Posted on by Dr. Francis Collins
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 .
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.
 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.
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
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 .
 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.
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
Posted on by Dr. Francis Collins
Throw a stone into a quiet pond, and you’ll see ripples expand across the water from the point where it went in. Now, neuroscientists have discovered that a different sort of ripple—an electrical ripple—spreads across the human brain when it strives to recall memories.
In memory games involving 14 very special volunteers, an NIH-funded team found that the split second before a person nailed the right answer, tiny ripples of electrical activity appeared in two specific areas of the brain . If the volunteer recalled an answer incorrectly or didn’t answer at all, the ripples were much less likely to appear. While many questions remain, the findings suggest that the short, high-frequency electrical waves seen in these brain ripples may play an unexpectedly important role in our ability to remember.
The new study, published in Science, builds on brain recording data compiled over the last several years by neurosurgeon and researcher Kareem Zaghloul at NIH’s National Institute of Neurological Disorders and Stroke (NINDS). Zaghloul’s surgical team often temporarily places 10-to-20 arrays of tiny electrodes into the brains of a people with drug-resistant epilepsy. As I’ve highlighted recently, the brain mapping procedure aims to pinpoint the source of a patient’s epileptic seizures. But, with a patient’s permission, the procedure also presents an opportunity to learn more about how the brain works, with exceptional access to its circuits.
One such opportunity is to explore how the brain stores and recalls memories. To do this, the researchers show their patient volunteers hundreds of pairs of otherwise unrelated words, such as “pencil and bishop” or “orange and navy.” Later, they show them one of the words and test their memory to recall the right match. All the while, electrodes record the brain’s electrical activity.
Previously published studies by Zaghloul’s lab [2, 3] and many others have shown that memory involves the activation of a number of brain regions. That includes the medial temporal lobe, which is involved in forming and retrieving memories, and the prefrontal cortex, which helps in organizing memories in addition to its roles in “executive functions,” such as planning and setting goals. Those studies also have highlighted a role for the temporal association cortex, another portion of the temporal lobe involved in processing experiences and words.
In their data collected in patients with epilepsy, Zaghloul’s team’s earlier studies had uncovered some telltale patterns. For instance, when a person correctly recalled a word pair, the brain showed patterns of activity that looked quite similar to those present when he or she first learned to make a word association.
Alex Vaz, one of Zaghloul’s doctoral students, thought there might be more to the story. There was emerging evidence in rodents that brain ripples—short bursts of high frequency electrical activity—are involved in learning. There was also some evidence in people that such ripples might be important for solidifying memories during sleep. Vaz wondered whether they might find evidence of ripples as well in data gathered from people who were awake.
Vaz’s hunch was correct. The reanalysis revealed ripples of electricity in the medial temporal lobe and the temporal association cortex. When a person correctly recalled a word pair, those two brain areas rippled at the same time.
Further analysis showed that the ripples appeared in those two areas a few milliseconds before a volunteer remembered a word and gave a correct answer. Your brain is working on finding an answer before you are fully aware of it! Those ripples also appear to trigger brain waves that look similar to those observed in the association cortex when a person first learned a word pair.
The finding suggests that ripples in this part of the brain precede and may help to prompt the larger brain waves associated with replaying and calling to mind a particular memory. For example, hearing the words, “The Fab Four” may ripple into a full memory of a favorite Beatles album (yes! Sgt. Pepper’s Lonely Hearts Club Band) or, if you were lucky enough, a memorable concert back in the day (I never had that chance).
Zaghloul’s lab continues to study the details of these ripples to learn even more about how they may influence other neural signals and features involved in memory. So, the next time you throw a stone into a quiet pond and watch the ripples, perhaps it will trigger an electrical ripple in your brain to remember this blog and ruminate about this fascinating new discovery in neuroscience.
 Coupled ripple oscillations between the medial temporal lobe and neocortex retrieve human memory. Vaz AP, Inati SK, Brunel N, Zaghloul KA. Science. 2019 Mar 1;363(6430):975-978.
 Cued Memory Retrieval Exhibits Reinstatement of High Gamma Power on a Faster Timescale in the Left Temporal Lobe and Prefrontal Cortex. Yaffe RB, Shaikhouni A, Arai J, Inati SK, Zaghloul KA. J Neurosci. 2017 Apr 26;37(17):4472-4480.
 Human Cortical Neurons in the Anterior Temporal Lobe Reinstate Spiking Activity during Verbal Memory Retrieval. Jang AI, Wittig JH Jr, Inati SK, Zaghloul KA. Curr Biol. 2017 Jun 5;27(11):1700-1705.e5.
