Mouse studies
Our mouse study of the effects of a month of stimulation of the anterior cingulate by optogenetics has moved forward over the summer. We have found clear changes in behavior due to increased spiking of output neurons in a 1 or 8 Hz rhythm. We have reported these findings at several meetings and our in the process of preparing a paper on them. The most recent oral report was the Huttenlocher lecture at the Sept. meeting of FLUX. This should soon appear on the Flux website and give a good picture of our current work.
We have also examined the underlying physiological changes due to stimulation. We have found that 1 Hz stimulation that increases the spiking of output neurons also yields an increase in oligodendrocytes. We are currently carrying on electron microscope (EM)studies that have the potential to show actual myelination and/or axonal density changes due to stimulation. Our paper will wait these finding. However, the change in oligodendrodtyes and the use of EM are discussed in the FLUX lecture.
We have examined brain tissue from the stimulated mice to determine whether any geneswere up-regulated. It turns out that many genes related to intercellular communication are up-regulated in the 8Hz condition. We plan to study this in more detail following our learning studies in mice.
We have begun to train mice in a discrimination learning paradigm. The mice can be trained and we will be using that to explore how learning influences their brain. Exploration of the stages of learning and how learning changes neural networks will be the focus of these studies over the coming several years.
Human Studies
In our previous post we have a paper on myelination and reaction time published in Cognitive Neuroscience. The paper received many comments and we have now provided additional information in our reply to comments below.
wm-and-rt-reply-july-11
Dr. Yiyuan Tang will conduct MRI studies of meditation and working memory learning at Texas Tech. One of the goals is to confirm the brain areas activated by the two methods of learning, a second is to see if the strength of the activation or of the white matter changes is correlated with improved RT following training. A third goal is to extract blood to determine if the same genes are up-regulated in humans as are found in mouse learning.
We have designed a new set of studies based on what we have found so far in the mice. These are summarized below:
Experiment 1 Choosing stimulation parameters
Our previous work has shown that humans given 20 hours of meditation training show improved efficiency of white matter in a number of tracts surrounding the Anterior Cingulate Cortex (ACC) as measured by Fractional Anisotropy (FA) in assays using Diffusion Tensor Imaging (Tang et al 2010, 2012).
We proposed (Posner, Tang & Lynch, 2014) that the white matter change might be a consequence of increased theta oscillations in the area of the ACC, changing precursor oligodendrocytes to an active form that might improve axonal density or myelination. To test this idea used mice who were treated so that neurons would be excited by laser light (optogenetics). We then exposed mice to a month of 1, 8 or 40 Hz stimulation for 20 .5 hour sessions. The laser stimulation of the ACC was compared to a no stimulation control group. We found a significant increase in active oligodendrocytes in the 1 Hz group, a small but insignificant increase in the 8 Hz group and a tendency toward a decrease in the 40 Hz group. In addition we found in behavioral tests following stimulation that the 8 Hz group spent significantly more time in the light when give a choice between light and dark areas than did the control, taken as a sign of reduced anxiety, and significantly more vertical rearing taken as a sign of exploration. The 1 Hz group showed the same tendency as the 8Hz group but the effects were smaller and non significant.
We now propose a human trial to determine (1) if low frequency stimulation intrinsic to the ACC can be produced non invasively in humans and (2) if this stimulation can be produced safely, will it increase the efficiency of white matter as measured by Fractional Anisotropy (FA) in DTI and improved functional connectivity. In order to determine if activating a brain network can increase the influence of stimulation, participants will either undergo stimulation at rest or when carrying out the Attention Network Test (ANT). We expect that performing the ANT will activate the ACC and thus increase the level of intrinsic oscillations in that brain area during stimulation.
Our first experiment compares the amplitude of low frequency neural oscillations in the area of the ACC induced by three different stimulation methods: (1) electrical stimulation from scalp electrodes (2) use of low frequency sensory stimulation in the form of amplitude modulated white noise or binaural beats and (3) biofeedback with instructions to relax and attempt to develop a state in which a visual display produces the highest level of relevant oscillatory activity (biofeedback). These three conditions will be compared to a control group who will practice the ANT (Attention network test) but will not undergo stimulation.
