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BRAIN Initiative

Celebrating NIH Science, Blogs, and Blog Readers!

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Happy holidays to one and all! As you may have heard, this is my last holiday season as the Director of the National Institutes of Health (NIH)—a post that I’ve held for the past 12 years and four months under three U.S. Presidents. And, wow, it really does seem like only yesterday that I started this blog!

At the blog’s outset, I said my goal was to “highlight new discoveries in biology and medicine that I think are game changers, noteworthy, or just plain cool.” More than 1,100 posts, 10 million unique visitors, and 13.7 million views later, I hope you’ll agree that goal has been achieved. I’ve also found blogging to be a whole lot of fun, as well as a great way to expand my own horizons and share a little of what I’ve learned about biomedical advances with people all across the nation and around the world.

So, as I sign off as NIH Director and return to my lab at NIH’s National Human Genome Research Institute (NHGRI), I want to thank everyone who’s ever visited this Blog—from high school students to people with health concerns, from biomedical researchers to policymakers. I hope that the evidence-based information that I’ve provided has helped and informed my readers in some small way.

In this my final post, I’m sharing a short video (see above) that highlights just a few of the blog’s many spectacular images, many of them produced by NIH-funded scientists during the course of their research. In the video, you’ll see a somewhat quirky collection of entries, but hopefully you will sense my enthusiasm for the potential of biomedical research to fight human disease and improve human health—from innovative immunotherapies for treating cancer to the gift of mRNA vaccines to combat a pandemic.

Over the years, I’ve blogged about many of the bold, new frontiers of biomedicine that are now being explored by research teams supported by NIH. Who would have imagined that, within the span of a dozen years, precision medicine would go from being an interesting idea to a driving force behind the largest-ever NIH cohort seeking to individualize the prevention and treatment of common disease? Or that today we’d be deep into investigations of precisely how the human brain works, as well as how human health may benefit from some of the trillions of microbes that call our bodies home?

My posts also delved into some of the amazing technological advances that are enabling breakthroughs across a wide range of scientific fields. These innovative technologies include powerful new ways of mapping the atomic structures of proteins, editing genetic material, and designing improved gene therapies.

So, what’s next for NIH? Let me assure you that NIH is in very steady hands as it heads into a bright horizon brimming with exceptional opportunities for biomedical research. Like you, I look forward to discoveries that will lead us even closer to the life-saving answers that we all want and need.

While we wait for the President to identify a new NIH director, Lawrence Tabak, who has been NIH’s Principal Deputy Director and my right arm for the last decade, will serve as Acting NIH Director. So, keep an eye out for his first post in early January!

As for me, I’ll probably take a little time to catch up on some much-needed sleep, do some reading and writing, and hopefully get out for a few more rides on my Harley with my wife Diane. But there’s plenty of work to do in my lab, where the focus is on type 2 diabetes and a rare disease of premature aging called Hutchinson-Gilford Progeria Syndrome. I’m excited to pursue those research opportunities and see where they lead.

In closing, I’d like to extend my sincere thanks to each of you for your interest in hearing from the NIH Director—and supporting NIH research—over the past 12 years. It’s been an incredible honor to serve you at the helm of this great agency that’s often called the National Institutes of Hope. And now, for one last time, Diane and I take great pleasure in sending you and your loved ones our most heartfelt wishes for Happy Holidays and a Healthy New Year!


Groundbreaking Study Maps Key Brain Circuit

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Biologists have long wondered how neurons from different regions of the brain actually interconnect into integrated neural networks, or circuits. A classic example is a complex master circuit projecting across several regions of the vertebrate brain called the basal ganglia. It’s involved in many fundamental brain processes, such as controlling movement, thought, and emotion.

In a paper published recently in the journal Nature, an NIH-supported team working in mice has created a wiring diagram, or connectivity map, of a key component of this master circuit that controls voluntary movement. This groundbreaking map will guide the way for future studies of the basal ganglia’s direct connections with the thalamus, which is a hub for information going to and from the spinal cord, as well as its links to the motor cortex in the front of the brain, which controls voluntary movements.

