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The Amazing Brain: Mapping Brain Circuits in Vivid Color

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Hop aboard as we fly up, down, left, and right through the information highways of the human brain! This captivating and eye-catching video was one of the winners of the 2019 “Show us Your Brain!” contest sponsored by the NIH-led Brain Research through Advancing Innovative Neurotechnologies® (BRAIN) Initiative.

The video travels through several portions of the brain’s white matter—bundles of fiber that carry nerve signals between the brain and the body, as well as within the brain itself. Fiber colors indicate directionality: left-right fibers (red), front-back fibers (green), and top-bottom fibers (blue).

Looking from the back, we start our journey deep within the brain in the limbic system, the area that helps control emotion, learning, and memory. About three seconds in, visual fibers pop into view extending from the eyes to various brain areas into the occipital lobe (one of four major brain lobes) in the back of the brain.

About two seconds later, flying over top as the brain starts rotating, we see various fiber bundles spray upward throughout the cerebral cortex, communicating information related to language processing, short-term memory, and other functions. About halfway through the video, several green bundles emerge arching across the brain’s midline. These bundles, called the corpus callosum, house the fibers enabling communication between left and right sides of the brain. Finally, the video closes as we see many different fiber bundles lighting up all over, enabling communication between different cortical and subcortical portions of the brain through association and projection pathways.

Dynamic maps like these are created using a 3D imaging technique called diffusion MRI tractography [1]. The technique tracks subtle pathways of water movement in the brain, and allows researchers to model the physical properties (connectional anatomy) that underlie the brain’s electrical properties (neuronal signaling). Postdoctoral researcher Ryan Cabeen and Arthur Toga, director of the University of Southern California Mark and Mary Stevens Neuroimaging and Informatics Institute, Los Angeles, used the method to study how white matter changes in developing and aging brains, as well as in brains affected by neurodegenerative or neurological disorders.

Scientific animator Jim Stanis produced the video with Cabeen and Toga. The team first created a population-averaged brain using high-quality diffusion MRI datasets from the Human Connectome Project ,and then used sophisticated computational tools to delineate each bundle manually .

The tractography technique lets scientists visualize and quantitatively analyze the brain’s wiring patterns, complementing our understanding of how the brain functions. Such methods are especially useful to learn about the organization of deep-brain areas that remain out of reach for scientists using current tools and imaging techniques.

Reference:

[1] Kernel regression estimation of fiber orientation mixtures in diffusion MRI. Cabeen RP, Bastin ME, Laidlaw DH. Neuroimage. 2016 Feb 15;127:158-172.

Links:

Arthur Toga (USC Mark and Mary Stevens Neuroimaging and Informatics Institute, Los Angeles)

Ryan Cabeen (USC Mark and Mary Stevens Neuroimaging and Informatics Institute)

qitwiki—Information about the Quantitative Imaging Toolkit (USC)

Human Connectome Project (USC)

Show Us Your Brain Contest! (BRAIN Initiative/NIH)

Brain Research through Advancing Innovative Neurotechnologies® (BRAIN) Initiative (NIH)

NIH Support: National Institute of Neurological Disorders and Stroke; National Institute of Mental Health


The Amazing Brain: Shining a Spotlight on Individual Neurons

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A major aim of the NIH-led Brain Research through Advancing Innovative Neurotechnologies® (BRAIN) Initiative is to develop new technologies that allow us to look at the brain in many different ways on many different scales. So, I’m especially pleased to highlight this winner of the initiative’s recent “Show Us Your Brain!” contest.

Here you get a close-up look at pyramidal neurons located in the hippocampus, a region of the mammalian brain involved in memory. While this tiny sample of mouse brain is densely packed with many pyramidal neurons, researchers used new ExLLSM technology to zero in on just three. This super-resolution, 3D view reveals the intricacies of each cell’s structure and branching patterns.

The group that created this award-winning visual includes the labs of X. William Yang at the University of California, Los Angeles, and Kwanghun Chung at the Massachusetts Institute of Technology, Cambridge. Chung’s team also produced another quite different “Show Us Your Brain!” winner, a colorful video featuring hundreds of neural cells and connections in a part of the brain essential to movement.

Pyramidal neurons in the hippocampus come in many different varieties. Some important differences in their functional roles may be related to differences in their physical shapes, in ways that aren’t yet well understood. So, BRAIN-supported researchers are now applying a variety of new tools and approaches in a more detailed effort to identify and characterize these neurons and their subtypes.

The video featured here took advantage of Chung’s new method for preserving brain tissue samples [1]. Another secret to its powerful imagery was a novel suite of mouse models developed in the Yang lab. With some sophisticated genetics, these models make it possible to label, at random, just 1 to 5 percent of a given neuronal cell type, illuminating their full morphology in the brain [2]. The result was this unprecedented view of three pyramidal neurons in exquisite 3D detail.

