People with Alzheimer’s disease develop defects in cognitive functions like memory as well as problems with noncognitive functions that can lead to anxiety and depression. In a paper published April 6 in the journal Cell Stem Cell, investigators used mice to study a process through which new neurons are generated in adulthood, called adult hippocampus neurogenesis (AHN). The research showed that deep brain stimulation of new neurons helped restore both cognitive and noncognitive functions in mouse models of Alzheimer’s disease.

“We were surprised to find that activating only a small population of adult-born new neurons was enough to make a significant contribution to these brain functions,” says senior author Juan Song, an associate professor at the University of North Carolina at Chapel Hill. The neurons were modified by deep brain stimulation of the suprammamillary nucleus (SuM), which is located in the hypothalamus. “We are eager to find out the mechanisms that underlie these beneficial effects,” Song says.

This research used two distinct mouse models of Alzheimer’s. The investigators used optogenetics to stimulate the SuM and enhance AHN in Alzheimer’s mice. Their earlier research had shown that stimulation of the SuM could increase the production of new neurons and improve their qualities in normal adult mice. In the new study, the investigators showed that this strategy was also effective in the Alzheimer’s mice, leading to the generation of new neurons that made better connections with other parts of the brain.

However, having more improved new neurons is not enough to improve memory and mood. Behavioral improvement in Alzheimer’s mice were seen only when these improved new neurons were activated by chemogenetics. The researchers used memory tests as well as established assessments to look for anxiety-like and depression-like behavior to confirm these improvements. The results suggested that multi-level enhancement of new neurons — enhancement in number, properties, and activity — is required for behavioral restoration in Alzheimer’s brains.

To further understand the mechanism, they also analyzed the protein changes in the hippocampus of Alzheimer’s mice in response to activation of SuM-modified adult-born new neurons. They found several well-known protein pathways activated inside cells, including those known to be important for improved memory performance, as well as those that allow clearance of the plaques related to Alzheimer’s.

“It was striking that multilevel enhancement of such a small number of adult-born new neurons made such a profound functional contribution to the animals’ diseased brains,” Song says. “We were also surprised to find that activation of SuM-enhanced neurons promoted the process that can potentially remove plaques.”

Future efforts of the team will focus on developing potential therapeutics that mimic the beneficial effects mediated by activation of SuM-modified new neurons. “We are hoping these drugs could exert therapeutic effects in patients with low or no hippocampal neurogenesis,” Song says. “Ultimately, the hope is to develop first-in-class, highly targeted therapies to treat Alzheimer’s and related dementia.”

For more than a century, scientists have known that while the commands that initiate movement come from the brain, the neurons that control locomotion once movement is underway reside within the spinal cord. In a study published January 20 in the journal Cell, researchers report that, in mice, they have identified one particular type of neuron that is both necessary and sufficient for regulating this type of movement. These neurons are called ventral spinocerebellar tract neurons (VSCTs).

“We hope that our findings will open up new avenues toward understanding how complex behaviors like locomotion come about and give us new insight into the mechanisms and biological principles that control this essential behavior,” says the paper’s senior author George Mentis, associate professor of pathology and cell biology in the Department of Neurology at Columbia University. “It’s also possible that our findings will lead to new ideas for therapeutic avenues, whether they involve treatments for spinal cord injury or neurodegenerative diseases that affect movement and motor control.”

VSCTs were discovered in the 1940s, but researchers have long believed that their main function was to relay messages about neuronal activity from the spinal cord to the cerebellum. The new study reports that instead they control locomotor behavior both during development and in adulthood.

“These findings were a huge surprise,” Mentis says. “One of the key discoveries in our study was that apart from their connection to the cerebellum, these neurons make connections with other spinal neurons that are also involved in locomotor behavior via their axon collaterals.”

The research involved several novel experimental approaches. One part of the research used optogenetics, employing LED light to regulate certain proteins that were expressed selectively in VSCTs to either activate or suppress the neuronal activity. Another set of experiments used chemogenetics, a process by which a chemical compound is used to activate or suppress synthetic ligands expressed artificially in these neurons, controlling their activity.

Leveraging the ability of intact spinal cords from newborn mice to function in a dish, the researchers showed that activation of VSCTs by light induced locomotor behavior. When VSCT activity was suppressed by light or by drugs, ongoing locomotor behavior was halted. During adulthood, freely moving mice stopped moving when the activity of VSCT was suppressed by injecting an inhibitory drug. Locomotor behavior was also tested by the ability of mice to swim. Mice were unable to swim and simply floated in the water when VSCTs were silenced. In all of these models and experiments, the researchers demonstrated that VSCTs alone were both necessary and sufficient for controlling locomotor activity — activating them was enough to induce activity while suppressing them was enough to stop it.

