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.

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.

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.

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.

Restoring Attention Networks.

The attention networks of the human brain have been under intensive study for more than twenty years and deficits of attention accompany many neurological and psychiatric conditions. There is more dispute about the centrality of attention deficits to these conditions. It appears to be time to study whether reducing deficits of attention alleviate the neurological or psychiatric disorder as a whole. In this paper we review human and animal research indicating the possibility of improving the function of brain networks underlying attention and their potential clinical role.

Changes in white matter in mice resulting from low-frequency brain stimulation.

Recent reports have begun to elucidate mechanisms by which learning and experience produce white matter changes in the brain. We previously reported changes in white matter surrounding the anterior cingulate cortex in humans after 2-4 weeks of meditation training. We further found that low-frequency optogenetic stimulation of the anterior cingulate in mice increased time spent in the light in a light/dark box paradigm, suggesting decreased anxiety similar to what is observed following meditation training. Here, we investigated the impact of this stimulation at the cellular level. We found that laser stimulation in the range of 1-8 Hz results in changes to subcortical white matter projection fibers in the corpus callosum. Specifically, stimulation resulted in increased oligodendrocyte proliferation, accompanied by a decrease in the g-ratio within the corpus callosum underlying the anterior cingulate cortex. These results suggest that low-frequency stimulation can result in activity-dependent remodeling of myelin, giving rise to enhanced connectivity and altered behavior.

Diversity in action: exchange of perspectives and reflections on taxonomies of individual differences.

Throughout the last 2500 years, the classification of individual differences in healthy people and their extreme expressions in mental disorders has remained one of the most difficult challenges in science that affects our ability to explore individuals' functioning, underlying psychobiological processes and pathways of development. To facilitate analyses of the principles required for studying individual differences, this theme issue brought together prominent scholars from diverse backgrounds of which many bring unique combinations of cross-disciplinary experiences and perspectives that help establish connections and promote exchange across disciplines. This final paper presents brief commentaries of some of our authors and further scholars exchanging perspectives and reflecting on the contributions of this theme issue.This article is part of the theme issue 'Diverse perspectives on diversity: multi-disciplinary approaches to taxonomies of individual differences'.

Temperament and brain networks of attention.

The attention networks of the human brain are important control systems that develop from infancy into adulthood. While they are common to everyone, they differ in efficiency, forming the basis of individual differences in attention. We have developed methods for measuring the efficiency of these networks in older children and adults and have also examined their development from infancy. During infancy the alerting and orienting networks are dominant in control of the infant's actions, but later an executive network dominates. Each network has been associated with its main neuromodulator and these have led to associations with genes related to that network neuromodulator. The links between parent reports of their child's effortful control and the executive attention network allow us to associate molecular mechanisms to fundamental behavioural outcomes.This article is part of the theme issue 'Diverse perspectives on diversity: multi-disciplinary approaches to taxonomies of individual differences'.

Rhythmic brain stimulation reduces anxiety-related behavior in a mouse model based on meditation training.

Meditation training induces changes at both the behavioral and neural levels. A month of meditation training can reduce self-reported anxiety and other dimensions of negative affect. It also can change white matter as measured by diffusion tensor imaging and increase resting-state midline frontal theta activity. The current study tests the hypothesis that imposing rhythms in the mouse anterior cingulate cortex (ACC), by using optogenetics to induce oscillations in activity, can produce behavioral changes. Mice were randomly assigned to groups and were given twenty 30-min sessions of light pulses delivered at 1, 8, or 40 Hz over 4 wk or were assigned to a no-laser control condition. Before and after the month all mice were administered a battery of behavioral tests. In the light/dark box, mice receiving cortical stimulation had more light-side entries, spent more time in the light, and made more vertical rears than mice receiving rhythmic cortical suppression or no manipulation. These effects on light/dark box exploratory behaviors are associated with reduced anxiety and were most pronounced following stimulation at 1 and 8 Hz. No effects were seen related to basic motor behavior or exploration during tests of novel object and location recognition. These data support a relationship between lower-frequency oscillations in the mouse ACC and the expression of anxiety-related behaviors, potentially analogous to effects seen with human practitioners of some forms of meditation.