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.

Sleep onset and duration uncoupled



Receptors producing synaptic inhibition regulate the time it takes to get to sleep. This work begins to dissect the biological mechanisms underlying the differences between various types of insomnia.

Drosophila are used as a model for understanding sleep because flies replicate many of the behavioral characteristics of mammalian sleep. This research has not yet produced evidence that the pathways targeted by insomnia drugs in humans are necessary for sleep in flies, however, casting doubt of the relevance of fly sleep as a model for human sleep.

Using genetics and pharmacology, Leslie Griffith and colleagues demonstrate that the biophysical properties of a particular inhibitory receptor influenced both falling and staying asleep in flies, but in different ways. Manipulating receptor desensitization only affected sleep onset, uncoupling the control of sleep initiation and maintenance.

This work further confirms the validity of Drosophila as a model of mammalian sleep and provides a biological explanation for a specific type of insomnia. Future studies exploring other aspects of sleep regulation involving inhibitory receptors may assist in better targeting of drugs designed to specifically influence one particular aspect of sleep without unnecessarily affecting other aspects.

Author contact:
Leslie Griffith (Brandeis University, Waltham, MA, USA)
Tel: +1 781 736 3125; E-mail: griffith@brandeis.edu

Learning in stressful times



The hippocampus is crucial for mediating the effects of stress on learning, even when this brain region is not directly involved in learning the task in question.

The hippocampus is important for some types of learning but not others. Eyeblink conditioning, for example, does not require the hippocampus. Animals respond to a shock to the eye by blinking, and when the shock is repeatedly paired with a noise learn to respond to the noise itself with an eyeblink – irrespective of whether it is accompanied by a shock.

Tracey Shors and colleagues previously reported that after rats have been stressed, eyeblink conditioning is enhanced in males and reduced in females – stress therefore modifies learning of the association between the noise and shock. The authors now find that selective damage to the hippocampus in rats makes these stress-induced modifications disappear. Lesioned male rats do not learn eyeblink conditioning any faster when they are stressed, and lesioned female rats are no worse. Without stress, both perform just like normal animals. These results indicate that neuronal activity in the hippocampus modifies learning after stress, even when the hippocampus is not directly involved in the learning process itself.


Author contact:

Tracey Shors (Rutgers University, Piscataway, NJ, USA)
Tel: +1 732 445 6968; E-mail: shors@rutgers.edu

Towards a treatment for epilepsy

Japanese neuroscientists from the RIKEN Brain Science Institute have uncovered a mechanism for an epileptic disorder which occurs in infants. “We hope to develop effective therapies for this intractable epilepsy from further work,” says project leader Kazuhiro Yamakawa.


Japanese neuroscientists have clarified the molecular basis of the intractable epileptic disorder known as severe myoclonic epilepsy in infancy (SMEI). In the process they have redefined the position and role of an important protein involved in controlling the firing of nerve impulses in the brain. The work also has generated a mouse model of severe myoclonic epilepsy that the researchers hope to use to study the condition and how to treat it.

More than 200 different mutations of the human SCN1A gene are known to be associated with human epileptic disorders including SMEI. The gene itself encodes an ion-channel protein, Nav1.1, which forms a pore in the plasma membrane that controls the in-flow of electrically-charged sodium ions into nerve cells. This is a significant step in the generation of nerve impulses. There is a homologous gene, Scn1a, in mice.

In a recent paper in The Journal of Neuroscience (1), researchers from the RIKEN Brain Science Institute, Wako, and their colleagues, describe how they produced a ‘knock-in’ mouse, by introducing a disease-causing, nonsense mutation found in SMEI patients into the middle of the Scn1a gene. Mouse pups which inherited copies of the mutant gene from both mother and father were markedly smaller (Fig. 1), developed epilepsy and an unstable gait by the second week after birth, and died within three weeks. Pups with only one copy of the mutant gene began epileptic seizures in the third week, and about 40% had died within three months.

Previous studies suggested that the Nav1.1 protein was distributed rather evenly throughout the brain and could be found in the projections of nerve cells known as dendrites. Using three different antibodies as probes, the RIKEN-based research team corrected this picture. The Nav1.1 proteins are more likely to be found on axons and cell bodies. In particular, they are found on inhibitory nerve cells that express the calcium-binding protein parvalbumin, often in the area known as the axon initial segment where nerve impulses are generated.

By measuring and comparing the output of excitatory and inhibitory neurons in normal and mutant mice, the research team found that the Nav1.1 channel proteins were needed not to initiate firing of the excitatory nerve, but to maintain the inhibitory pulse, thus preventing epileptic seizures.

“We hope to develop effective therapies for this intractable epilepsy from further work,” says project leader Kazuhiro Yamakawa.

Reference

1. Ogiwara, I., Miyamoto, H., Morita, N., Atapour, N., Mazaki, E., Inoue, I., Takeuchi, T., Itohara, S., Yanagawa, Y., Obata, K., Furuichi, T., Hensch, T.K. & Yamakawa, K. Nav1.1 localizes to axons of parvalbumin-positive inhibitory interneurons: A circuit basis for epileptic seizures in mice carrying an Scn1a gene mutation. The Journal of Neuroscience 27, 5903–5914 (2007).