Mentis acknowledges that there are limitations to conducting this type of research in mice, including the fact that while humans are bipedal, mice are quadrupedal; thus, their locomotion could be regulated in a different way. But he notes that other research on neurodegenerative diseases and processes in mice has led to clinical trials in human patients, suggesting that these findings are also likely to be applicable.

For their next steps, the team plans to identify and map precisely the neuronal circuits that VSCTs make with motor neurons and other spinal neurons. They also would like to identify select genetic markers and uncover potential subpopulations of VSCTs and explore their role in different modes of locomotion. Finally, they plan to explore how the function of VSCTs is altered in the context of pathology and neurodegenerative diseases.

People often unconsciously synchronize bodily functions like heartbeat and breathing when they share an experience, such as a live performance or have a personal conversation. According to a new study, subjects’ heart rates synchronize even if they are just listening to a story by themselves, and this synchronization only occurs when the subjects are paying attention to the story. The findings from the research are reported September 14 in the journal Cell Reports.

“There’s a lot of literature demonstrating that people synchronize their physiology with each other. But the premise is that somehow you’re interacting and physically present the same place,” says co-senior author Lucas Parra, a professor at City College of New York. “What we have found is that the phenomenon is much broader, and that simply following a story and processing stimulus will cause similar fluctuations in people’s heart rates. It’s the cognitive function that drives your heart rate up or down.”

“What’s important is that the listener is paying attention to the actions in the story,” adds co-senior author Jacobo Sitt (@jdsitt), a researcher at the Paris Brain Institute and Inserm. “It’s not about emotions, but about being engaged and attentive, and thinking about what will happen next. Your heart responds to those signals from the brain.”

The investigators conducted a series of four experiments to explore the role of consciousness and attention in synchronizing participants’ heart rates. In the first, healthy volunteers listened to an audiobook of Jules Verne’s 20,000 Leagues Under the Sea. As they listened, their heart rate changed based on what was happening in the story, as measured by electrocardiogram (EKG). The researchers found that the majority of subjects showed increases and decreases in their heart rate at the same points in the narrative.

In the second experiment, volunteers watched short instructional videos. Because the videos were educational with no underlying emotional variations, this experiment confirmed that emotional engagement in a story was not playing a part. The first time they watched the videos, heart rates across the subjects showed similar fluctuations. The participants then watched the videos a second time while counting backwards in their heads. That time, the lack of attention resulted in a drop in the synchronization of heart rates across subjects, confirming that attention was important.

In the third experiment, the subjects listened to short children’s stories, some while attentive and others while being distracted, and then were asked to recall facts from the stories. The researchers found that the fluctuations seen in the participants’ heart rates were predictive of how well they did at answering questions about the story—more synchronization predicted better test scores. This indicated that changes in heart rate were a signal of conscious processing of the narrative.

When the researchers looked at changes in breathing rates, they didn’t see the same synchronization among the subjects. This was surprising, since breathing is known to affect heart rate.

The fourth experiment was similar to the first, but it included both healthy volunteers and patients with disorders of consciousness—such as those in comas or persistent vegetative states. All subjects were presented with an audiobook of a children’s story. As expected, the patients had lower rates of heart synchronization than did healthy controls. When the patients were examined six months later, some of them with higher synchronization had regained some consciousness.

“This study is still very preliminary, but you can imagine this being an easy test that could be implemented to measure brain function,” Sitt says. “It doesn’t require a lot of equipment. It even could be performed in an ambulance on the way to the hospital.” He notes that much more validation is needed with larger numbers of patients as well as comparisons to accepted tests of brain function like EEGs and fMRIs. This is something his group is continuing to study.

Parra says such research is also important for understanding mindfulness and the brain-body connection. “Neuroscience is opening up in terms of thinking of the brain as part of an actual anatomical, physical body,” he says. “This research is a step in the direction of looking at the brain-body connection more broadly, in terms of how the brain affects the body.”

For most adults who lose their vision, blindness results from damage to the eyes or optic nerve while the brain remains intact. For decades, researchers have proposed developing a device that could restore sight by bypassing damaged eyes and delivering visual information from a camera directly to the brain. In study published in the journal Cell, researchers from Baylor College of Medicine report that they are one step closer to this goal.

They describe an approach in which implanted electrodes are stimulated in a dynamic sequence, essentially “tracing” shapes on the surface of the visual cortex that participants were able to “see.”