Epilepsy Information Page (National Institute of Neurological Disorders and Stroke/NIH)
Brain Basics (NINDS)
Zaghloul Lab (NINDS)
NIH Support: National Institute of Neurological Disorders and Stroke; National Institute of General Medical Sciences
Posted on by Dr. Francis Collins
If laughter really is the best medicine, wouldn’t it be great if we could learn more about what goes on in the brain when we laugh? Neuroscientists recently made some major progress on this front by pinpointing a part of the brain that, when stimulated, never fails to induce smiles and laughter.
In their study conducted in three patients undergoing electrical stimulation brain mapping as part of epilepsy treatment, the NIH-funded team found that stimulation of a specific tract of neural fibers, called the cingulum bundle, triggered laughter, smiles, and a sense of calm. Not only do the findings shed new light on the biology of laughter, researchers hope they may also lead to new strategies for treating a range of conditions, including anxiety, depression, and chronic pain.
In people with epilepsy whose seizures are poorly controlled with medication, surgery to remove seizure-inducing brain tissue sometimes helps. People awaiting such surgeries must first undergo a procedure known as intracranial electroencephalography (iEEG). This involves temporarily placing 10 to 20 arrays of tiny electrodes in the brain for up to several weeks, in order to pinpoint the source of a patient’s seizures in the brain. With the patient’s permission, those electrodes can also enable physician-researchers to stimulate various regions of the patient’s brain to map their functions and make potentially new and unexpected discoveries.
In the new study, published in The Journal of Clinical Investigation, Jon T. Willie, Kelly Bijanki, and their colleagues at Emory University School of Medicine, Atlanta, looked at a 23-year-old undergoing iEEG for 8 weeks in preparation for surgery to treat her uncontrolled epilepsy . One of the electrodes implanted in her brain was located within the cingulum bundle and, when that area was stimulated for research purposes, the woman experienced an uncontrollable urge to laugh. Not only was the woman given to smiles and giggles, she also reported feeling relaxed and calm.
As a further and more objective test of her mood, the researchers asked the woman to interpret the expression of faces on a computer screen as happy, sad, or neutral. Electrical stimulation to the cingulum bundle led her to see those faces as happier, a sign of a generally more positive mood. A full evaluation of her mental state also showed she was fully aware and alert.
To confirm the findings, the researchers looked to two other patients, a 40-year-old man and a 28-year-old woman, both undergoing iEEG in the course of epilepsy treatment. In those two volunteers, stimulation of the cingulum bundle also triggered laughter and reduced anxiety with otherwise normal cognition.
Willie notes that the cingulum bundle links many brain areas together. He likens it to a super highway with lots of on and off ramps. He suspects the spot they’ve uncovered lies at a key intersection, providing access to various brain networks regulating mood, emotion, and social interaction.
Previous research has shown that stimulation of other parts of the brain can also prompt patients to laugh. However, what makes stimulation of the cingulum bundle a particularly promising approach is that it not only triggers laughter, but also reduces anxiety.
The new findings suggest that stimulation of the cingulum bundle may be useful for calming patients’ anxieties during neurosurgeries in which they must remain awake. In fact, Willie’s team did so during their 23-year-old woman’s subsequent epilepsy surgery. Each time she became distressed, the stimulation provided immediate relief. Also, if traditional deep brain stimulation or less invasive means of brain stimulation can be developed and found to be safe for long-term use, they may offer new ways to treat depression, anxiety disorders, and/or chronic pain.
Meanwhile, Willie’s team is hard at work using similar approaches to map brain areas involved in other aspects of mood, including fear, sadness, and anxiety. Together with the multidisciplinary work being mounted by the NIH-led BRAIN Initiative, these kinds of studies promise to reveal functionalities of the human brain that have previously been out of reach, with profound consequences for neuroscience and human medicine.
 Cingulum stimulation enhances positive affect and anxiolysis to facilitate awake craniotomy. Bijanki KR, Manns JR, Inman CS, Choi KS, Harati S, Pedersen NP, Drane DL, Waters AC, Fasano RE, Mayberg HS, Willie JT. J Clin Invest. 2018 Dec 27.
Video: Patient’s Response (Bijanki et al. The Journal of Clinical Investigation)
Epilepsy Information Page (National Institute of Neurological Disease and Stroke/NIH)
Jon T. Willie (Emory University, Atlanta, GA)
NIH Support: National Institute of Neurological Disease and Stroke; National Center for Advancing Translational Sciences