Parkinson’s disease
Groundbreaking Study Maps Key Brain Circuit
Posted on by Dr. Francis Collins
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
The Amazing Brain: Deep Brain Stimulation for OCD
Posted on by Dr. Francis Collins
The winners of the “Show Us Your BRAINs!” Photo and Video contest are chosen each year based on their eye-catching ability to capture the creative spirit of the Brain Research through Advancing Innovative Neurotechnologies® (BRAIN) Initiative. This year’s first-place video certainly fits the bill while highlighting encouraging efforts to help people with the most severe and hard-to-treat form of obsessive compulsive disorder (OCD), a psychiatric illness marked by recurrent unwanted or distressing thoughts and repetitive behaviors.
Most cases of OCD can be effectively treated with a combination of pharmacotherapy and cognitive behavioral therapy. But for a small subset of individuals with severe, intractable, and debilitating OCD, other approaches are needed.
The video shows a 360-degree view of the brain of a person with severe OCD. At about 15 seconds into the video, the brain’s outer surface fades away to reveal the critical brain structures that serve as landmarks for targeting the disorder.
These include the anterior commissure (orange), helping to transfer information between the brain’s two hemispheres; caudate nucleus (dark blue), involved in various higher neurological functions, such as learning and memory; putamen (light blue), which plays a role in learning and motor control; and ventral striatum (yellow), part of the brain’s circuitry for decision-making and reward-related behavior.
This person is a participant in a clinical trial to alleviate OCD symptoms using deep brain stimulation (DBS). In DBS, electrodes are implanted deep in the brain to deliver electrical impulses that regulate abnormal, repetitive brain impulses. The straight lines (purple) are wire leads, each bearing a single electrode topped with an electrical contact (white). These leads connect to a pacemaker-like device implanted in the chest (not shown) that delivers electrical impulses that ease the patient’s distressing thoughts and unwanted behaviors.
The video took a true team effort. Nicole Provenza, a graduate student in the lab of David Borton, Brown University, Providence, RI, produced it with the project’s principal investigator Wayne Goodman, lead neurosurgeon Sameer Sheth, and research assistant Raissa Mathura, all at Baylor College of Medicine, Houston. Another vital contributor was Noam Peled, MGH/HST Martinos Center for Biomedical Imaging, Charlestown, MA.
The team produced the video primarily to help explain how DBS works for people with OCD. But such visualizations are also helping them to see where exactly in the brain electrodes have been placed during surgery in each of their study participants.
Right now, the location of DBS electrodes can’t be imaged using MRI. So CT scans must be taken after surgery that combine X-ray images from different angles. The researchers then carefully align the MRI and CT scans and load them into special software called Multi-Modality Visualization Tool (MMVT). The software enables simultaneous 3D visualization and analysis of brain imaging data captured in different ways.
Using MMVT, Provenza and colleagues labelled the brain regions of interest and spun the image around to see just where those leads were placed in this particular individual with OCD. They then captured many still images, which they stitched together to produce this remarkable video.
Deep brain stimulation is used to treat Parkinson’s disease and other movement disorders. But earlier attempts to treat severe and intractable OCD with DBS haven’t yet succeeded in the way researchers had hoped. This innovative team seeks to change that in the future by using more responsive and adaptive systems, capable of sensing the abnormal brain impulses as they happen and responding at just the right time [1].
Reference:
[1] The case for adaptive neuromodulation to treat severe intractable mental disorders. Provenza NR, Matteson ER, Allawala AB, Barrios-Anderson A, Sheth SA, Viswanathan A, McIngvale E, Storch EA, Frank MJ, McLaughlin NCR, Cohn JF, Goodman WK, Borton DA. Front Neurosci. 2019 Feb 26;13:152.
Links:
Brain Research through Advancing Innovative Neurotechnologies® (BRAIN) Initiative (NIH)
Obsessive-Compulsive Disorder (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)
Borton Lab (Brown University, Providence, RI)
Wayne Goodman (Baylor College of Medicine, Houston)
Noam Peled (MGH/HST Martinos Center for Biomedical Imaging, Charlestown, MA)
Show Us Your BRAINs! Photo and Video Contest (BRAIN Initiative/NIH)
NIH Support: National Institute of Neurological Disorders and Stroke; National Institute of Mental Health
See the Human Cardiovascular System in a Whole New Way
Posted on by Dr. Francis Collins
Watch this brief video and you might guess you’re seeing an animated line drawing, gradually revealing a delicate take on a familiar system: the internal structures of the human body. But this movie doesn’t capture the work of a talented sketch artist. It was created using the first 3D, full-body imaging device using positron emission tomography (PET).
The device is called an EXPLORER (EXtreme Performance LOng axial REsearch scanneR) total-body PET scanner. By pairing this scanner with an advanced method for reconstructing images from vast quantities of data, the researchers can make movies.