“When we used electrical stimulation to dynamically trace letters directly on patients’ brains, they were able to ‘see’ the intended letter shapes and could correctly identify different letters,” said Dr. Daniel Yoshor, professor and chair of neurosurgery and senior author on the paper. “They described seeing glowing spots or lines forming the letters, like skywriting.”

Previous attempts to stimulate the visual cortex have been less successful. Earlier methods treated each electrode like a pixel in a visual display, stimulating many of them at the same time. Participants could detect spots of light but found it hard to discern visual objects or forms. “Rather than trying to build shapes from multiple spots of light, we traced outlines,” said Dr. Michael Beauchamp, professor and in neurosurgery, director of the Core for Advanced MRI and first author on the paper. “Our inspiration for this was the idea of tracing a letter in the palm of someone’s hand.”

The investigators tested the approach in four sighted people who had electrodes implanted in their brains to monitor epilepsy and two blind people who had electrodes implanted over their visual cortex as part of a study of a visual cortical prosthetic device. Stimulation of multiple electrodes in sequences produced perceptions of shapes that subjects were able to correctly identify as specific letters.

The approach, the researchers say, demonstrates that it could be possible for blind people to regain the ability to detect and recognize visual forms by using technology that inputs visual information directly into the brain, should they wish to. The researchers note, however, that several obstacles must be overcome before this technology could be implemented in clinical practice.

“The primary visual cortex, where the electrodes were implanted, contains half a billion neurons. In this study we stimulated only a small fraction of these neurons with a handful of electrodes,” Beauchamp said. “An important next step will be to work with neuroengineers to develop electrode arrays with thousands of electrodes, allowing us to stimulate more precisely. Together with new hardware, improved stimulation algorithms will help realize the dream of delivering useful visual information to blind people.

While we might often take our sense of touch for granted, for researchers developing technologies to restore limb function in people paralyzed due to spinal cord injury or disease, re-establishing the sense of touch is an essential part of the process. And on April 23 in the journal Cell, a team of researchers at Battelle and the Ohio State University Wexner Medical Center report that they have been able to restore sensation to the hand of a research participant with a severe spinal cord injury using a brain-computer interface (BCI) system. The technology harnesses neural signals that are so miniscule they can’t be perceived and enhances them via artificial sensory feedback sent back to the participant, resulting in greatly enriched motor function.

“We’re taking subperceptual touch events and boosting them into conscious perception,” says first author Patrick Ganzer, a principal research scientist at Battelle. “When we did this, we saw several functional improvements. It was a big eureka moment when we first restored the participant’s sense of touch.”

The participant in this study is Ian Burkhart, a 28-year-old man who suffered a spinal cord injury during a diving accident in 2010. Since 2014, Burkhart has been working with investigators on a project called NeuroLife that aims to restore function to his right arm. The device they have developed works through a system of electrodes on his skin and a small computer chip implanted in his motor cortex. This setup, which uses wires to route movement signals from the brain to the muscles, bypassing his spinal cord injury, gives Burkhart enough control over his arm and hand to lift a coffee mug, swipe a credit card, and play Guitar Hero.

“Until now, at times Ian has felt like his hand was foreign due to lack of sensory feedback,” Ganzer says. “He also has trouble with controlling his hand unless he is watching his movements closely. This requires a lot of concentration and makes simple multitasking like drinking a soda while watching TV almost impossible.”

The investigators found that although Burkhart had almost no sensation in his hand, when they stimulated his skin, a neural signal — so small it was his brain was unable to perceive it — was still getting to his brain. Ganzer explains that even in people like Burkhart who have what is considered a “clinically complete” spinal cord injury, there are almost always a few wisps of nerve fiber that remain intact. The Cell paper explains how they were able to boost these signals to the level where the brain would respond.

The subperceptual touch signals were artificially sent back to Burkhart using haptic feedback. Common examples of haptic feedback are the vibration from a mobile phone or game controller that lets the user feel that something is working. The new system allows the subperceptual touch signals coming from Burkhart’s skin to travel back to his brain through artificial haptic feedback that he can perceive.

The advances in the BCI system led to three important improvements. They enable Burkhart to reliably detect something by touch alone: in the future, this may be used to find and pick up an object without being able to see it. The system also is the first BCI that allows for restoration of movement and touch at once, and this ability to experience enhanced touch during movement gives him a greater sense of control and lets him to do things more quickly. Finally, these improvements allow the BCI system to sense how much pressure to use when handling an object or picking something up — for example, using a light touch when picking up a fragile object like a Styrofoam cup but a firmer grip when picking up something heavy.

