Molecular Mechanisms for Changing Brain Connectivity in Mice and Humans.

The goal of this study was to examine commonalities in the molecular basis of learning in mice and humans. In previous work we have demonstrated that the anterior cingulate cortex (ACC) and hippocampus (HC) are involved in learning a two-choice visuospatial discrimination task. Here, we began by looking for candidate genes upregulated in mouse ACC and HC with learning. We then determined which of these were also upregulated in mouse blood. Finally, we used RT-PCR to compare candidate gene expression in mouse blood with that from humans following one of two forms of learning: a working memory task (network training) or meditation (a generalized training shown to change many networks). Two genes were upregulated in mice following learning: caspase recruitment domain-containing protein 6 (Card6) and inosine monophosphate dehydrogenase 2 (Impdh2). The Impdh2 gene product catalyzes the first committed step of guanine nucleotide synthesis and is tightly linked to cell proliferation. The Card6 gene product positively modulates signal transduction. In humans, Card6 was significantly upregulated, and Impdh2 trended toward upregulation with training. These genes have been shown to regulate pathways that influence nuclear factor kappa B (NF-κB), a factor previously found to be related to enhanced synaptic function and learning.

Essential team science skills for biostatisticians on collaborative research teams.

Introduction: Despite the critical role that quantitative scientists play in biomedical research, graduate programs in quantitative fields often focus on technical and methodological skills, not on collaborative and leadership skills. In this study, we evaluate the importance of team science skills among collaborative biostatisticians for the purpose of identifying training opportunities to build a skilled workforce of quantitative team scientists. Methods: Our workgroup described 16 essential skills for collaborative biostatisticians. Collaborative biostatisticians were surveyed to assess the relative importance of these skills in their current work. The importance of each skill is summarized overall and compared across career stages, highest degrees earned, and job sectors. Results: Survey respondents were 343 collaborative biostatisticians spanning career stages (early: 24.2%, mid: 33.8%, late: 42.0%) and job sectors (academia: 69.4%, industry: 22.2%, government: 4.4%, self-employed: 4.1%). All 16 skills were rated as at least somewhat important by > 89.0% of respondents. Significant heterogeneity in importance by career stage and by highest degree earned was identified for several skills. Two skills ("regulatory requirements" and "databases, data sources, and data collection tools") were more likely to be rated as absolutely essential by those working in industry (36.5%, 65.8%, respectively) than by those in academia (19.6%, 51.3%, respectively). Three additional skills were identified as important by survey respondents, for a total of 19 collaborative skills. Conclusions: We identified 19 team science skills that are important to the work of collaborative biostatisticians, laying the groundwork for enhancing graduate programs and establishing effective on-the-job training initiatives to meet workforce needs.

How understanding and strengthening brain networks can contribute to elementary education.

Imaging the human brain during the last 35 years offers potential for improving education. What is needed is knowledge on the part of educators of all types of how this potential can be realized in practical terms. This paper briefly reviews the current level of understanding of brain networks that underlie aspects of elementary education and its preparation for later learning. This includes the acquisition of reading, writing and number processing, improving attention and increasing the motivation to learn. This knowledge can enhance assessment devices, improve child behavior and motivation and lead to immediate and lasting improvements in educational systems.

The Evolution and Future Development of Attention Networks.

The goal of this paper is to examine how the development of attention networks has left many important issues unsolved and to propose possible directions for solving them by combining human and animal studies. The paper starts with evidence from citation mapping that indicates attention has played a central role in integrating cognitive and neural studies into Cognitive Neuroscience. The integration of the fields depends in part upon similarities and differences in performance over a wide variety of animals. In the case of exogenous orienting of attention primates, rodents and humans are quite similar, but this is not so with executive control. In humans, attention networks continue to develop at different rates during infancy and childhood and into adulthood. From age four on, the Attention Network Test (ANT) allows measurement of individual differences in the alerting, orienting and executive networks. Overt and covert orienting do overlap in their anatomy, but there is evidence of some degree of functional independence at the cellular level. The attention networks frequently work together with sensory, memory and other networks. Integration of animal and human studies may be advanced by examining common genes involved in individual attention networks or their integration with other brain networks. Attention networks involve widely scattered computation nodes in different brain areas, both cortical and subcortical. Future studies need to attend to the white matter that connects them and the direction of information flow during task performance.

Fifty years integrating neurobiology and psychology to study attention.