Ultimately, the goal of these and other BRAIN Initiative researchers is to produce a dynamic picture of the brain that, for the first time, shows how individual cells and complex neural circuits interact in both time and space. I look forward to their continued progress, which promises to revolutionize our understanding of how the human brain functions in both health and disease.

References:

[1] Protection of tissue physicochemical properties using polyfunctional crosslinkers. Park YG, Sohn CH, Chen R, McCue M, Yun DH, Drummond GT, Ku T, Evans NB, Oak HC, Trieu W, Choi H, Jin X, Lilascharoen V, Wang J, Truttmann MC, Qi HW, Ploegh HL, Golub TR, Chen SC, Frosch MP, Kulik HJ, Lim BK, Chung K. Nat Biotechnol. 2018 Dec 17.

[2] Genetically-directed Sparse Neuronal Labeling in BAC Transgenic Mice through Mononucleotide Repeat Frameshift. Lu XH, Yang XW. Sci Rep. 2017 Mar 8;7:43915.

Links:

Chung Lab (Massachusetts Institute of Technology, Cambridge)

Yang Lab (University of California, Los Angeles)

Show Us Your Brain! (BRAIN Initiative/NIH)

Brain Research through Advancing Innovative Neurotechnologies® (BRAIN) Initiative (NIH)

NIH Support: National Institute of Mental Health; National Institute of Neurological Disorders and Stroke; National Institute of Biomedical Imaging and Bioengineering


Anesthesia Study Yields New Insights into Neuroscience of Sleep

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Woman receiving anesthesia
Credit: iStock/herjua

General anesthesia has been around since the 1840s, when most people still traveled by horse and buggy. Yet, in this age of jet planes and electric cars, there are still many unknowns about how general anesthesia works.

The prevailing view has long been that general anesthesia exerts a sedative effect that puts us under, along with a pain-relieving effect that works by temporarily shutting down transmission of sensations from other parts of the body to the brain. Now, researchers have discovered that, at least in mice, some types of general anesthesia may actually activate a specialized area of the brain—findings that not only may provide new insights into anesthesia, but may enhance our understanding of sleep.

In a recent study in the journal Neuron, the NIH-supported lab of Fan Wang at Duke University, Durham, NC, used general anesthesia as a tool to learn more about mammalian brain activity. When they placed mice under multiple classes of general anesthesia, a cluster of neurons were activated in the brain’s hypothalamus that produce slow, oscillating waves similar to those observed in the brains of mice that were sleeping deeply. When these neurons were later artificially deactivated, the effects of general anesthesia were shortened. Experiments in sleeping mice also showed that similar deactivation disrupts natural sleep. The discovery suggests there may be a neural pathway in the mammalian brain that is shared by general anesthesia and natural sleep, perhaps opening the door to new drugs for anesthesia, pain management, and sleep disorders [1].

Specifically, Wang’s group is focused on a part of the hypothalamus called the supraoptic nucleus (SON), which consists of about 3,000 neurons. These neurons are wired into the brain’s neuroendocrine system, a vast regulatory system between brain and body. Each SON neuron has two arms: one extends to the base of the brain, where it triggers the pituitary gland to release hormones; the other directly releases peptide hormones into the general circulation.

It’s not altogether surprising that the hypothalamus would be involved regulating sleep. Previous work had indicated that another part of the hypothalamus might serve as an on-off switch between wakefulness and sleep [2]. The neurons also secrete neuropeptides, such as galanin and GABA. that inhibit areas of the brainstem involved in wakefulness.

But what most fascinated Wang is that her experiments found that SOS cells fire constantly in mice that have been kept awake past their normal bedtime, but stop firing once the animals are allowed to sleep. This prompted her team to turn its attention to the 80 percent of SON neurons that secrete the hormones dynorphin and vasopressin, which are secreted in the general circulation and send a wide range of signals to organs throughout the body.

Though mice are not humans and much more work remains to be done, Wang says her data raise the possibility that sleep, like hunger, may be regulated by a feedback loop of hormones, traveling from brain to other body parts and back. As proposed, the SON cells secrete hormones into the body during periods of wakefulness. As the level of the secreted messengers build up, the body signals to the brain that it’s tired, prompting the SOS neurons to activate a different program, sending signals that tell other parts of the brain to go to sleep.

Discovering a homeostatic sleep mechanism certainly wasn’t what surgeon William T. G. Morton had in mind when he first demonstrated the concept of general anesthesia in the 19th Century. Yet more than 175 years later, Morton’s major clinical advance is now yielding unexpected benefits for basic neuroscience research, providing yet another example of how one never knows where biomedical exploration may take us.