The investigators’ long-term goal is to develop a BCI system that works as well in the home as it does in the laboratory. They are working on creating a next-generation sleeve containing the required electrodes and sensors that could be easily put on and taken off. They also aim to develop a system that can be controlled with a tablet rather than a computer, making it smaller and more portable.

“It has been amazing to see the possibilities of sensory information coming from a device that was originally created to only allow me to control my hand in a one-way direction,” Burkhart says.

The treatment for brain arteriovenous malformation (AVM) consists of observation, surgery, stereotactic radiosurgery, or endovascular embolization—either on its own or before surgery to remove the AVM. But these techniques don’t always yield a safe cure for patients, most of whom are young and experiencing debilitating symptoms.

Brigham and Women’s Hospital created the AVM Program, directed by neurosurgeon Nirav J. Patel, MD, to address this challenge and look for better solutions. The program is made up of cerebrovascular neurosurgeons, neuro-interventional radiologists, and vascular neurologists who collaborate on the development of interdisciplinary approaches. The team’s goal is to provide the best possible nonsurgical and surgical treatment options for people with AVMs.

“We at the Brigham started this program to help cure patients,” Dr. Patel says. “They often show up on our doorstep years after their initial diagnosis with a lot of misinformation. When someone in their teens or 20s is told they have a ticking time bomb in their brains, it’s very hard for them to hear. When we tell them we can cure them, they are shocked.”

Providing the Best Outcomes for Patients

Dr. Patel’s primary focus is a surgical technique that involves sealing off the feeding arteries to the AVM with clips before surgical resection (in other words, a surgical embolization), rather than blocking the arteries by endovascular embolization. “By using this AVM technique, we avoid the risks and costs of endovascular embolization,” he says. “The procedure takes longer and requires much more practice and surgical skill, but it often delivers better patient outcomes.”

After being trained in the technique by neurosurgeon Michael Morgan, AO, in Australia, Dr. Patel brought this approach to the Brigham. He’s made it his mission to offer the procedure to anyone who could benefit from it and train others to perform this delicate operation.

Toward that end, he sees the training of residents and fellows as an especially important role. “Everyone is expected to improve their microsurgical techniques,” he says. “It’s nothing special, just a lot of hard work that gets them there.”

Dr. Patel has built a 3D skills lab where trainees can practice working with brain blood vessels safely and perform bypass and repair. Training is done initially under a microscope with plastic tubes that simulate blood vessels. Dr. Patel also leads a preclinical rodent lab where residents and fellows can further hone their surgical techniques.

Creating Programs to Help AVM Patients Internationally

Many of Dr. Patel’s former trainees have taken the techniques with them upon moving on to faculty positions as far away as Japan, as well as to Puerto Rico and other parts of the United States.

Dr. Patel and his team have also traveled internationally to train local surgeons and provide care for patients unable to travel to the Brigham for surgery. In the summer of 2022, he journeyed to Paraguay, where he performed surgery on three patients. The trip was made in collaboration with the charity Solidarity Bridge—including the group’s program director, Lindsey Douchette, MPA, and neurosurgeon Richard Moser, MD—and neurosurgeon José Kuzli, MD, at the Hospital Nacional de Itaugua in Asuncion. Brigham anesthesiologist Grace Youngsook Kim, MD, and scrub nurse Carlos Vazquez accompanied Dr. Patel, with Vazquez also serving as a translator for Spanish-speaking patients.

“In addition to helping these patients, I shared my techniques with surgeons from all over the country who came to learn,” Dr. Patel says. “For countries like Paraguay that don’t have the instrumentation and resources to perform presurgical embolizations, teaching this procedure can make a profound difference in the lives of many patients with AVM. Our goal is to create a program there that is self-sustaining.” Dr. Patel had previously traveled to Puerto Rico, where he performed two AVM procedures and helped set up a similar program.

In the United States, Dr. Patel works with insurance companies to help patients out of network obtain coverage for treatment at the Brigham. He recently treated a 29-year-old mother of four from Chicago who experienced debilitating side effects after several failed embolizations.

A Continued Focus on Research

Dr. Patel notes that the role of the AVM Program is not only to develop new surgical techniques but also to refine all treatments that can benefit patients. This includes research in animal models to understand cerebral physiology and neuronal regeneration.

“We’re hoping to find a molecular marker for AVM that we can target and treat through medical means,” he says. “We’re working on sensitization of the endothelium inside the arteries. Eventually, we may be able to give patients a pill that makes their arteries selectively sensitive to radiation.” This might eventually provide another good treatment option for patients who cannot have surgeries like the ones that Dr. Patel performs.