This image illustrates the new "colorimetric technique" developed by researchers at Florida Atlantic University to map four dimensions (4D) of brain data using EEG signals at once. Using this fourth dimension will dramatically change the way neuroscientists are able to understand how the brain operates, shedding insight on a number of psychiatric and neurological disorders and opening up new ways to study therapeutic interventions, in particular the effects of drugs.

Groundbreaking Technique Reveals Modus Operandi of the Intact Living Brain

Dynamical Theory and Novel 4D Colorimetric Method Reveal the Essential Modus Operandi of the Intact Living Brain--Study shows how areas in the brain integrate and segregate at the same time.

For the brain to achieve its intricate functions such as perception, action, attention and decision making, neural regions have to work together yet still retain their specialized roles. Excess or lack of timely coordination between brain areas lies at the core of a number of psychiatric and neurological disorders such as epilepsy, schizophrenia, autism, Parkinson’s disease, sleep disorders and depression. How the brain is coordinated is a complex and difficult problem in need of new theoretical insights as well as new methods of investigation. In groundbreaking research published in the January 2009 issue and featured on the cover of Progress in Neurobiology, researchers at Florida Atlantic University’s Center for Complex Systems and Brain Sciences in the Charles E. Schmidt College of Science propose a theoretical model of the brain’s coordination dynamics and apply a novel 4D colorimetric method to human neurophysiological data collected in the laboratory. The article, titled “Brain coordination dynamics: true and false faces of phase synchrony and metastability,” is co-authored by Drs. Emmanuelle Tognoli, an expert in neurophysiology and research assistant professor in the Center’s Human Brain and Behavior Laboratory, and J. A. Scott Kelso, the Glenwood and Martha Creech Eminent Scholar in Science and founder of the Center. The authors’ theory and data show that both tendencies co-occur in the brain and are essential for its normal function. Their research demonstrates that coordination involves a subtle kind of ballet in the brain, and like dancers, cortical areas are capable of coming together as an ensemble (integration) while still exhibiting a tendency to do their own thing (segregation).

“A lot of emphasis in neuroscience these days is on what the parts do,” said Kelso. “But understanding the coordination of multiple parts in a complex system such as the brain is a fundamental challenge. Using our approach, key predictions of cortical coordination dynamics can now be tested, thereby revealing the essential modus operandi of the intact living brain.”

Tognoli and Kelso developed a novel colorimetric technique that simultaneously maps four dimensions of brain data (magnitude, 2D of cortical surface and time) in order to capture true synchronization in electroencephalographic (EEG) signals. Because of the fourth dimension afforded by this colorimetric method, it is possible to observe and interpret oscillatory activity of the entire brain as it evolves in time, millisecond by millisecond. Moreover, the authors’ method applies to continuous non-averaged EEG data thereby de-emphasizing the notion of “an average brain.” The authors demonstrate that only in continuous EEG can real synchronization be sorted from false synchronization – a kind of synchronization that arises from the spread of electrical fields and volume conduction rather than from genuine interactions between brain areas.

Most of the time, activity from multiple brain areas look coordinated; however, in actuality, there is far less synchrony than what appears to be. With the support of mathematical models that reproduce the biases of real brain records in synthetic data, the authors show how to tell apart real and false episodes of synchronization. For the first time, true episodes of brain coordination can be spotted directly in EEG records and carefully analyzed.

In addition to shedding insight on the way the brain normally operates, Tognoli and Kelso’s research provides a much-needed framework to understand the coordination dynamics of brain areas in a variety of pathological conditions. Their approach allows a precise parsing of “brain states” and is likely to open up new ways to study therapeutic interventions, in particular the effects of drugs (pharmaco-dynamics). Their approach will also help improve the design of brain computer interfaces used to help people who are paralyzed.

“In the future, it may be possible to fluently read the processes of the brain from the EEG like one reads notes from a musical score,” said Tognoli. “Our technique is already providing a unique view on brain dynamics. It shows how activity grows and dies in individual brain areas and how multiple areas engage in and disengage from working together as a coordinated team.”

In addition to simple linear synchronization between brain areas, the authors describe more subtle modes of coordination during which areas may cooperate (integrate) and at the same time retain their functional specificity (segregation).

“This property of metastability falls out of our theory and is crucial for the brain,” said Kelso. “The brain is a complex nonlinear dynamical system, and it needs to coordinate the activity of diverse and remotely connected parts in order to extract and communicate meaningful information.”

