CI: -0.74, 1.90]) nor any secondary ERP outcomes at mo 3 or 12, despite improvements in hemoglobin and ferritin concentrations from iron syrup and MNPs in this nested substudy. CONCLUSION: In Bangladeshi children with >40% anemia prevalence, iron or MNP interventions alone are insufficient to improve neural indices of habituation. This trial was registered at the Australian New Zealand Clinical Trials Registry as ACTRN12617000660381.

Memory Complaints in Healthy Middle-Aged Adults Are Not Associated with Memory or Sustained Attention Performance.

OBJECTIVE: To examine the associations between the number and type of memory complaints with memory and sustained attention performance in healthy middle-aged adults. METHOD: Sixty-six healthy individuals aged 35-64 years (Mage = 47.73 years) were administered the seven Questions, Rey Auditory Verbal Learning Test, Sustained Attention to Response Task, and Depression Anxiety Stress Scales 21. RESULTS: The number of memory complaints was not associated with memory or sustained attention performance but was associated with anxiety symptoms. The type of memory complaint was likewise not associated with memory or sustained attention performance. The complaints "recent change in ability to remember things" and "trouble remembering things from one second to the next" were associated with anxiety symptoms. CONCLUSION: Complaints about memory in otherwise healthy middle-aged adults do not reliably indicate memory or sustained attention performance. Rather, these complaints are more likely to be associated with heightened, but nevertheless subclinical, anxiety.

Mice with an autism-associated R451C mutation in neuroligin-3 show a cautious but accurate response style in touchscreen attention tasks.

One of the earliest identifiable features of autism spectrum disorder (ASD) is altered attention. Mice expressing the ASD-associated R451C mutation in synaptic adhesion protein neuroligin-3 (NL3) exhibit impaired reciprocal social interactions and repetitive and restrictive behaviours. The role of this mutation in attentional abnormalities has not been established. We assessed attention in male NL3R451C mice using two well-established tasks in touchscreen chambers. In the 5-choice serial reaction task, rodents were trained to attend to light stimuli that appear in any one of five locations. While no differences between NL3R451C and WT mice were seen in accuracy or omissions, slower response times and quicker reward collection latencies were seen across all training and probe trials. In the rodent continuous-performance test, animals were required to discriminate, and identify a visual target pattern over multiple distractor stimuli. NL3R451C mice displayed enhanced ability to attend to stimuli when task-load was low during training and baseline but lost this advantage when difficulty was increased by altering task parameters in probe trials. NL3R451C mice made less responses to the distractor stimuli, exhibiting lower false alarm rates during all training stages and in probe trials. Slower response times and quicker reward latencies were consistently seen in NL3R451C mice in the rCPT. Slower response times are a major cognitive phenotype reported in ASD patients and are indicative of slower processing speed. Enhanced attention has been shown in a subset of ASD patients and we have demonstrated this phenotype also exists in the NL3R451C mouse model.

Maternal warmth is associated with network segregation across late childhood: A longitudinal neuroimaging study.

The negative impact of adverse experiences in childhood on neurodevelopment is well documented. Less attention however has been given to the impact of variations in "normative" parenting behaviors. The influence of these parenting behaviors is likely to be marked during periods of rapid brain reorganization, such as late childhood. The aim of the current study was to investigate associations between normative parenting behaviors and the development of structural brain networks across late childhood. Data were collected from a longitudinal sample of 114 mother-child dyads (54% female children, M age 8.41 years, SD = 0.32 years), recruited from low socioeconomic areas of Melbourne, Australia. At the first assessment parenting behaviors were coded from two lab-based interaction tasks and structural magnetic resonance imaging (MRI) scans of the children were performed. At the second assessment, approximately 18 months later (M age 9.97 years, SD = 0.37 years) MRI scans were repeated. Cortical thickness (CT) was extracted from T1-weighted images using FreeSurfer. Structural covariance (SC) networks were constructed from partial correlations of CT estimates between brain regions and estimates of network efficiency and modularity were obtained for each time point. The change in these network measures, from Time 1 to Time 2, was also calculated. At Time 2, less positive maternal affective behavior was associated with higher modularity (more segregated networks), while negative maternal affective behavior was not related. No support was found for an association between local or global efficacy and maternal affective behaviors at Time 2. Similarly, no support was demonstrated for associations between maternal affective behaviors and change in network efficiency and modularity, from Time 1 to Time 2. These results indicate that normative variations in parenting may influence the development of structural brain networks in late childhood and extend current knowledge about environmental influences on structural connectivity in a developmental context.

Which Measures From a Sustained Attention Task Best Predict ADHD Group Membership?

Difficulty with sustaining attention to a task is a hallmark of ADHD. It would be useful to know which measures of sustained attention best predict a diagnosis of ADHD. Participants were 129 children with a diagnosis of ADHD and 129 matched controls who completed the fixed Sustained Attention to Response Task (SART). The number of commission and omission errors, standard deviation of response time (SDRT), tau, fast and slow frequency variability, d-prime, and mu were able to successfully classify children with and without ADHD. The mean response time, criterion, and sigma were not able to classify participants. The best classifiers were d-prime (0.75 Area Under the Receiver Operated Characteristic), tau (.74), SDRT (0.74), omission errors (0.72), commission errors (0.71), and SFAUS (0.70). This list of the best classifier measures derived from the SART may prove useful for the planning of future studies.