This 3D animation drawn from the paper’s findings captures the biological beauty of these intricate connections. It starts out zooming around four of the six horizontal layers of the motor cortex. At about 6 seconds in, the video focuses on nerve cell projections from the thalamus (blue) connecting to cortex nerve cells that provide input to the basal ganglia (green). It also shows connections to the cortex nerve cells that input to the thalamus (red).

At about 25 seconds, the video scans back to provide a quick close-up of the cell bodies (green and red bulges). It then zooms out to show the broader distribution of nerve cells within the cortex layers and the branched fringes of corticothalamic nerve cells (red) at the top edge of the cortex.

The video comes from scientific animator Jim Stanis, University of Southern California Mark and Mary Stevens Neuroimaging and Informatics Institute, Los Angeles. He collaborated with Nick Foster, lead author on the Nature paper and a research scientist in the NIH-supported lab of Hong-Wei Dong at the University of California, Los Angeles.

The two worked together to bring to life hundreds of microscopic images of this circuit, known by the unusually long, hyphenated name: the cortico-basal ganglia-thalamic loop. It consists of a series of subcircuits that feed into a larger signaling loop.

The subcircuits in the loop make it possible to connect thinking with movement, helping the brain learn useful sequences of motor activity. The looped subcircuits also allow the brain to perform very complex tasks such as achieving goals (completing a marathon) and adapting to changing circumstances (running uphill or downhill).

Although scientists had long assumed the cortico-basal ganglia-thalamic loop existed and formed a tight, closed loop, they had no real proof. This new research, funded through NIH’s Brain Research Through Advancing Innovative Neurotechnologies® (BRAIN) Initiative, provides that proof showing anatomically that the nerve cells physically connect, as highlighted in this video. The research also provides electrical proof through tests that show stimulating individual segments activate the others.

Detailed maps of neural circuits are in high demand. That’s what makes results like these so exciting to see. Researchers can now better navigate this key circuit not only in mice but other vertebrates, including humans. Indeed, the cortico-basal ganglia-thalamic loop may be involved in a number of neurological and neuropsychiatric conditions, including Huntington’s disease, Parkinson’s disease, schizophrenia, and addiction. In the meantime, Stanis, Foster, and colleagues have left us with a very cool video to watch.

Reference:

[1] The mouse cortico-basal ganglia-thalamic network. Foster NN, Barry J, Korobkova L, Garcia L, Gao L, Becerra M, Sherafat Y, Peng B, Li X, Choi JH, Gou L, Zingg B, Azam S, Lo D, Khanjani N, Zhang B, Stanis J, Bowman I, Cotter K, Cao C, Yamashita S, Tugangui A, Li A, Jiang T, Jia X, Feng Z, Aquino S, Mun HS, Zhu M, Santarelli A, Benavidez NL, Song M, Dan G, Fayzullina M, Ustrell S, Boesen T, Johnson DL, Xu H, Bienkowski MS, Yang XW, Gong H, Levine MS, Wickersham I, Luo Q, Hahn JD, Lim BK, Zhang LI, Cepeda C, Hintiryan H, Dong HW. Nature. 2021;598(7879):188-194.

Links:

Brain Basics: Know Your Brain (National Institute of Neurological Disorders and Stroke/NIH)

Dong Lab (University of California, Los Angeles)

Mark and Mary Stevens Neuroimaging and Informatics Institute (University of Southern California, Los Angeles)

The Brain Research Through Advancing Innovative Neurotechnologies® (BRAIN) Initiative (NIH)

NIH Support: Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute on Deafness and Other Communication Disorders; National Institute of Mental Health


Tapping Into The Brain’s Primary Motor Cortex

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If you’re like me, you might catch yourself during the day in front of a computer screen mindlessly tapping your fingers. (I always check first to be sure my mute button is on!) But all that tapping isn’t as mindless as you might think.