At the time of the start of Biological Psychology cognitive studies had developed approaches to measuring cognitive processes. However, linking these to the underlying biology in the typical human brain had hardly begun. A critical step came in 1988 when methods for imaging the human brain in cognitive tasks began. By 1990 it was possible to describe three brain networks that carried out the hypothesized cognitive functions outlined 20 years before. Their development was traced in infancy, first using age-appropriate tasks and later through resting state imaging. Imaging was applied to both voluntary and involuntary cued shifts of visual orienting in humans and primates, and a summary was presented in 2002. By 2008 these new imaging findings were used to test hypotheses about the genes involved in each network. Recently, studies of mice using optogenetics to control populations of neurons have brought us closer to a synthesis of how attention and memory networks operate together in human learning. Perhaps the coming years will bring us to an integrated theory of aspects of attention using data from all the levels that can illuminate these issues, thus fulfilling a key goal of the Journal.

Beyond Infant's Looking: The Neural Basis for Infant Prediction Errors.

Contemporary conceptualizations on infant cognitive development focus on predictive processes; the basic idea is that the brain continuously creates predictions about what is expected and that the divergence between predicted and actual perceived data yields a prediction error. This prediction error updates the model from which the predictions are generated and therefore is a basic mechanism for learning and adaptation to the dynamics of the ever-changing environment. In this article, we review the types of available empirical evidence supporting the idea that predictive processes can be found in infancy, especially emphasizing the contribution of electrophysiology as a potential method for testing the similarity of the brain mechanisms for processing prediction errors in infants to those of adults. In infants, as with older children, adolescents, and adults, predictions involve synchronization bursts of middle-central theta reflecting brain activity in the anterior cingulate cortex. We discuss how early in development such brain mechanisms develop and open questions that still remain to be empirically investigated.

Physical, Mental, and General Health Outcomes Among Childhood Cancer Survivors From the Behavioral Risk Factor Surveillance System Survey.

OBJECTIVES: To examine the physical, mental, and general health among young adult childhood cancer survivors (CCS). SAMPLE & SETTING: This secondary analysis study used data from the Behavioral Risk Factor Surveillance System. The analytic sample included 697 young adult CCS (537 women; 160 men). METHODS & VARIABLES: Chi-square tests of independence were done to compare the rates across cancer survivorship groups on categorical variables. Logistic regression was performed to determine correlates with physical, mental, and general health. RESULTS: Female CCS had a significantly (p < 0.0001) greater number of "no days" in which they reported good physical, mental, and general health compared to male CCS. Female CCS were more likely to experience 30 days of poor physical health compared to male CCS (odds ratio [OR] = 1.8, p < 0.05) when controlling for education, race, and age. Depressed female CCS had higher odds of being in poor physical, mental, and general health (OR = 2.9, 7.6, and 2.6, respectively). IMPLICATIONS FOR NURSING: Findings support the need for continued screening, following published practice guidelines, among young adult female CCS for emotional distress with the use of well-established distress and psychosocial assessment measures.

The Relationship Between Student Voice and Student Engagement in Urban High Schools.

Drawing on student self-report survey data, this study examines student engagement across 67 urban high schools in the School District of Philadelphia. Results show that schools with higher rates of affective, behavioral, and cognitive engagement differ significantly from schools with other engagement profiles in students' average reports of teacher care and student voice. Path analyses lend support for self-determination theory and corroborate qualitative research that observes that student voice can improve student engagement. By highlighting the roles of teacher care and feelings of competence and belonging, this study identifies key means by which student voice influences student engagement. Supplementary Information: The online version contains supplementary material available at 10.1007/s11256-022-00637-2.

Effortless training of attention and self-control: mechanisms and applications.

For the past 50 years, cognitive scientists have assumed that training attention and self-control must be effortful. However, growing evidence suggests promising effects of effortless training approaches such as nature exposure, flow experience, and effortless practice on attention and self-control. This opinion article focuses on effortless training of attention and self-control. We begin by introducing our definitions of effortful and effortless training and reviewing the growing literature on these two different forms of training. We then discuss the similarities and differences in their respective behavioral outcomes and neural correlates. Finally, we propose a putative neural mechanism of effortless training. We conclude by highlighting promising directions for research, development, and application of effortless training.

Decision Making as a Learned Skill in Mice and Humans.