Tognoli points out that subtle regimes of coordination are advantageous for the brain and are faster, more powerful and less energetically costly, thereby creating rich modes of interaction that surpass those of simple linear modes of coordination.

For a long time, scientists have strictly emphasized one kind of synchronization called ‘inphase’ or ‘zero-lag synchrony’ looking only at who is coordinated with whom and not observing the details of how they are coordinated. Through their research, Tognoli and Kelso have shown that the brain uses a much wider repertoire of synchronization patterns than just inphase. For example, brain areas may lock their oscillations together but keep a different phase.

This characteristic is also a key to the brain’s dynamic complexity. Areas may encode distinct information when they coordinate with one phase difference or another, and the brain may finely tune itself, such as in learning, by altering the lag at which its areas coordinate rather than just switching synchrony on and off. Such a brain would have a far greater combinatorial and computational power than the old model of the ‘inphase brain’. But to understand the principals at work, the lag or ‘relative phase’ between coupled oscillations in the brain needs to be systematically studied.

“This work lies at the intersection of neuroscience and complexity science,” said Dr. Gary Perry, dean of the Charles E. Schmidt College of Science. “Drs. Kelso and Tognoli have successfully developed the specific conceptual and methodological tools needed to capture and observe these important features in empirical data. Their unique approach and findings will help to shed light on some of world’s most debilitating and costly health disorders.”

The authors’ research is supported by the National Institute of Mental Health, National Institute of Neurological Disorders and Stroke, National Science Foundation, U.S. Office of Naval Research and the Davimos Family Endowment for Excellence in Science.

- FAU -

Florida Atlantic University opened its doors in 1964 as the fifth public university in Florida. Today, the University serves more than 26,000 undergraduate and graduate students on seven campuses strategically located along 150 miles of Florida's southeastern coastline. Building on its rich tradition as a teaching university, with a world-class faculty, FAU hosts ten colleges: College of Architecture, Urban & Public Affairs, Dorothy F. Schmidt College of Arts & Letters, the Charles E. Schmidt College of Biomedical Science, the Barry Kaye College of Business, the College of Education, the College of Engineering & Computer Science, the Harriet L. Wilkes Honors College, the Graduate College, the Christine E. Lynn College of Nursing and the Charles E. Schmidt College of Science.

Seeking schizophrenia genes

Researchers map genetic alterations associated with human schizophrenia


Japanese scientists have linked atypical expression patterns of the gene FABP7, which encodes the brain fatty acid binding protein 7, with human schizophrenia. Although initially attributed to environmental abnormalities, this debilitating disease is now accepted as being influenced by a strong, yet likely multifactorial, genetic component.

The phenotypic, or behavioral, outcomes of schizophrenia are perhaps just as complicated as the genotypic alterations underlying the disease. Fortunately, suppression of a particular startle response—known as prepulse inhibition (PPI)—provides an easily measurable biological readout of the sensory motor gating mechanisms that are often impaired in schizophrenia.

In an effort to identify genes associated with schizophrenia, a team led by Takeo Yoshikawa at the RIKEN Brain Science Institute in Wako, mapped genetic alterations associated with PPI in mice1.

After tracking the PPI responses of a panel of distinct inbred mouse strains for over one year, the researchers intercrossed the strains having the lowest and highest PPI scores. Next, the team scanned the genomes of the progeny for sets of microsatellite markers, or genetic ‘tags’, and compared the presence of these tags with the PPI scores.

Using progressively rigorous sets of tags, the researchers linked impaired PPI to a region of chromosome 10 containing approximately 30 genes. The team honed in on Fabp7 (Fig. 1), one gene within this region, because of its influence over the metabolism of the polyunsaturated fatty acid DHA (docosahexaenoic acid), a process often impaired in schizophrenia.

Encouragingly, although stronger in males than in females, human schizophrenia patients exhibit abnormally high expression of FABP7 similar to mice exhibiting defective PPI responses. Notably, mice rendered genetically deficient in Fabp7 also score low in PPI measurements and display stronger behavioral responses to chronic NMDA receptor antagonist treatment, another feature of schizophrenia.

Although the team detected defects in the maintenance of neural progenitor cells in Fabp7-deficient mice, future work is needed to elucidate the precise molecular mechanism through which alterations in Fabp7 expression promote schizophrenia-like behavior in mice and humans.

