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The Amazing Brain: Motor Neurons of the Cervical Spine

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Today, you may have opened a jar, done an upper body workout, played a guitar or a piano, texted a friend, or maybe even jotted down a grocery list longhand. All of these “skilled” arm, wrist, and hand movements are made possible by the bundled nerves, or circuits, running through a part of the central nervous system in the neck area called the cervical spine.

This video, which combines sophisticated imaging and computation with animation, shows the density of three types of nerve cells in the mouse cervical spine. There are the V1 interneurons (red), which sit between sensory and motor neurons; motor neurons associated with controlling the movement of the bicep (blue); and motor neurons associated with controlling the tricep (green).

At 4 seconds, the 3D animation morphs to show all the colors and cells intermixed as they are naturally in the cervical spine. At 8 seconds, the animation highlights the density of these three cells types. Notice in the bottom left corner, a light icon appears indicating the different imaging perspectives. What’s unique here is the frontal, or rostral, view of the cervical spine. The cervical spine is typically imaged from a lateral, or side, perspective.

Starting at 16 seconds, the animation highlights the location and density of each of the individual neurons. For the grand finale, viewers zoom off on a brief fly-through of the cervical spine and a flurry of reds, blues, and greens.

The video comes from Jamie Anne Mortel, a research assistant in the lab of Samuel Pfaff, Salk Institute, La Jolla, CA. Mortel is part of a team supported by the NIH-led Brain Research through Advancing Innovative Neurotechnologies® (BRAIN) Initiative that’s developing a comprehensive atlas of the circuitry within the cervical spine that controls how mice control their forelimb movements, such as reaching and grasping.

This basic research will provide a better understanding of how the mammalian brain and spinal cord work together to produce movement. More than that, this research may provide valuable clues into better treating paralysis to arms, wrists, and/or hands caused by neurological diseases and spinal cord injuries.

As a part of this project, the Pfaff lab has been busy developing a software tool to take their imaging data from different parts of the cervical spine and present it in 3D. Mortel, who likes to make cute cartoon animations in her spare time, noticed that the software lacked animation capability. So she took the initiative and spent the next three weeks working after hours to produce this video—her first attempt at scientific animation. No doubt she must have been using a lot of wrist and hand movements!

With a positive response from her Salk labmates, Mortel decided to enter her scientific animation debut in the 2021 Show Us BRAINs! Photo and Video Contest. To her great surprise and delight, Mortel won third place in the video competition. Congratulations, and continued success for you and the team in producing this much-needed atlas to define the circuitry underlying skilled arm, wrist, and hand movements.


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

Spinal Cord Injury Information Page (National Institute of Neurological Disorders and Stroke/NIH)

Samuel Pfaff (Salk Institute, La Jolla, CA)

Show Us Your BRAINs! Photo and Video Contest (Brain Initiative/NIH)

NIH Support: National Institute of Neurological Disorders and Stroke

The Amazing Brain: A Sharper Image of the Pyramidal Tract

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Flip the image above upside down, and the shape may remind you of something. If you think it resembles a pyramid, then you and a lot of great neuroscientists are thinking alike. What you are viewing is a colorized, 3D reconstruction of a pyramidal tract, which are bundles of nerve fibers that originate from the brain’s cerebral cortex and relay signals to the brainstem or the spinal cord. These signals control many important activities, including the voluntary movement of our arms, legs, head, and face.

For a while now, it’s been possible to combine a specialized form of magnetic resonance imaging (MRI) with computer modeling tools to produce 3D reconstructions of complicated networks of nerve fibers, such as the pyramidal tract. Still, for technical reasons, the quality of these reconstructions has remained poor in parts of the brain where nerve fibers cross at angles of 40 degrees or less.

The video above demonstrates how adding a sophisticated algorithm, called Orientation Distribution Function (ODF)-Fingerprinting, to such modeling can help overcome this problem when reconstructing a pyramidal tract. It has potential to enhance the reliability of these 3D reconstructions as neurosurgeons begin to use them to plan out their surgeries to help ensure they are carried out with the utmost safety and precision.

In the first second of the video, you see gray, fuzzy images from a diffusion MRI of the pyramidal tract. But, very quickly, a more colorful, detailed 3D reconstruction begins to appear, swiftly filling in from the top down. Colors are used to indicate the primary orientations of the nerve fibers: left to right (red), back to front (green), and top to bottom (blue). The orange, magenta, and other colors represent combinations of these primary directional orientations.

About three seconds into the video, a rough draft of the 3D reconstruction is complete. The top of the pyramidal tract looks pretty good. However, looking lower down, you can see distortions in color and relatively poor resolution of the nerve fibers in the middle of the tract—exactly where the fibers cross each other at angles of less than 40 degrees. So, researchers tapped into the power of their new ODF-Fingerprinting software to improve the image—and, starting about nine seconds into the video, you can see an impressive final result.