Attention is a necessary component in many forms of human and animal learning. Numerous studies have described how attention and memory interact when confronted with a choice point during skill learning. In both animal and human studies, pathways have been found that connect the executive and orienting networks of attention to the hippocampus. The anterior cingulate cortex, part of the executive attention network, is linked to the hippocampus via the nucleus reuniens of the thalamus. The parietal cortex, part of the orienting attention network, accesses the hippocampus via the entorhinal cortex. These studies have led to specific predictions concerning the functional role of each pathway in connecting the cortex to the hippocampus. Here, we review some of the predictions arising from these studies. We then discuss potential methods for manipulating the two pathways and assessing the directionality of their functional connection using viral expression techniques in mice. New studies may allow testing of a behavioral model specifying how the two pathways work together during skill learning.

Using Treatment Fidelity Measures to Understand Walking Recovery: A Secondary Analysis From the Community Ambulation Project.

OBJECTIVES: Physical therapist intervention studies can be deemed ineffective when, in fact, they may not have been delivered as intended. Measurement of treatment fidelity (TF) can address this issue. The purpose of this study was to describe TF of a home-based intervention, identify factors associated with TF, and examine whether components of TF were associated with the outcome of change in 6-minute walk distance (∆6MWD). METHODS: This is a secondary analysis of community-dwelling hip fracture participants who completed standard therapy and were randomly assigned to the active intervention (Push). Push was 16 weeks of lower extremity strengthening, function, and endurance training. TF was defined as delivery (attendance rate, exercise duration) and receipt (progression in training load, heart rate reserve [HRR] during endurance training, and exercise position [exercise on floor]). The outcome was ∆6MWD. Independent variables included baseline (demographic and clinical) measures. Descriptive statistics were calculated; linear and logistic regressions were performed. RESULTS: Eighty-nine participants were included in this analysis; 59 (66%) had attendance of 75% or greater. Participants walked for 20 minutes or more for 78% of sessions. The average training load increased by 22%; the mean HRR was 35%; and 61 (69%) participants exercised on the floor for at least 75% of sessions. Regression analyses showed that a higher body mass index and greater baseline 6MWD were related to components of TF; 4 out of 5 components of TF were significantly related to ∆6MWD. The strongest TF relationship showed that those who exercised on the floor improved by 62 m (95% CI = 31-93 m) more than those who did not get on the floor. CONCLUSIONS: Measures of TF should extend beyond attendance rate. This analysis demonstrates how measures of TF, including program attendance, progression in training load, endurance duration, and exercising on the floor were significantly related to improvement in 6MWD in participants post hip fracture. IMPACT: This careful analysis of treatment fidelity assured that the intervention was delivered and received as intended. Analysis of data from a large trial with participants after hip fracture showed that regular attendance, frequent endurance training for 20 minutes, increases in lower extremity training loads, and exercising on the floor were associated with improvements in the outcome of 6-minute-walk distance. The strongest association with improvement was exercising on the floor.

Increasing the amplitude of intrinsic theta in the human brain.

In a mouse study we found increased myelination of pathways surrounding the anterior cingulate cortex (ACC) following stimulation near the theta rhythm (4-8 Hz), and evidence that this change in connectivity reduced behavioral anxiety. We cannot use the optogenetic methods with humans that were used in our mouse studies. This paper examines whether it is possible to enhance intrinsic theta amplitudes in humans using less invasive methods. The first experiment compares electrical, auditory and biofeedback as methods for increasing intrinsic theta rhythm amplitudes in the Anterior Cingulate Cortex (ACC). These methods are used alone or in conjunction with a task designed to activate the same area. The results favor using electrical stimulation in conjunction with a task targeting this region. Stimulating the ACC increases intrinsic theta more in this area than in a control area distant from the site of stimulation, suggesting some degree of localization of the stimulation. In Experiment 2, we employed electrical stimulation with the electrodes common to each person, or with electrodes selected from an individual head model. We targeted the ACC or Motor Cortex (PMC). At baseline, intrinsic theta is higher in the ACC than the PMC. In both areas, theta can be increased in amplitude by electrical stimulation plus task. In the PMC, theta levels during stimulation plus task are not significantly higher than during task alone. There is no significant difference between generic and individual electrodes. We discuss steps needed to determine whether we can use the electrical stimulation + task to improve the connectivity of white matter in different brain areas.

Developing attention in typical children related to disabilities.

We define attention by three basic functions. The first is obtaining and maintaining the alert state. The second is orienting overtly or covertly to sensory stimuli. The third is selection among competing responses. These three functions correspond to three separable brain networks. Control of the alert state develops in infancy but continues to change till adulthood. During childhood, the orienting network provides a means of controlling affective responses, e.g., by looking away from negative events and toward positive or novel events. The executive network mediates between competing voluntary responses by resolving conflicts. Executive control improves rapidly over the first 7 years of life. Autistic spectrum disorders and attention deficit hyperactivity disorder are two disorders that have been shown to involve deficits in attention networks. We examine connections between developing attention networks and these disorders.