For this movie in particular, the researchers injected small amounts of a short-lived radioactive tracer—an essential component of all PET scans—into the lower leg of a study volunteer. They then sat back as the scanner captured images of the tracer moving up the leg and into the body, where it enters the heart. The tracer moves through the heart’s right ventricle to the lungs, back through the left ventricle, and up to the brain. Keep watching, and, near the 30-second mark, you will see in closer focus a haunting capture of the beating heart.
This groundbreaking scanner was developed and tested by Jinyi Qi, Simon Cherry, Ramsey Badawi, and their colleagues at the University of California, Davis [1]. As the NIH-funded researchers reported recently in Proceedings of the National Academy of Sciences, their new scanner can capture dynamic changes in the body that take place in a tenth of a second [2]. That’s faster than the blink of an eye!
This movie is composed of frames captured at 0.1-second intervals. It highlights a feature that makes this scanner so unique: its ability to visualize the whole body at once. Other medical imaging methods, including MRI, CT, and traditional PET scans, can be used to capture beautiful images of the heart or the brain, for example. But they can’t show what’s happening in the heart and brain at the same time.
The ability to capture the dynamics of radioactive tracers in multiple organs at once opens a new window into human biology. For example, the EXPLORER system makes it possible to measure inflammation that occurs in many parts of the body after a heart attack, as well as to study interactions between the brain and gut in Parkinson’s disease and other disorders.
EXPLORER also offers other advantages. It’s extra sensitive, which enables it to capture images other scanners would miss—and with a lower dose of radiation. It’s also much faster than a regular PET scanner, making it especially useful for imaging wiggly kids. And it expands the realm of research possibilities for PET imaging studies. For instance, researchers might repeatedly image a person with arthritis over time to observe changes that may be related to treatments or exercise.
Currently, the UC Davis team is working with colleagues at the University of California, San Francisco to use EXPLORER to enhance our understanding of HIV infection. Their preliminary findings show that the scanner makes it easier to capture where the human immunodeficiency virus (HIV), the cause of AIDS, is lurking in the body by picking up on signals too weak to be seen on traditional PET scans.
While the research potential for this scanner is clearly vast, it also holds promise for clinical use. In fact, a commercial version of the scanner, called uEXPLORER, has been approved by the FDA and is in use at UC Davis [3]. The researchers have found that its improved sensitivity makes it much easier to detect cancers in patients who are obese and, therefore, harder to image well using traditional PET scanners.
As soon as the COVID-19 outbreak subsides enough to allow clinical research to resume, the researchers say they’ll begin recruiting patients with cancer into a clinical study designed to compare traditional PET and EXPLORER scans directly.
As these researchers, and other researchers around the world, begin to put this new scanner to use, we can look forward to seeing many more remarkable movies like this one. Imagine what they will reveal!
References:
[1] First human imaging studies with the EXPLORER total-body PET scanner. Badawi RD, Shi H, Hu P, Chen S, Xu T, Price PM, Ding Y, Spencer BA, Nardo L, Liu W, Bao J, Jones T, Li H, Cherry SR. J Nucl Med. 2019 Mar;60(3):299-303.
[2] Subsecond total-body imaging using ultrasensitive positron emission tomography. Zhang X, Cherry SR, Xie Z, Shi H, Badawi RD, Qi J. Proc Natl Acad Sci U S A. 2020 Feb 4;117(5):2265-2267.
[3] “United Imaging Healthcare uEXPLORER Total-body Scanner Cleared by FDA, Available in U.S. Early 2019.” Cision PR Newswire. January 22, 2019.
Links:
Positron Emission Tomography (PET) (NIH Clinical Center)
EXPLORER Total-Body PET Scanner (University of California, Davis)
Cherry Lab (UC Davis)
Badawi Lab (UC Davis Medical Center, Sacramento)
NIH Support: National Cancer Institute; National Institute of Biomedical Imaging and Bioengineering; Common Fund
New Grants Explore Benefits of Music on Health
Posted on by Dr. Francis Collins
It’s not every day you get to perform with one of the finest voices on the planet. What an honor it was to join renowned opera singer Renée Fleming back in May for a rendition of “How Can I Keep from Singing?” at the NIH’s J. Edward Rall Cultural Lecture. Yet our duet was so much more. Between the song’s timeless message and Renée’s matchless soprano, the music filled me with a profound sense of joy, like being briefly lifted outside myself into a place of beauty and well-being. How does that happen?
Indeed, the benefits of music for human health and well-being have long been recognized. But biomedical science still has a quite limited understanding of music’s mechanisms of action in the brain, as well as its potential to ease symptoms of an array of disorders including Parkinson’s disease, stroke, and post-traumatic stress disorder (PTSD). In a major step toward using rigorous science to realize music’s potential for improving human health, NIH has just awarded $20 million over five years to support the first research projects of the Sound Health initiative. Launched a couple of years ago, Sound Health is a partnership between NIH and the John F. Kennedy Center for the Performing Arts, in association with the National Endowment for the Arts.
