Scientists manipulate consciousness in rats

NIH-funded study may guide deep brain stimulation therapies used for neurological disorders

Scientists showed that they could alter brain activity of rats and either wake them up or put them in an unconscious state by changing the firing rates of neurons in the central thalamus, a region known to regulate arousal. The study, published ineLIFE, was partially funded by the National Institutes of Health.

"Our results suggest the central thalamus works like a radio dial that tunes the brain to different states of activity and arousal," said Jin Hyung Lee, Ph.D., assistant professor of neurology, neurosurgery and bioengineering at Stanford University, and a senior author of the study.

Located deep inside the brain the thalamus acts as a relay station sending neural signals from the body to the cortex. Damage to neurons in the central part of the thalamus may lead to problems with sleep, attention, and memory. Previous studies suggested that stimulation of thalamic neurons may awaken patients who have suffered a traumatic brain injury from minimally conscious states.

Dr. Lee's team flashed laser pulses onto light sensitive central thalamic neurons of sleeping rats, which caused the cells to fire. High frequency stimulation of 40 or 100 pulses per second woke the rats. In contrast, low frequency stimulation of 10 pulses per second sent the rats into a state reminiscent of absence seizures that caused them to stiffen and stare before returning to sleep.

"This study takes a big step towards understanding the brain circuitry that controls sleep and arousal," Yejun (Janet) He, Ph.D., program director at NIH's National Institute of Neurological Disorders and Stroke (NINDS).

When the scientists used functional magnetic resonance imaging (fMRI) to scan brain activity, they saw that high and low frequency stimulation put the rats in completely different states of activity.

Cortical brain areas where activity was elevated during high frequency stimulation became inhibited with low frequency stimulation. Electrical recordings confirmed the results. Neurons in the somatosensory cortex fired more during high frequency stimulation of the central thalamus and less during low frequency stimulation.

"Dr. Lee's innovative work demonstrates the power of using imaging technologies to study the brain at work," said Guoying Liu, Ph.D., a program director at the NIH's National Institute of Biomedical Imaging and Bioengineering (NIBIB).

How can changing the firing rate of the same neurons in one region lead to different effects on the rest of the brain?

Further experiments suggested the different effects may be due to a unique firing pattern by inhibitory neurons in a neighboring brain region, the zona incerta, during low frequency stimulation. Cells in this brain region have been shown to send inhibitory signals to cells in the sensory cortex.

Electrical recordings showed that during low frequency stimulation of the central thalamus, zona incerta neurons fired in a spindle pattern that often occurs during sleep. In contrast, sleep spindles did not occur during high frequency stimulation. Moreover, when the scientists blocked the firing of the zona incerta neurons during low frequency stimulation of the central thalamus, the average activity of sensory cortex cells increased.

Although deep brain stimulation of the thalamus has shown promise as a treatment for traumatic brain injury, patients who have decreased levels of consciousness show slow progress through these treatments.

"We showed how the circuits of the brain can regulate arousal states," said Dr. Lee. "We hope to use this knowledge to develop better treatments for brain injuries and other neurological disorders."

National Institute of Neurological Disorders and Stroke

Nanotechnology World Association

Injectable electronics promise sharper view of brain

It’s a notion that might have come from the pages of a science-fiction novel — an electronic device that can be injected directly into the brain, or other body parts, and treat everything from neurodegenerative disorders to paralysis.

Sounds unlikely, until you visit Charles Lieber’s lab.

Led by Lieber, the Mark Hyman Jr. Professor of Chemistry, an international team of researchers has developed a method of fabricating nanoscale electronic scaffolds that can be injected via syringe. The scaffolds can then be connected to devices and used to monitor neural activity, stimulate tissues, or even promote regeneration of neurons. The research is described in a June 8 paper in Nature Nanotechnology.

Contributors to the work include Jia Liu, Tian-Ming Fu, Zengguang Cheng, Guosong Hong, Tao Zhou, Lihua Jin, Madhavi Duvvuri, Zhe Jiang, Peter Kruskal, Chong Xie, Zhigang Suo, and Ying Fang.

“I do feel that this has the potential to be revolutionary,” Lieber said. “This opens up a completely new frontier where we can explore the interface between electronic structures and biology. For the past 30 years, people have made incremental improvements in micro-fabrication techniques that have allowed us to make rigid probes smaller and smaller, but no one has addressed this issue — the electronics/cellular interface — at the level at which biology works.”

In an earlier study, scientists in Lieber’s lab demonstrated that cardiac or nerve cells grown with embedded scaffolds could be used to create “cyborg” tissue. Researchers were then able to record electrical signals generated by the tissue, and to measure changes in those signals as they administered cardio- or neuro-stimulating drugs.

“We were able to demonstrate that we could make this scaffold and culture cells within it, but we didn’t really have an idea how to insert that into pre-existing tissue,” Lieber said. “But if you want to study the brain or develop the tools to explore the brain-machine interface, you need to stick something into the body. When releasing the electronics scaffold completely from the fabrication substrate, we noticed that it was almost invisible and very flexible, like a polymer, and could literally be sucked into a glass needle or pipette. From there, we simply asked, ‘Would it be possible to deliver the mesh electronics by syringe needle injection?’”

Though not the first attempt at implanting electronics into the brain — deep brain stimulation has been used to treat a variety of disorders for decades — the nanofabricated scaffolds operate on a completely different scale.