Similarly, why males seem to be more strongly affected by Fabp7 over-expression remains unclear. However, sex hormone-responsive elements in the DNA regions controlling Fabp7 expression might play a role.

“It is well known that malnutrition in utero increases the probability of future schizophrenia. Our results raise the importance of cohort studies to examine whether replenishment of DHA in pregnant mothers can be beneficial in reducing the chance of schizophrenia development in offspring,” says Yoshikawa.
Reference

1. Watanabe, A., Toyota, T., Owada, Y., Hayashi, T., Iwayama, Y., Matsumata, M., Ishitsuka, Y., Nakaya, A., Maekawa, M., Ohnishi, T., et al. Fabp7 maps to a quantitative trait locus for a schizophrenia endophenotype. PLoS Biology 5, 2469–2483 (2007).

How Ketamine ("Special K") Impairs Brain Circuitry


Description

Use of ketamine raising concerns by researchers at the UCSD School of Medicine who have found that ketamine leads to the impairments in brain circuitry observed in both drug abusers and schizophrenic patients by causing increased production of a toxic free radical called “superoxide.”

Scientists know that the drug ketamine – street name “Special K” – can induce schizophrenia-like symptoms in drug abusers. Ketamine is also used as an anesthetic and, more recently, as an antidepressant – raising concerns by researchers at the University of California, San Diego (UCSD) School of Medicine, who have found that ketamine leads to the impairments in brain circuitry observed in both drug abusers and schizophrenic patients by causing increased production of a toxic free radical called “superoxide.” Their findings, which could point the way to novel treatments for schizophrenia, will be published in the December 7 issue of the journal Science.

A research team led by Laura Dugan, M.D., Larry L. Hillblom Professor of Geriatrics and research scholar with the UCSD Stein Institute for Research on Aging, discovered an unexpected link between the inflammatory enzyme complex NADPH oxidase and the dysfunction of certain brain neurons exposed to ketamine. NADPH oxidase is normally found in white blood cells circulating outside the brain, where it helps kill bacterial and fungal infections by producing superoxide, a compound that can cause substantial damage to cells.

“Because of NADPH oxidase’s protective role in fighting infection, it was very surprising to find that the complex wears a second hat – it is also critical for modulating signaling in the brain,” said first author M. Margarita Behrens, Ph.D., Division of Geriatric Medicine, UCSD School of Medicine.

According to Behrens, it was known that ketamine initially impairs the inhibitory circuitry in the brain’s cortex and hippocampus by blocking the NMDA receptor, a molecule on the cell surface that controls the activity of neurons. But the UCSD researchers discovered that, as a result of blocking the receptor, ketamine also substantially increased the activity of NADPH oxidase, causing further disruption of neuronal signaling.

“Ketamine causes a ‘disinhibition’ of brain circuitry, taking the brakes off the system and causing overexcitation of the brain in response to a stimulus,” said Behrens. “This overexcitation activates NADPH oxidase, which then produces superoxide – resulting in detrimental changes in key synaptic proteins and profoundly affecting nervous system function.”

The result is impairment of the brain circuitry involved in memory, attention and other key functions related to learning. Loss of such functions sets up individuals for psychosis and deficits in information processing, resulting in symptoms such as hallucinations and delusions, as well as social withdrawal and cognitive problems, according to Behrens.

Using ketamine, Behrens and Dugan mimicked features of schizophrenia in mice, and then analyzed neurons in a region of the mouse brain that corresponds to the prefrontal cortex in humans where profound changes occur in patients with schizophrenia. The researchers found a substantial increase in the activity of NADPH oxidase, and that this activity made some neurons in this inhibitory circuitry “disappear.” When the researchers blocked the activity of NADPH oxidase with an inhibitor, or with a compound that annihilates superoxide, these neurons were protected.

“Our findings suggest that compounds that inhibit NADPH oxidase in the brain, without totally blocking its protective function of killing bacteria, could provide future therapies for schizophrenia or other diseases in humans that exhibit similar changes in neural circuitry,” said Behrens.

Additional contributors to the paper include Sameh S. Ali, Diep N. Dao, Jacinta Lucero, Grigoriy Shekhtman and Kevin L. Quick, Department of Medicine, UCSD Division of Geriatric Medicine. The research was funded in part by the Larry L. Hillblom Endowment and NARSAD.