References:

[1] A Common Neuroendocrine Substrate for Diverse General Anesthetics and Sleep. Jiang-Xie LF, Yin L, Zhao S, Prevosto V, Han BX, Dzirasa K, Wang F. Neuron. 2019 Apr 18. pii: S0896-6273(19)30296-X.

[2] Activation of ventrolateral preoptic neurons during sleep. Sherin JE, Shiromani PJ, McCarley RW, Saper CB. Science. 1996 Jan 12;271(5246):216-219.

Links:

Anesthesia (National Institute of General Medical Sciences/NIH)

History of Anesthesia (Wood Library Museum of Anesthesiology, Schaumburg, IL)

Brain Basics: Understanding Sleep (National Institute of Neurological Disorders and Stroke/NIH)

Fan Wang (Duke University School of Medicine, Durham, NC)

NIH Support: National Institute of Mental Health


Singing for the Fences

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Credit: NIH

I’ve sung thousands of songs in my life, mostly in the forgiving company of family and friends. But, until a few years ago, I’d never dreamed that I would have the opportunity to do a solo performance of the Star-Spangled Banner in a major league ballpark.

When I first learned that the Washington Nationals had selected me to sing the national anthem before a home game with the New York Mets on May 24, 2016, I was thrilled. But then another response emerged: yes, that would be called fear. Not only would I be singing before my biggest audience ever, I would be taking on a song that’s extremely challenging for even the most accomplished performer.

The musician in me was particularly concerned about landing the anthem’s tricky high F note on “land of the free” without screeching or going flat. So, I tracked down a voice teacher who gave me a crash course about how to breathe properly, how to project, how to stay on pitch on a high note, and how to hit the national anthem out of the park. She suggested that a good way to train is to sing the entire song with each syllable replaced by “meow.” It sounds ridiculous, but it helped—try it sometime. And then I practiced, practiced, practiced. I think the preparation paid off, but watch the video to decide for yourself!

Three years later, the scientist in me remains fascinated by what goes on in the human brain when we listen to or perform music. The NIH has even partnered with the John F. Kennedy Center for the Performing Arts to launch the Sound Health initiative to explore the role of music in health. A great many questions remain to be answered. For example, what is it that makes us enjoy singers who stay on pitch and cringe when we hear someone go sharp or flat? Why do some intervals sound pleasant and others sound grating? And, to push that line of inquiry even further, why do we tune into the pitch of people’s voices when they are speaking to help figure out if they are happy, sad, angry, and so on?

To understand more about the neuroscience of pitch, a research team, led by Bevil Conway of NIH’s National Eye Institute, used functional MRI imaging to study activity in the region of the brain involved in processing sound (the auditory cortex), both in humans and in our evolutionary relative, the macaque monkey [1]. For purposes of the study, published recently in Nature Neuroscience, pitch was defined as the harmonic sounds that we hear when listening to music.

For humans and macaques, their auditory cortices lit up comparably in response to low- and high-frequency sound. But only humans responded selectively to harmonic tones, while the macaques reacted to toneless, white noise sounds spanning the same frequency range. Based on what they found in both humans and monkeys, the researchers suspect that macaques experience music and other sounds differently than humans. They also go on to suggest that the perception of pitch must have provided some kind of evolutionary advantage for our ancestors, and has therefore apparently shaped the basic organization of the human brain.

But enough about science and back to the ballpark! In front of 33,009 pitch-sensitive Homo sapiens, I managed to sing our national anthem without audible groaning from the crowd. What an honor it was! I pass along this memory to encourage each of you to test your own pitch this Independence Day. Let’s all celebrate the birth of our great nation. Have a happy Fourth!

Reference:

[1] Divergence in the functional organization of human and macaque auditory cortex revealed by fMRI responses to harmonic tones. Norman-Haignere SV, Kanwisher N, McDermott JH, Conway BR. Nat Neurosci. 2019 Jun 10. [Epub ahead of print]

Links:

Our brains appear uniquely tuned for musical pitch (National Institute of Neurological Diseases and Stroke news release)

Sound Health: An NIH-Kennedy Center Partnership (NIH)

Bevil Conway (National Eye Institute/NIH)

NIH Support: National Institute of Neurological Diseases and Stroke; National Eye Institute; National Institute of Mental Health


Honoring a Champion of Biomedical Research

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Dr. Francis Collins poses with John Edward Porter in front of a wall display honoring Mr. Porter
It was my great pleasure on May 9, 2019 to help dedicate a new exhibit honoring Congressman John Edward Porter (left) for his strong leadership on behalf of NIH research. The exhibit is located at the Porter Neuroscience Research Center on NIH’s Bethesda, MD campus. Credit: NIH

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