“Existing techniques are crude relative to the way the brain is wired,” Lieber said. “Whether it’s a silicon probe or flexible polymers … they cause inflammation in the tissue that requires periodically changing the position or the stimulation.

“But with our injectable electronics, it’s as if it’s not there at all. They are one million times more flexible than any state-of-the-art flexible electronics and have subcellular feature sizes. They’re what I call ‘neuro-philic’ — they actually like to interact with neurons.”

The process for fabricating the scaffolds is similar to that used to etch microchips, and begins with a dissolvable layer deposited on a substrate. To create the scaffold, researchers lay out a mesh of nanowires sandwiched in layers of organic polymer. The first layer is then dissolved, leaving the flexible mesh, which can be drawn into a needle and administered like any other injection.

The input-output of the mesh can then be connected to standard measurement electronics so that the integrated devices can be addressed and used to stimulate or record neural activity.

“These type of things have never been done before, from both a fundamental neuroscience and medical perspective,” Lieber said. “It’s really exciting — there are a lot of potential applications.”

Going forward, researchers hope to better understand how the body reacts to the injectable electronics over longer periods.

Harvard’s Office of Technology Development has filed for a provisional patent on the technology and is actively seeking commercialization opportunities.

“The idea of being able to precisely position and record from very specific areas, or even from specific neurons over an extended period of time — this could, I think, make a huge impact on neuroscience,” Lieber said.

Source: http://www.nanotechnologyworld.org/#!Injectable-electronics-promise-sharper-view-of-brain/c89r/5575efe90cf219f1772f8682

Capturing brain activity with sculpted light

Researchers in Vienna develop new imaging technique to study the function of entire nervous systems   Scientists at the Campus Vienna Biocenter (Austria) have found a way to overcome some of the limitations of light microscopy. Applying the new technique, they can record the activity of a worm’s brain with high temporal and spatial resolution, ultimately linking brain anatomy to brain function. The journal Nature Methods publishes the details in its current issue.

A major aim of today’s neuroscience is to understand how an organism’s nervous system processes sensory input and generates behavior. To achieve this goal, scientists must obtain detailed maps of how the nerve cells are wired up in the brain, as well as information on how these networks interact in real time.

The organism many neuroscientists turn to in order to study brain function is a tiny, transparent worm found in rotting soil. The simple nematode C. elegans is equipped with just 302 neurons that are connected by roughly 8000 synapses. It is the only animal for which a complete nervous system has been anatomically mapped.

Researchers have so far focused on studying the activity of single neurons and small networks in the worm, but have not been able to establish a functional map of the entire nervous system. This is mainly due to limitations in the imaging-techniques they employ: the activity of single cells can be resolved with high precision, but simultaneously looking at the function of all neurons that comprise entire brains has been a major challenge. Thus, there was always a trade-off between spatial or temporal accuracy and the size of brain regions that could be studied.

Scientists at Vienna’s Research Institute of Molecular Pathology (IMP), the Max Perutz Laboratories (MFPL), and the Research Platform Quantum Phenomena & Nanoscale Biological Systems (QuNaBioS) of the University of Vienna have now closed this gap and developed a high speed imaging technique with single neuron resolution that bypasses these limitations. In a paper published online in Nature Methods, the teams of Alipasha Vaziri and Manuel Zimmer describe the technique which is based on their ability to “sculpt” the three-dimensional distribution of light in the sample. With this new kind of microscopy, they are able to record the activity of 70% of the nerve cells in a worm’s head with high spatial and temporal resolution.  

“Previously, we would have to scan the focused light by the microscope in all three dimensions”, says quantum physicist Robert Prevedel. “That takes far too long to record the activity of all neurons at the same time. The trick we invented tinkers with the light waves in a way that allows us to generate “discs” of light in the sample. Therefore, we only have to scan in one dimension to get the information we need. We end up with three-dimensional videos that show the simultaneous activities of a large number of neurons and how they change over time.” Robert Prevedel is a Senior Postdoc in the lab of Alipasha Vaziri, who is an IMP-MFPL Group Leader and is heading the Research Platform Quantum Phenomena & Nanoscale Biological Systems (QuNaBioS) of the University of Vienna, where the new technique was developed. 

However, the new microscopic method is only half the story. Visualising the neurons requires tagging them with a fluorescent protein that lights up when it binds to calcium, signaling the nerve cells’ activity. “The neurons in a worm’s head are so densely packed that we could not distinguish them on our first images”, explains neurobiologist Tina Schrödel, co-first author of the study. “Our solution was to insert the calcium sensor into the nuclei rather than the entire cells, thereby sharpening the image so we could identify single neurons.” Tina Schrödel is a Doctoral Student in the lab of the IMP Group Leader Manuel Zimmer.

The new technique that came about by a close collaboration of physicists and neurobiologists has great potentials beyond studies in worms, according to the researchers. It will open up the way for experiments that were not possible before. One of the questions that will be addressed is how the brain processes sensory information to “plan” specific movements and then executes them. This ambitious project will require further refinement of both the microscopy methods and computational methods in order to study freely moving animals. The team in Vienna is set to achieve this goal in the coming two years.  

Source: http://medienportal.univie.ac.at/presse/aktuelle-pressemeldungen/detailansicht/artikel/capturing-brain-activity-with-sculpted-light/