While a research participant performs a simple motor task, tapping her fingers together, this video shows blood flow within the folds of her brain’s primary motor cortex (gray and white), which controls voluntary movement. Areas of high brain activity (yellow and red) emerge in the omega-shaped “hand-knob” region, the part of the brain controlling hand movement (right of center) and then further back within the primary somatic cortex (which borders the motor cortex toward the back of the head).

About 38 seconds in, the right half of the video screen illustrates that the finger tapping activates both superficial and deep layers of the primary motor cortex. In contrast, the sensation of a hand being brushed (a sensory task) mostly activates superficial layers, where the primary sensory cortex is located. This fits with what we know about the superficial and deep layers of the hand-knob region, since they are responsible for receiving sensory input and generating motor output to control finger movements, respectively [1].

The video showcases a new technology called zoomed 7T perfusion functional MRI (fMRI). It was an entry in the recent Show Us Your BRAINs! Photo and Video Contest, supported by NIH’s Brain Research Through Advancing Innovative Neurotechnologies® (BRAIN) Initiative.

The technology is under development by an NIH-funded team led by Danny J.J. Wang, University of Southern California Mark and Mary Stevens Neuroimaging and Informatics Institute, Los Angeles. Zoomed 7T perfusion fMRI was developed by Xingfeng Shao and brought to life by the group’s medical animator Jim Stanis.

Measuring brain activity using fMRI to track perfusion is not new. The brain needs a lot of oxygen, carried to it by arteries running throughout the head, to carry out its many complex functions. Given the importance of oxygen to the brain, you can think of perfusion levels, measured by fMRI, as a stand-in measure for neural activity.

There are two things that are new about zoomed 7T perfusion fMRI. For one, it uses the first ultrahigh magnetic field imaging scanner approved by the Food and Drug Administration. The technology also has high sensitivity for detecting blood flow changes in tiny arteries and capillaries throughout the many layers of the cortex [2].

Compared to previous MRI methods with weaker magnets, the new technique can measure blood flow on a fine-grained scale, enabling scientists to remove unwanted signals (“noise”) such as those from surface-level arteries and veins. Getting an accurate read-out of activity from region to region across cortical layers can help scientists understand human brain function in greater detail in health and disease.

Having shown that the technology works as expected during relatively mundane hand movements, Wang and his team are now developing the approach for fine-grained 3D mapping of brain activity throughout the many layers of the brain. This type of analysis, known as mesoscale mapping, is key to understanding dynamic activities of neural circuits that connect brain cells across cortical layers and among brain regions.

Decoding circuits, and ultimately rewiring them, is a major goal of NIH’s BRAIN Initiative. Zoomed 7T perfusion fMRI gives us a window into 4D biology, which is the ability to watch 3D objects over time scales in which life happens, whether it’s playing an elaborate drum roll or just tapping your fingers.

References:

[1] Neuroanatomical localization of the ‘precentral knob’ with computed tomography imaging. Park MC, Goldman MA, Park MJ, Friehs GM. Stereotact Funct Neurosurg. 2007;85(4):158-61.

[2]. Laminar perfusion imaging with zoomed arterial spin labeling at 7 Tesla. Shao X, Guo F, Shou Q, Wang K, Jann K, Yan L, Toga AW, Zhang P, Wang D.J.J bioRxiv 2021.04.13.439689.

Links:

Brain Basics: Know Your Brain (National Institute of Neurological Disorders and Stroke)

Laboratory of Functional MRI Technology (University of Southern California Mark and Mary Stevens Neuroimaging and Informatics Institute)

The Brain Research Through Advancing Innovative Neurotechnologies® (BRAIN) Initiative (NIH)

Show Us Your BRAINs! Photo and Video Contest (BRAIN Initiative)

NIH Support: National Institute of Neurological Disorders and Stroke; National Institute of Biomedical Imaging and Bioengineering; Office of the Director


Precision Deep Brain Stimulation Shows Initial Promise for Severe Depression

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Caption: Implanted deep brain stimulation with one lead (blue) in the amygdala, and the other lead (red) in the ventral capsule/ventral striatum. Credit: Ken Probst, University of California, San Francisco

For many people struggling with depression, antidepressants and talk therapy can help to provide relief. But for some, the treatments don’t help nearly enough. I’m happy to share some early groundbreaking research in alleviating treatment-resistant depression in a whole new way: implanting a pacemaker-like device capable of delivering therapeutic electrical impulses deep into the brain, aiming for the spot where they can reset the depression circuit.