Each person will be run for one hour in one of the conditions. For half of the session they will carry out the ANT (Attention Network Task) while undergoing stimulation and for the other half they will undergo stimulation at rest. Analysis of variance will compare each experimental group with control subjects both with and without the ANT.
Experiment 2 Does internal stimulation change white matter?
All subjects will be run in 22 sessions over a one month period. The first and last session will involve MRI. During these sessions DTI and fMRI will be collected while
Performing the ANT and at rest. The 20 half hour long sessions will be devoted either to the selected stimulation method while performing the ANT or at rest (experimental) or reading a short story or performing the ANT (control). We will examine DTI and functional connectivity over the whole brain during the pre- and post-tests to determine differences between experimental and control group in improved efficiency of various white matter tracts. A similar analysis will be performed within each experimental subject between the condition when they are performing the ANT and those when they are not performing the ANT.
These comparisons will tell us whether stimulation can influence changes in white matter or functional connectivity and its specificity to the ACC. We hypothesize that performing the ANT during training will tend to localize change to the ACC and perhaps other circuits involved in the task.
Experiment 3 Does stimulation enhance meditation training?
If our stimulation methods do improve FA we will determine if stimulation works by the same mechanism as meditation. One experimental group will be trained in IBMT over two weeks of ten .5 hour sessions. A second group will have the same .5 hour session of IBMT training along with .5 hour of stimulation. A third group will have stimulation alone. We will examine white matter change before and after training for each group using DTI and functional connectivity. If meditation and stimulation act by the same mechanism we expect that stimulation and meditation training will interact to produce the effect on white matter change. For example, white matter change might be greater when the two are applied together than for either one alone . If the two methods are independent there would be no significant interaction between training and stimulation.
References
Posner, M.I., Tang, Y.Y. & Lynch, G. (2014) Mechanisms of white matter change induced by meditation. Frontiers in Psychology published: 27 October 2014 doi:10.3389/fpsyg.2014.01220
Tang, Y., Lu, Q., Geng, X., Stein, E.A., Yang, Y., & Posner, M.I. (2010) Short termmental training induces white-matter changes in the anterior cingulate PNAS 107 16649-16652
Outreach
We continue to try to apply our framework to various issues in development, education and clinical areas.
We received an invitation to prepare a paper on attention for Current Opinion in Pediatrics. The paper emphasizes very recent papers that are related to this topic and we have provided an on line pdf below.
current-opinion-in-pediatrics-pdf
Recently Habibollah Ghassemzadeh paid a visit to Eugene. He brought a paper seeking to update exposure therapy for Obsessive Compulsive Disorder.. He worked with Mary Rothbart and me to connect historical work with current neurobiolgical studies related to attention. We have a draft paper which we hope to publish in the future after further work.
I am working with Aron Barbey , Univ. of Illinois to develop a special issue of Trends in Neuroscience and Education on Intelligence. The announcement of the issues is below. We hope also to develop an approach to the topic based upon our current work.
Special Issue on Intelligence and the Brain
Co-Editors: Aron K. Barbey and Michael Posner
Recent innovations in the psychological and brain sciences have advanced our understanding of human intelligence. Rather than engaging a single brain structure or operating at a fixed level of performance throughout adulthood, emerging evidence indicates that intelligence is mediated by a distributed neural system whose functions can be significantly enhanced by specific types of intervention. Early discoveries in the neurosciences revealed that experience can modify brain structure long after brain development is complete, but we are only now beginning to establish methods to enhance the function of specific brain systems and to optimize core facets of intellectual ability. It is now clear that experience alters the synaptic organization of the brain and that such changes reflect adaptive mechanisms for human learning and memory. In this Special Issue of Trends in Neuroscience and Education, we invite original empirical work, review and opinion papers, and methodological papers that: (1) promote an interdisciplinary approach to understanding the nature of human intelligence, calling for a synthesis of research across cognitive science and systems biology; (2) set the stage for major advances in the scientific effort to enhance intelligence through experimental intervention (e.g., cognitive training, aerobic fitness training, mindfulness meditation, etc.); and (3) demonstrate how the scientific effort to improve the mind is fundamentally changing our understanding of human intelligence – supporting new perspectives about its dynamic and adaptive nature and motivating new insights about how intelligence emerges through evolution and development, is cultivated through experience and cognitive training, and is altered through psychiatric illness and neurological disease.
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