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.

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.

The attention system of the human brain: 20 years after.

Here, we update our 1990 Annual Review of Neuroscience article, "The Attention System of the Human Brain." The framework presented in the original article has helped to integrate behavioral, systems, cellular, and molecular approaches to common problems in attention research. Our framework has been both elaborated and expanded in subsequent years. Research on orienting and executive functions has supported the addition of new networks of brain regions. Developmental studies have shown important changes in control systems between infancy and childhood. In some cases, evidence has supported the role of specific genetic variations, often in conjunction with experience, that account for some of the individual differences in the efficiency of attentional networks. The findings have led to increased understanding of aspects of pathology and to some new interventions.

The neuroscience of mindfulness meditation.

Research over the past two decades broadly supports the claim that mindfulness meditation - practiced widely for the reduction of stress and promotion of health - exerts beneficial effects on physical and mental health, and cognitive performance. Recent neuroimaging studies have begun to uncover the brain areas and networks that mediate these positive effects. However, the underlying neural mechanisms remain unclear, and it is apparent that more methodologically rigorous studies are required if we are to gain a full understanding of the neuronal and molecular bases of the changes in the brain that accompany mindfulness meditation.

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.

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.

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.

Brief meditation training induces smoking reduction.

More than 5 million deaths a year are attributable to tobacco smoking, but attempts to help people either quit or reduce their smoking often fail, perhaps in part because the intention to quit activates brain networks related to craving. We recruited participants interested in general stress reduction and randomly assigned them to meditation training or a relaxation training control. Among smokers, 2 wk of meditation training (5 h in total) produced a significant reduction in smoking of 60%; no reduction was found in the relaxation control. Resting-state brain scans showed increased activity for the meditation group in the anterior cingulate and prefrontal cortex, brain areas related to self-control. These results suggest that brief meditation training improves self-control capacity and reduces smoking.

Oscar Marin and the Creation of a Cognitive Neuropsychology Laboratory.

During the 1980s, the Cognitive Neuropsychology Laboratory at Good Samaritan Hospital, Portland, Oregon, made important strides in the study of brain injury. Created and headed by Oscar Marin and the author, in affiliation with the University of Oregon, the lab brought together students, fellows, and visiting experts in neurology, psychology, psychiatry, neuropsychology, neurobiology, neurophysiology, and computation. Their patient-focused collaborations produced groundbreaking research in language and its disorders, bradyphrenia, neglect, cerebellar function and impairment, and the psychology of music. The lab hosted the meeting that they documented in the influential 1985 book Attention and Performance XI: Mechanisms of Attention. The lab's members have gone on to lead distinguished careers and continue making major contributions to cognitive neuroscience.

Mechanisms of white matter changes induced by meditation.

Using diffusion tensor imaging, several recent studies have shown that training results in changes in white matter efficiency as measured by fractional anisotropy (FA). In our work, we found that a form of mindfulness meditation, integrative body-mind training (IBMT), improved FA in areas surrounding the anterior cingulate cortex after 4-wk training more than controls given relaxation training. Reductions in radial diffusivity (RD) have been interpreted as improved myelin but reductions in axial diffusivity (AD) involve other mechanisms, such as axonal density. We now report that after 4-wk training with IBMT, both RD and AD decrease accompanied by increased FA, indicating improved efficiency of white matter involves increased myelin as well as other axonal changes. However, 2-wk IBMT reduced AD, but not RD or FA, and improved moods. Our results demonstrate the time-course of white matter neuroplasticity in short-term meditation. This dynamic pattern of white matter change involving the anterior cingulate cortex, a part of the brain network related to self-regulation, could provide a means for intervention to improve or prevent mental disorders.

Improving creativity performance by short-term meditation.

BACKGROUND: One form of meditation intervention, the integrative body-mind training (IBMT) has been shown to improve attention, reduce stress and change self-reports of mood. In this paper we examine whether short-term IBMT can improve performance related to creativity and determine the role that mood may play in such improvement. METHODS: Forty Chinese undergraduates were randomly assigned to short-term IBMT group or a relaxation training (RT) control group. Mood and creativity performance were assessed by the Positive and Negative Affect Schedule (PANAS) and Torrance Tests of Creative Thinking (TTCT) questionnaire respectively. RESULTS: As predicted, the results indicated that short-term (30 min per day for 7 days) IBMT improved creativity performance on the divergent thinking task, and yielded better emotional regulation than RT. In addition, cross-lagged analysis indicated that both positive and negative affect may influence creativity in IBMT group (not RT group). CONCLUSIONS: Our results suggested that emotion-related creativity-promoting mechanism may be attributed to short-term meditation.

Short-term meditation induces changes in brain resting EEG theta networks.

Many studies have reported meditation training has beneficial effects on brain structure and function. However, very little is known about meditation-induced changes in brain complex networks. We used network analysis of electroencephalography theta activity data at rest before and after 1-week of integrative body-mind training (IBMT) and relaxation training. The results demonstrated the IBMT group (but not the relaxation group) exhibited significantly smaller average path length and larger clustering coefficient of the entire network and two midline electrode nodes (Fz and Pz) after training, indicating enhanced capacity of local specialization and global information integration in the brain. The findings provide the evidence for meditation-induced network plasticity and suggest that IBMT might be helpful for alterations in brain networks.

Short term integrative meditation improves resting alpha activity and stroop performance.

Our previous research showed that short term meditation training reduces the time to resolve conflict in the flanker task. Studies also show that resting alpha increases with long term meditation practice. The aim of this study is to determine whether short term meditation training both increases resting alpha activity and reduces the time to resolve conflict in the Stroop task and whether these two effects are related. Forty-three Chinese undergraduates were randomly assigned an experiment group given 5 days meditation training using integrative body-mind training (IBMT) and a relaxation training control. After training, only the IBMT group showed decreased conflict reaction time (RT), and increased resting mean alpha power. Moreover, the higher the enhancement of resting alpha power, the stronger the improvement of conflict RT. The results indicate that short term meditation diffusely enhances alpha and improves the ability to deal with conflict and moreover these two effects are positively related.

Short-term meditation induces white matter changes in the anterior cingulate.

The anterior cingulate cortex (ACC) is part of a network implicated in the development of self-regulation and whose connectivity changes dramatically in development. In previous studies we showed that 3 h of mental training, based on traditional Chinese medicine (integrative body-mind training, IBMT), increases ACC activity and improves self-regulation. However, it is not known whether changes in white matter connectivity can result from small amounts of mental training. We here report that 11 h of IBMT increases fractional anisotropy (FA), an index indicating the integrity and efficiency of white matter in the corona radiata, an important white-matter tract connecting the ACC to other structures. Thus IBMT could provide a means for improving self-regulation and perhaps reducing or preventing various mental disorders.

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.

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.

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.

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.