The researchers who produced this amazing video are Patryk Filipiak and colleagues in the NIH-supported lab of Steven Baete, Center for Advanced Imaging Innovation and Research, New York University Grossman School of Medicine, New York. The work paired diffusion MRI data from the NIH Human Connectome Project with the ODF-Fingerprinting algorithm, which was created by Baete to incorporate additional MRI imaging data on the shape of nerve fibers to infer their directionality [1].

This innovative approach to imaging recently earned Baete’s team second place in the 2021 “Show Us Your BRAINs” Photo and Video contest, sponsored by the NIH-led Brain Research through Advancing Innovative Neurotechnologies® (BRAIN) Initiative. But researchers aren’t stopping there! They are continuing to refine ODF-Fingerprinting, with the aim of modeling the pyramidal tract in even higher resolution for use in devising new and better ways of helping people undergoing neurosurgery.


[1] Fingerprinting Orientation Distribution Functions in diffusion MRI detects smaller crossing angles. Baete SH, Cloos MA, Lin YC, Placantonakis DG, Shepherd T, Boada FE. Neuroimage. 2019 Sep;198:231-241.


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

Human Connectome Project (University of Southern California, Los Angeles)

Steven Baete (Center for Advanced Imaging Innovation and Research, New York University Grossman School of Medicine, New York)

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

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

Understanding Neuronal Diversity in the Spinal Cord

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Cross-section image of spinal cord showing glowing green and magenta neurons.
Credit: Salk Institute, La Jolla, CA

The spinal cord, as a key part of our body’s central nervous system, contains millions of neurons that actively convey sensory and motor (movement) information to and from the brain. Scientists have long sorted these spinal neurons into what they call “cardinal” classes, a classification system based primarily on the developmental origin of each nerve cell. Now, by taking advantage of the power of single-cell genetic analysis, they’re finding that spinal neurons are more diverse than once thought.

This image helps to visualize the story. Each dot represents the nucleus of a spinal neuron in a mouse; humans have a very similar arrangement. Most of these neurons are involved in the regulation of motor control, but they also differ in important ways. Some are involved in local connections (green), such as those that signal outward to a limb and prompt us to pull away reflexively when we touch painful stimuli, such as a hot frying pan. Others are involved in long-range connections (magenta), relaying commands across spinal segments and even upward to the brain. These enable us, for example, to swing our arms while running to help maintain balance.

It turns out that these two types of spinal neurons also have distinctive genetic signatures. That’s why researchers could label them here in different colors and tell them apart. Being able to distinguish more precisely among spinal neurons will prove useful in identifying precisely which ones are affected by a spinal cord injury or neurodegenerative disease, key information in learning to engineer new tissue to heal the damage.

This image comes from a study, published recently in the journal Science, conducted by an NIH-supported team led by Samuel Pfaff, Salk Institute for Biological Studies, La Jolla, CA. Pfaff and his colleagues, including Peter Osseward and Marito Hayashi, realized that the various classes and subtypes of neurons in our spines arose over the course of evolutionary time. They reasoned that the most-primitive original neurons would have gradually evolved subtypes with more specialized and diverse capabilities. They thought they could infer this evolutionary history by looking for conserved and then distinct, specialized gene-expression signatures in the different neural subtypes.

The researchers turned to single-cell RNA sequencing technologies to look for important similarities and differences in the genes expressed in nearly 7,000 mouse spinal neurons. They then used this vast collection of genomic data to group the neurons into closely related clusters, in much the same way that scientists might group related organisms into an evolutionary family tree based on careful study of their DNA.

The first major gene expression pattern they saw divided the spinal neurons into two types: sensory-related and motor-related. This suggested to them that one of the first steps in spinal cord evolution may have been a division of labor of spinal neurons into those two fundamentally important roles.

Further analyses divided the sensory-related neurons into excitatory neurons, which make neurons more likely to fire; and inhibitory neurons, which dampen neural firing. Then, the researchers zoomed in on motor-related neurons and found something unexpected. They discovered the cells fell into two distinct molecular groups based on whether they had long-range or short-range connections in the body. Researches were even more surprised when further study showed that those distinct connectivity signatures were shared across cardinal classes.

All of this means that, while previously scientists had to use many different genetic tags to narrow in on a particular type of neuron, they can now do it with just two: a previously known tag for cardinal class and the newly discovered genetic tag for long-range vs. short-range connections.

Not only is this newfound ability a great boon to basic neuroscientists, it also could prove useful for translational and clinical researchers trying to determine which specific neurons are affected by a spinal injury or disease. Eventually, it may even point the way to strategies for regrowing just the right set of neurons to repair serious neurologic problems. It’s a vivid reminder that fundamental discoveries, such as this one, often can lead to unexpected and important breakthroughs with potential to make a real difference in people’s lives.