What’s so groundbreaking about the latest approach—so far, performed in just one patient—is that the electrodes didn’t simply deliver constant electrical stimulation. The system could recognize the specific pattern of brain activity associated with the patient’s depressive symptoms and deliver electrical impulses to the brain circuit where it could provide the most relief.

While much more study is needed, this precision approach to deep brain stimulation (DBS) therapy offered immediate improvement to the patient, a 36-year-old woman who’d suffered from treatment-resistant major depressive disorder since childhood. Her improvement has lasted now for more than a year.

This precision approach to DBS has its origins in clinical research supported through NIH’s Brain Research Through Advancing Innovative Neurotechnologies® (BRAIN) Initiative. A team, led by Edward Chang, a neurosurgeon at the University of California San Francisco’s (UCSF) Epilepsy Center, discovered while performing DBS that the low mood in some patients with epilepsy before surgery was associated with stronger activity in a “subnetwork” deep within the brain’s neural circuitry. The subnetwork involved crosstalk between the brain’s amygdala, which mediates fear and other emotions, and the hippocampus, which aids in memory.

Researchers led by Andrew Krystal, UCSF, Weill Institute for Neurosciences, attempted in the latest work to translate this valuable lead into improved care for depression. Their results were published recently in the journal Nature Medicine [1].

Krystal and colleagues, including Chang and Katherine Scangos, who is the first author of the new study, began by mapping patterns of brain activity in the patient that was associated with the onset of her low moods. They then customized an FDA-approved DBS device to respond only when it recognized those specific patterns. Called NeuroPace® RNS®, the device includes a small neurostimulator and measures about 6 by 3 centimeters, allowing it to be fully implanted inside a person’s skull. There, it continuously monitors brain activity and can deliver electrical stimulation via two leads, as shown in the image above [2].

Researchers found they could detect and predict high symptom severity best in the amygdala, as previously reported. The next question was where the electrical stimulation would best relieve those troubling brain patterns and associated symptoms. They discovered that stimulation in the brain’s ventral capsule/ventral striatum, part of the brain’s circuitry for decision-making and reward-related behavior, led to the most consistent and sustained improvements. Based on these findings, the team devised an on-demand and immediate DBS therapy that was unique to the patient’s condition.

It will be important to learn whether this precision approach to DBS is broadly effective for managing treatment-resistant depression and perhaps other psychiatric conditions. It will take much more study and time before such an approach to treating depression can become more widely available. Also, it is not yet clear just how much it would cost. But these remarkable new findings certainly point the way toward a promising new approach that will hopefully one day bring another treatment option for those in need of relief from severe depression.

References:

[1] Closed-loop neuromodulation in an individual with treatment-resistant depression. Scangos KW, Khambhati AN, Daly PM, Makhoul GS, Sugrue LP, Zamanian H, Liu TX, Rao VR, Sellers KK, Dawes HE, Starr PA, Krystal AD, Chang EF. Nat Med. 2021 Oct;27(10):1696-1700

[2] The NeuroPace® RNS® System for responsive neurostimulation, NIH BRAIN Initiative.

