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.

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.

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.

Using item response theory to evaluate the Children's Behavior Questionnaire: Considerations of general functioning and assessment length.

Although the Children's Behavior Questionnaire (CBQ; Rothbart, Ahadi, Hershey, & Fisher, 2001) is the most popular assessment for childhood temperament, its psychometric qualities have yet to be examined using Item Response Theory (IRT) methods. These methods highlight in detail the specific contributions of individual items for measuring different facets of temperament. Importantly, with 16 scales for tapping distinct aspects of child functioning (195 items total), the CBQ's length can be prohibitive in many contexts. The detailed information about item functioning provided by IRT methods is therefore especially useful. The current study used IRT methods to analyze the CBQ's 16 temperament scales and identify potentially redundant items. An abbreviated "IRT form" was generated based on these results and evaluated across four independent validation samples. The IRT form was compared to the original and short CBQ forms (Putnam & Rothbart, 2006). Results provide fine-grained detail on the CBQ's psychometric functioning and suggest it is possible to remove up to 39% of the original form's items while largely preserving the measurement precision and content coverage of each scale. This study provides considerable psychometric information about the CBQ's items and scales and highlights future avenues for creating even more efficient high-quality temperament assessments. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

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.

Methylation polymorphism influences practice effects in children during attention tasks.

Epigenetic mechanisms mediate the influence of experience on gene expression. Methylation is a principal method for inducing epigenetic effects on DNA. In this paper, we examine alleles of the methylenetetrahydrofolate reductase (MTHFR) gene that vary enzyme activity, altering the availability of the methyl donor and thus changing the efficiency of methylation. We hypothesized that alleles of the MTHFR gene would influence behavior in an attention-related task in conjunction with genes known to influence attention. We found that seven-year-old children homozygous for the C allele of MTHFR in interaction with the catechol O-methyltransferase (COMT) gene showed greater improvement in overall reaction time (RT) and in conflict resolution with practice on the Attention Network Test (ANT). This finding indicates that methylation may operate on or through genes that influence executive network operation. However, MTHFR T allele carriers showed faster overall RT and conflict resolution. Some children showed an initial improvement in ANT RT followed by a decline in performance, and we found that alleles of the dopamine beta-hydroxylase (DBH) gene were related to this performance decline. These results suggest a genetic dissociation between improvement while learning a skill and reduction in performance with continued practice.

White matter and reaction time: Reply to commentaries.

We appreciate the many comments we received on our discussion paper and believe that they reflect a recognition of the importance of this topic worldwide. We point out in this reply that there appears to be a confusion between the role of oscillations in creating white matter and other functions of oscillations in communicating between neural areas during task performance or at rest. We also discuss some mechanisms other than the enhancement of white matter that must influence reaction time. We recognize the limited understanding we have of transfer and outline some future directions designed to improve our understanding of this process.

How changes in white matter might underlie improved reaction time due to practice.

Why does training on a task reduce the reaction time for performing it? New research points to changes in white matter pathways as one likely mechanism. These pathways connect remote brain areas involved in performing the task. Genetic variations may be involved in individual differences in the extent of this improvement. If white matter change is involved in improved reaction time with training, it may point the way toward understanding where and how generalization occurs. We examine the hypothesis that brain pathways shared by different tasks may result in improved performance of cognitive tasks remote from the training.

Developing brain networks of attention.

PURPOSE OF REVIEW: Attention is a primary cognitive function critical for perception, language, and memory. We provide an update on brain networks related to attention, their development, training, and pathologies. RECENT FINDINGS: An executive attention network, also called the cingulo-opercular network, allows voluntary control of behavior in accordance with goals. Individual differences among children in self-regulation have been measured by a higher order factor called effortful control, which is related to the executive network and to the size of the anterior cingulate cortex. SUMMARY: Brain networks of attention arise in infancy and are related to individual differences, including pathology during childhood. Methods of training attention may improve performance and ameliorate pathology.

Circuitry of self-control and its role in reducing addiction.

We discuss the idea that addictions can be treated by changing the mechanisms involved in self-control with or without regard to intention. The core clinical symptoms of addiction include an enhanced incentive for drug taking (craving), impaired self-control (impulsivity and compulsivity), negative mood, and increased stress re-activity. Symptoms related to impaired self-control involve reduced activity in control networks including anterior cingulate (ACC), adjacent prefrontal cortex (mPFC), and striatum. Behavioral training such as mindfulness meditation can increase the function of control networks and may be a promising approach for the treatment of addiction, even among those without intention to quit.