[1] Conserved genetic signatures parcellate cardinal spinal neuron classes into local and projection subsets. Osseward PJ 2nd, Amin ND, Moore JD, Temple BA, Barriga BK, Bachmann LC, Beltran F Jr, Gullo M, Clark RC, Driscoll SP, Pfaff SL, Hayashi M. Science. 2021 Apr 23;372(6540):385-393.


What Are the Parts of the Nervous System? (Eunice Kennedy Shriver National Institute of Child Health and Human Development/NIH)

Spinal Cord Injury (National Institute of Neurological Disorders and Stroke/NIH)

Samuel Pfaff (Salk Institute, La Jolla, CA)

NIH Support: National Institute of Mental Health; National Institute of Neurological Disorders and Stroke; Eunice Kennedy Shriver National Institute of Child Health and Human Development

Putting 3D Printing to Work to Heal Spinal Cord Injury

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3D printed scaffold for spinal repair
Credit: Jacob Koffler and Wei Zhu, University of California, San Diego

For people whose spinal cords are injured in traffic accidents, sports mishaps, or other traumatic events, cell-based treatments have emerged as a potential avenue for encouraging healing. Now, taking advantage of advances in 3D printing technology, researchers have created customized implants that may boost the power of cell-based therapies for repairing injured spinal cords.

Made of soft hydrogels that mimic spinal cord tissue, the implant pictured here measures just 2 millimeters across and is about as thick as a penny. It was specially designed to encourage healing in rats with spinal cord injuries. The tiny, open channels that surround the solid “H”-shaped core are designed to guide the growth of new neural extensions, keeping them aligned properly with the spinal cord.

When left on their own, neural cells have a tendency to grow haphazardly. But the 3D-printed implant is engineered to act as a scaffold, keeping new cells directed toward the goal of patching up the injured part of the spinal cord.

For the new work, an NIH-funded research team, led by Jacob Koffler, Wei Zhu, Shaochen Chen, and Mark Tuszynski of the University of California, San Diego (UCSD), used an innovative 3D printing technology called microscale continuous projection printing. This technology relies on a computer projection system and precisely controlled mirrors, which direct light into a solution containing photo-sensitive polymers and cells to produce the final product. Using this approach, the researchers fabricated finely detailed, rodent-sized implants in less than 2 seconds. That’s about 1,000 times faster than a traditional 3D printer!

In a study published recently in Nature Medicine, the researchers placed their custom-made implants, loaded with rat embryonic neural stem cells, into the injured spinal cords of 11 rats. Other rats with similar injuries received empty implants or stem cells without the implant. Within 5 months, rats with the cell-loaded implants had new neural cells bridging the injured area, along with spontaneous regrowth of blood vessels to feed the new neural tissue. Most importantly, they had regained use of their hind limbs. Animals receiving empty implants or cell-based therapy without an implant didn’t show that kind of recovery.

The new findings offer proof-of-principle that 3D printing technology can be used to create implants tailored to the precise shape and size of an injury. In fact, the researchers have already scaled up the process to produce 4-centimeter-sized implants to match several different, complex spinal cord injuries in humans. These implants were printed in a mere 10 minutes.

The UCSD team continues to work on further improvements, including the addition of growth factors or other ingredients that may further encourage neuron growth and functional recovery. If all goes well, the team hopes to launch human clinical trials of their cell-based treatments for spinal cord injury within a few years. And that should provide hope for the hundreds of thousands of people around the world who suffer serious spinal cord injuries each year.


[1] Biomimetic 3D-printed scaffolds for spinal cord injury repair. Koffler J, Zhu W, Qu X, Platoshyn O, Dulin JN, Brock J, Graham L, Lu P, Sakamoto J, Marsala M, Chen S, Tuszynski MH. Nat Med. 2019 Feb;25(2):263-269.


Spinal Cord Injury Information Page (National Institute of Neurological Disorders and Stroke/NIH)

Stem Cell Information (NIH)

Koffler Lab (University of California, San Diego)

Shaochen Chen (UCSD)

Tuszynski Lab (UCSD)

NIH Support: National Institute of Biomedical Imaging and Bioengineering; National Institute of Child Health and Human Development

Snapshots of Life: Healing Spinal Cord Injuries

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Nerve cell on a nanofiber gel

Credit: Mark McClendon, Zaida Alvarez Pinto, Samuel I. Stupp, Northwestern University, Evanston, IL

When someone suffers a fully severed spinal cord, it’s considered highly unlikely the injury will heal on its own. That’s because the spinal cord’s neural tissue is notorious for its inability to bridge large gaps and reconnect in ways that restore vital functions. But the image above is a hopeful sight that one day that could change.

Here, a mouse neural stem cell  (blue and green) sits in a lab dish, atop a special gel containing a mat of synthetic nanofibers (purple). The cell is growing and sending out spindly appendages, called axons (green), in an attempt to re-establish connections with other nearby nerve cells.

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