Links:

Depression (National Institute of Mental Health/NIH)

Deep Brain Stimulation for Parkinson’s Disease and other Movement Disorders (National Institute of Neurological Disorders and Stroke/NIH)

Andrew Krystal (University of California San Francisco)

Katherine Scangos (UCSF)

Edward Chang (UCSF)

NIH Support: National Institute of Neurological Disorders and Stroke


First Comprehensive Census of Cell Types in Brain Area Controlling Movement

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Credit: SciePro/Shutterstock; BRAIN Initiative Cell Census Network, Nature, 2021

The primary motor cortex is the part of the brain that enables most of our skilled movements, whether it’s walking, texting on our phones, strumming a guitar, or even spiking a volleyball. The region remains a major research focus, and that’s why NIH’s Brain Research Through Advancing Innovative Neurotechnologies® (BRAIN) Initiative – Cell Census Network (BICCN) has just unveiled two groundbreaking resources: a complete census of cell types present in the mammalian primary motor cortex, along with the first detailed atlas of the region, located along the back of the frontal lobe in humans (purple stripe above).

This remarkably comprehensive work, detailed in a flagship paper and more than a dozen associated articles published in the journal Nature, promises to vastly expand our understanding of the primary motor cortex and how it works to keep us moving [1]. The papers also represent the collaborative efforts of more than 250 BICCN scientists from around the world, teaming up over many years.

Started in 2013, the BRAIN Initiative is an ambitious project with a range of groundbreaking goals, including the creation of an open-access reference atlas that catalogues all of the brain’s many billions of cells. The primary motor cortex was one of the best places to get started on assembling an atlas because it is known to be well conserved across mammalian species, from mouse to human. There’s also a rich body of work to aid understanding of more precise cell-type information.

Taking advantage of recent technological advances in single-cell analysis, the researchers categorized into different types the millions of neurons and other cells in this brain region. They did so on the basis of morphology, or shape, of the cells, as well as their locations and connections to other cells. The researchers went even further to characterize and sort cells based on: their complex patterns of gene expression, the presence or absence of chemical (or epigenetic) marks on their DNA, the way their chromosomes are packaged into chromatin, and their electrical properties.

The new data and analyses offer compelling evidence that neural cells do indeed fall into distinct types, with a high degree of correspondence across their molecular genetic, anatomical, and physiological features. These findings support the notion that neural cells can be classified into molecularly defined types that are also highly conserved or shared across mammalian species.

So, how many cell types are there? While that’s an obvious question, it doesn’t have an easy answer. The number varies depending upon the method used for sorting them. The researchers report that they have identified about 25 classes of cells, including 16 different neuronal classes and nine non-neuronal classes, each composed of multiple subtypes of cells.

These 25 classes were determined by their genetic profiles, their locations, and other characteristics. They also showed up consistently across species and using different experimental approaches, suggesting that they have important roles in the neural circuitry and function of the motor cortex in mammals.

Still, many precise features of the cells don’t fall neatly into these categories. In fact, by focusing on gene expression within single cells of the motor cortex, the researchers identified more potentially important cell subtypes, which fall into roughly 100 different clusters, or distinct groups. As scientists continue to examine this brain region and others using the latest new methods and approaches, it’s likely that the precise number of recognized cell types will continue to grow and evolve a bit.

This resource will now serve as a springboard for future research into the structure and function of the brain, both within and across species. The datasets already have been organized and made publicly available for scientists around the world.

The atlas also now provides a foundation for more in-depth study of cell types in other parts of the mammalian brain. The BICCN is already engaged in an effort to generate a brain-wide cell atlas in the mouse, and is working to expand coverage in the atlas for other parts of the human brain.

The cell census and atlas of the primary motor cortex are important scientific advances with major implications for medicine. Strokes commonly affect this region of the brain, leading to partial or complete paralysis of the opposite side of the body.

By considering how well cell census information aligns across species, scientists also can make more informed choices about the best models to use for deepening our understanding of brain disorders. Ultimately, these efforts and others underway will help to enable precise targeting of specific cell types and to treat a wide range of brain disorders that affect thinking, memory, mood, and movement.

Reference:

[1] A multimodal cell census and atlas of the mammalian primary motor cortex. BRAIN Initiative Cell Census Network (BICCN). Nature. Oct 6, 2021.

Links:

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

BRAIN Initiative – Cell Census Network (BICCN) (NIH)

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


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