With support from 10 NIH institutes and centers, the Sound Health awardees will, among other things, study how music might improve the motor skills of people with Parkinson’s disease. Previous research has shown that the beat of a metronome can steady the gait of someone with Parkinson’s disease, but more research is needed to determine exactly why that happens.
Other fascinating areas to be explored by the Sound Health awardees include:
• Assessing how active music interventions, often called music therapies, affect multiple biomarkers that correlate with improvement in health status. The aim is to provide a more holistic understanding of how such interventions serve to ease cancer-related stress and possibly even improve immune function.
• Investigating the effects of music on the developing brain of infants as they learn to talk. Such work may be especially helpful for youngsters at high risk for speech and language disorders.
• Studying synchronization of musical rhythm as part of social development. This research will look at how this process is disrupted in children with autism spectrum disorder, possibly suggesting ways of developing music-based interventions to improve communication.
• Examining the memory-related impacts of repeated exposures to a certain song or musical phrase, including those “earworms” that get “stuck” in our heads. This work might tell us more about how music sometimes serves as a cue for retrieving associated memories, even in people whose memory skills are impaired by Alzheimer’s disease or other cognitive disorders.
• Tracing the developmental timeline—from childhood to adulthood—of how music shapes the brain. This will include studying how musical training at different points on that timeline may influence attention span, executive function, social/emotional functioning, and language skills.
We are fortunate to live in an exceptional time of discovery in neuroscience, as well as an extraordinary era of creativity in music. These Sound Health grants represent just the beginning of what I hope will be a long and productive partnership that brings these creative fields together. I am convinced that the power of science holds tremendous promise for improving the effectiveness of music-based interventions, and expanding their reach to improve the health and well-being of people suffering from a wide variety of conditions.
Links:
The Soprano and the Scientist: A Conversation About Music and Medicine, (National Public Radio, June 2, 2017)
NIH Workshop on Music and Health, January 2017
Sound Health (NIH)
NIH Support: National Center for Complementary and Integrative Health; National Eye Institute; National Institute on Aging; National Institute on Alcohol Abuse and Alcoholism; National Institute on Deafness and Other Communication Disorders; National Institute of Mental Health; National Institute of Neurological Disorders and Stroke; National Institute of Nursing Research; Office of Behavioral and Social Sciences Research; Office of the Director
The Amazing Brain: Zooming Through the Globus Pallidus Externa
Posted on by Dr. Francis Collins
The Brain Research through Advancing Innovative Neurotechnologies® (BRAIN) Initiative continues to find new ways to visualize neurons interconnecting into the billions of circuits that control our thoughts, feelings, and movements. This video, another winner in the initiative’s “Show Us Your Brain!” contest, offers a beautiful example of how these imaging techniques are getting better all the time.
The video features a millimeter-thick block of fixed tissue from a part of the mouse brain that’s known for its role in controlling voluntary movement. It’s called the globus pallidus externa (GPE). The video takes us inside the 3D landscape of the GPE, zooming in on the many neural cell bodies (yellow) and their arm-like extensions (red) that receive or transmit information. There’s also another class of neural cells called interneurons (blue) that act only within the circuit.
The video comes from the lab of Kwanghun Chung, Massachusetts Institute of Technology, Cambridge, in collaboration with Byungkook Lim’s group at the University of California, San Diego, and showcases a technique called SHIELD [1]. Brain tissue is extremely delicate to work with and prone to damage. SHIELD, developed in the Chung lab, offers a new way around this longstanding problem.
SHIELD uses polyepoxides, which are epoxy resins often used to produce glues. The researchers’ polyepoxide of choice has a flexible backbone and five branches, which bind to proteins and other molecules in place, including DNA and RNA. The molecule’s flexibility allows it to bind in multiple places along a single biomolecule and form supportive cross-links with other nearby molecules.
All of this support renders the tissue and its biological information extremely stable, even when exposed to heat and other harsh conditions. This makes it possible for researchers to label proteins, RNA, and various other biomolecules of interest simultaneously, as you see shown here in this remarkable video. SHIELD even allowed them to trace the many projections of multiple neural cell types and their connections within the GPE at once.
In the future, the team hopes to learn whether differences in the projection patterns of these neurons or in their molecular details may influence Parkinson’s disease and other illnesses that affect motor control. With this imaging advance and others through the BRAIN Initiative, mapping the biocircuitry of the brain just keeps getting better all the time.
Reference:
[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.
Links:
Brain Basics: Know Your Brain (National Institute of Neurological Disorders and Stroke/NIH)
Chung Lab (Massachusetts Institute of Technology, Cambridge)
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
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