Synchronization in dynamical systems, particularly biological systems, is a relatively poorly understood phenomenon. Yet it is a problem of immense importance in problems ranging from animal flocking to neural synchronization in pathological states such as epilepsy. Since seizures are generally understood to result from the synchronization of large ensembles of periodically firing neurons, they can be considered as a problem of synchronized (nonlinear) oscillators. The essence of this project is to take an interdisciplinary approach to understanding synchronization in seizure development, combining imaging of seizure spread through the rat neocortex with computational simulations based in nonlinear-dynamical models of neural activity. Seizure spread will be imaged using the intrinsic optical signal, calcium-sensitive dyes, and voltage-sensitive dyes, making it possible to map the spread of brain activity with high spatial and temporal resolution, in order to determine the changes in synchronization of neural activity as a seizure develops, spreads, and dies away. These experimental studies will be complemented by computational models which will be used not only for comparison with experimental results, but also to investigate the dynamical mechanisms of seizure spread through the brain. Synchrony and loss of synchrony are important in many brain functions other than epilepsy, such as attention and perhaps even consciousness, as well as many other complex biological and physical systems. Thus the work undertaken in this CAREER activity will have a broad impact on general problems in the physics of complex systems.
This award also supports an interdisciplinary outreach program within local St. Louis area high schools that provides students with an introduction to some of the most dramatic moments in the development of interdisciplinary science via active learning and via the life stories of the scientists whose work has helped to break down boundaries between fields. The PI also works with local teachers to develop means of expanding the outreach program by creating portable learning modules that teachers can use in their own classrooms. The program emphasizes how new ideas arise through unexpected connections between old ones. The program thus has the intellectual merit of being a study of the creative process itself, exploring this process both through the life stories of scientists of old, and through the awakening imaginative capabilities of the students themselves.
The primary goal of this project was to combine brain imaging techniques with analysis methods from nonlinear physics, in order to investigate the role of synchronization in the onset, development and termination of seizures. We used a voltage-sensitive dye imaging technique to investigate drug-induced seizure activity in the rat neocortex (top layers of the brain) in the living animal. The voltage-sensitive is absorbed in the membranes of the cells in the brain, and gives a fluorescent signal when the cells are activated; in essence, it is as if we place an EEG electrode at every point in the brain we are imaging. Initial experimental studies, as we were getting the experimental system running, included experimental comparison of voltage-sensitive dye imaging and other brain imaging methods; this work was published in the journal Optics Letters. Our main experimental study demonstrated a sharp increase in synchronization of brain activity during seizures. Synchronization, measured with techniques from nonlinear physics, was particularly strong between nearby areas of the brain, but remained very strong between all areas of the brain involved in the seizure. This result indicates that brain activity can become highly synchronized during seizures (a controversial topic, since some studies from other research groups have found recently high synchrony during seizures, and others have not), and contributes to the important discussion over the mechanisms of seizure development. This basic science result may hopefully have eventual clinical relevance in terms of the development of treatments for epilepsy, such as the development of devices to break up synchrony, and thus promote seizure termination. This work was presented at a number of scientific meetings, comprised the main part of the doctoral dissertation of one of my graduate students (Dr. Daisuke Takeshita), and was recently published in the journal Chaos. In addition to our experimental studies of synchronization during seizures, my group performed a number of computer simulation studies of seizure activity, using nonlinear equations that simulate the electrical activity of neurons. We found dramatic increases in synchronization under various conditions, including a condition that mimicked the effect of 4-aminopyridine, the drug we used in our experiments to trigger seizure activity. This work was published in two papers, both in the journal Physical Review E; it formed the basis for the master's thesis of my student Oliver Weihberger, and a portion of the PhD dissertation of Daisuke Takeshita. We also applied synchronization analysis to another serious medical condition of the brain -- traumatic brain injury. (This was not part of the initial proposal, but was approved as additional work to be done under the grant by our Program Officer.) Using data obtained by collaborators in New York, which showed how normal and brain-injured subjects tracked a moving target, graduate student Roxana Contreras and I showed that normal subjects synchronize their eye movements much better with the target than do brain injured subjects. We also found an increase in eye-target synchrony as normal subjects were given "cognitive load", i.e., things to think about while doing the eye tracking task, in this case as set of words to remember. Synchrony increased for an intermediate number of words to remember -- this can be thought of as a little bit of multitasking, which can make someone more alert, while too much information (say, 9 words to remember instead of 5) is overwhelming. This effect had been demonstrated before, but not using the physics-based technique of synchronization analysis. The effect did NOT occur in brain injured subjects; we hypothesize that this results from damage to connections in the brain during closed-head injury. Such injuries often cause damage to connections between the cerebellum, which controls eye movement, and the frontal cortex, the seat of focus and attention. These studies may ultimately lead to faster methods of diagnosing brain injury in patients such as civilians in car accidents, or military personnel who have been subjected to IED attacks. The work was published in two papers, one in the Journal of Biological Physics, and another in Brain Research, and comprised a large portion of Dr. Contreras's PhD dissertation. Other related work, done by doctoral student Nathan Dees, involved the application of synchronization techniques to attempt to relate functional magnetic resonance brain imaging to electroencephalography (EEG) in normal human subjects. Most recently, the last graduate students to be supported by the project, Kaushalya Premachandra and Adam Scott, have been continuing computational studies of seizure activity. Kaushalya has obtained evidence for "phase transition" behavior during the onset of synchronization. Adam has developed a model to simulate how seizures end, including the depletion of a key neurotransmitter, glutamate. His model produces results which are quite similar to our experimental findings. Future work will concern a deeper study of the precise dynamics of seizure termination, which may be an important new direction for the development of anti-epilepsy treatments.