Layering and positioning neurons

Multipolar-to-biopolar neuronal transition is essential during brain development. A team of Japanese scientists have determined that a protein called cyclin-dependent kinase 5 (Cdk5) is required for neurons to develop their proper shape.

A team of Japanese scientists led by Toshio Ohshima, at the RIKEN Brain Science Institute, Wako, has determined that a protein called cyclin-dependent kinase 5 (Cdk5) is required for neurons to develop their proper shape. Morphological defects from a lack of Cdk5 affect the position and function of neurons in many parts of the brain, including the cerebral cortex—or gray matter.

Reporting in the June issue of Development (1), Ohshima and colleagues extend their previous work that demonstrated proper migration of neurons to form the normal six layers of the cortex failed to occur in mice lacking Cdk5.

All cells of the body express Cdk proteins which are necessary for controlling when and how long cells divide. However, Cdk5 is different from other Cdk proteins in that it must be activated by specific ‘accessory’ proteins that are most highly expressed in neurons.

Ohshima and colleagues used several experimental approaches, including introducing a fluorescent ‘tag’ protein into developing brains to follow neuron migration in real-time, to evaluate the function of Cdk5.

As cortical neuron layers develop, the shape of neurons shifts from cells with multiple neuronal projections, or multipolar neurites, to cells with fewer neurites ‘pointing’ in opposite directions (‘bipolar’). The team found that in brains lacking Cdk5, however, the neurons remain multipolar.

This morphological defect was especially pronounced in so-called ‘pyramidal’ neurons (Fig. 1), which are specialized neurons with a single apical (‘top’) dendrite and many basal (‘bottom’) dendrites (hence their bipolar morphology) that represent nearly 80% of the neurons in the cortex.

Commenting on their work Ohshima says that he was initially intrigued with Cdk5 because it regulates proteins associated with devastating diseases such as Alzheimer’s and Amyotrophic Lateral Sclerosis. Serendipitously, however, the team found developmental defects in mice lacking Cdk5, which prompted further experiments.

The team’s new contribution adds to the well-accepted view that Cdk5 function is essential for normal brain development. Of particular note, the team found that pyramidal neurons require Cdk5 for multipolar-to-bipolar transition. But exactly which protein substrates Cdk5 regulates to bring about this transition is still not well understood.

“There are some candidates for Cdk5 substrates, but I have no direct evidence to say which one may be involved in its function,” says Ohshima. Indeed, the next step is to uncover the molecular pathway regulated by Cdk5. Using proteomics approaches—a combination of techniques to understand how proteins interact with one another—is one way Ohshima thinks he and his team can move forward.
Reference

1. Ohshima, T., Hirasawa, M., Tabata, H., Mutoh, T., Adachi, T., Suzuki, H., Saruta, K., Iwasato, T., Itohara, S., Hashimoto, M. et al. Cdk5 is required for multipolar-to-bipolar transition during radial neuronal migration and proper dendrite development of pyramidal neurons in the cerebral cortex. Development 134, 2273–2282 (2007).

Neuroscience: Serotonin and the brain

Serotonin is used faster in the winter by people suffering from seasonal depression when compared with a control group, according to research to be published in Neurpsychopharmacology this month. The research also shows that serotonin usage returns to normal both where depression is treated effectively and during the summer months.

In depression, studies have found that the brain has too little of a neurotransmitter known as serotonin. However, why the brains of people with depression have low levels of serotonin is not known. Matthaus Williet and colleagues studied the primary way that the brain removes serotonin, known as the serotonin transporter, using an easily accessible model system: the blood platelets. The researchers tested this for a specific type of depression, known as seasonal depression; a depression that worsens in the winter and improves in the summer. This finding, if replicated, could help identify people at risk for depression and could lead to development of a new line of treatment.

Contact:

Matthaus Willeit (Medical University Vienna, Austria)

Tel: +43 1 40 400 3543; E-mail: matthaeus.willeit@medunivien.ac.at

The political brain


People with a more liberal outlook may have a greater sensitivity to cues signalling the need to change a habitual response. The study shows that self-rated liberalism is associated with a type of brain activity involved in regulating conflict between a habitual tendency and an alternative response.

Previous psychological work found that, on average, conservatives tend to be more persistent in their judgements and decision-making, while liberals are more likely to be open to new experiences. These differences are related to a process known as conflict monitoring, a mechanism for detecting when a habitual response is not appropriate for a new situation.

David Amodio and colleagues recorded electrical activity from the brain using electroencephalograms (EEGs) in people who rated themselves as either conservative or liberal. During these recordings, subjects had to quickly press a button when they saw a cue, which was presented often enough that the button-press became habitual. However, subjects occasionally saw another, infrequent cue signalling them to withhold their habitual button press. When such response inhibition was required, liberals had significantly greater neural activity originating in the anterior cingulate cortex – known to be involved in conflict monitoring. Liberals were also more successful at withholding their habitual response when they saw the infrequent cue. The findings support previous suggestions that political orientation may in part reflect differences in cognitive mechanisms.


Author contact:

David Amodio, (New York University, NY, USA)
Tel: +1 212 998 3875; E-mail: david.amodio@nyu.edu