Rehabilitating the brain through meditation and electrical stimulation.

This paper is a review of our recent studies and ideas related to the neuropsychological issues that Robert Rafal and I worked together to understand attention and hopefully improve it in a variety of patients. Rehabilitation is also a goal of my current research to determine if non invasive stimuli can improve white matter in humans. We have found that fractional anisotropy (FA) is improved in pathways surrounding the anterior cingulate cortex (ACC) following two week to four weeks of meditation training. We hypothesized that the frontal theta increased following meditation training might be a cause of the improved connectivity. This was confirmed by a mouse study using optogenetics to impose theta rhythms in the ACC. We have evidence that electrical stimulation while performing a task that activates the ACC can also increase theta. We plan studies to determine whether two to four weeks of stimulation can improve FA in pathways surrounding the anterior cingulate.

Illuminating the Neural Circuits Underlying Orienting of Attention.

Human neuroimaging has revealed brain networks involving frontal and parietal cortical areas as well as subcortical areas, including the superior colliculus and pulvinar, which are involved in orienting to sensory stimuli. Because accumulating evidence points to similarities between both overt and covert orienting in humans and other animals, we propose that it is now feasible, using animal models, to move beyond these large-scale networks to address the local networks and cell types that mediate orienting of attention. In this opinion piece, we discuss optogenetic and related methods for testing the pathways involved, and obstacles to carrying out such tests in rodent and monkey populations.

Differential Involvement of Three Brain Regions during Mouse Skill Learning.

Human skill learning is marked by a gradual decrease in reaction time (RT) and errors as the skill is acquired. To better understand the influence of brain areas thought to be involved in skill learning, we trained mice to associate visual-spatial cues with specific motor behaviors for a water reward. Task acquisition occurred over weeks and performance approximated a power function as often found with human skill learning. Using optogenetics we suppressed the primary visual cortex (V1), anterior cingulate cortex (ACC), or dorsal hippocampus (dHC) on 20% of trials at different stages of learning. Intermittent suppression of the V1 greatly reduced task performance on suppressed trials across multiple stages but did not change the overall rate of learning. In accord with some recent models of skill learning, ACC suppression produced higher error rates on suppressed trials throughout learning the skill, with effects intensifying in the later stages. This would suggest that cognitive influences mediated by the anterior cingulate continue throughout learning. Suppression of the hippocampus only modestly affected performance, with largely similar effects seen across stages. These results indicate different degrees of V1, ACC, and dHC involvement in acquisition and performance of this visual-spatial task and that the structures operate in parallel, and not in series, across learning stages.

Frontal theta activity and white matter plasticity following mindfulness meditation.

Both brain alpha and theta power have been examined in the mindfulness meditation literature and suggested as key biological signatures that potentially facilitate a successful meditative state. However, the exact role of how alpha and theta waves contribute to the initiation and maintenance of a meditative state remains elusive. In this perspective paper, we discuss the role of frontal midline theta (FMθ) activity in brain white matter plasticity following mindfulness meditation. In accordance with the previous studies in humans, we propose that FMθ activity indexes the control needed to maintain the meditation state; whereas alpha activity is related to the preparation needed to achieve the meditative state. Without enough mental preparation, one often struggles with and has difficulty achieving a meditative state. Animal work provides further evidence supporting the hypothesis that mindfulness meditation induces white matter changes through increasing FMθ activity. These studies shed light on how to effectively enhance brain plasticity through mindfulness meditation.

Anxiety and Brain Networks of Attentional Control.

Advances in the study of brain networks can be applied to our understanding of anxiety disorders (eg, generalized anxiety, obsessive-compulsive, and posttraumatic stress disorders) to enable us to create targeted treatments. These disorders have in common an inability to control thoughts, emotions, and behaviors related to a perceived threat. Here we review animal and human imaging studies that have revealed separate brain networks related to various negative emotions. Research has supported the idea that brain networks of attention serve to control emotion networks as well as the thoughts and behaviors related to them. We discuss how attention networks can modulate both positive and negative affect. Disorders arise from both abnormal activation of negative affect and a lack of attentional control. Training attention has been one way to foster improved attentional control. We review attention training studies as well as efforts to generally improve attention networks through stimulation in self-regulation.