NS/ Brain imaging is on the move with wearable scanning development
Neuroscience biweekly vol. 86, 24th May — 7th June
TL;DR
- New research has demonstrated that a wearable brain scanner can measure brain function whilst people are standing and walking around. This breakthrough could help better understand and diagnose a range of neurological problems that affect movement, including Parkinson’s Disease, stroke and concussion.
- Neuroscientists have shown how vitamin D deficiency affects developing neurons in the brain’s dopamine circuit, which may lead to dopamine dysfunction seen in adults with schizophrenia.
- Researchers found that in neurons that produced the neuropeptide NMS, the interaction between molecules SIK3 and HDAC4 has a critical role in sleep regulation through both the length of the circadian period and sleep homeostasis. Given the similarities among different mammals, new information about how the circadian system works in mice could lead to new treatments for sleep and circadian rhythm disorders in humans.
- The mental distress of cognitive dissonance — encountering information that conflicts with how we act or what we believe — can lead to added pressure on the neck and low back during lifting and lowering tasks, new research suggests.
- Researchers induced a hibernation-like state in mice by using ultrasound to stimulate the hypothalamus preoptic area in the brain, which helps to regulate body temperature and metabolism. The findings show the first noninvasive and safe method to induce such a state; a similar condition has been previously proposed for spaceflight or for patients with life-threatening health conditions.
- Scientists have developed ‘Dynamic Prospect Theory,’ which integrates the most popular model in behavioral economics — prospect theory and a well-established model from neuroscience — reinforcement learning theory. In doing so, they created a dynamic model that successfully explains decision-to-decision changes in the gambling behavior of humans and monkeys. In particular, they found that after unexpected wins both humans and monkeys tend to behave as if they thought that they are more likely to win again.
- Patients with MS show structural abnormalities in their white matter even before MS inflammation develops. This is the conclusion of a new study by the Netherlands Institute for Neuroscience (NIN) in Amsterdam and the Max Planck Institute for Multidisciplinary Sciences in Göttingen (MPI). Could this finding be a target for a new treatment to prevent MS inflammation?
- Powerful magnetic pulses applied to the scalp to stimulate the brain can bring fast relief to many severely depressed patients for whom standard treatments have failed. Yet it’s been a mystery exactly how transcranial magnetic stimulation, as the treatment is known, changes the brain to dissipate depression. Now, research led by Stanford Medicine scientists has found that the treatment works by reversing the direction of abnormal brain signals.
- Researchers have discovered that the oldest-old, those who live to be 90+ and have superior cognitive skills, have similar levels of brain pathology as Alzheimer’s patients, however, they also have less brain pathology of other neurodegenerative diseases that cause memory and thinking problems.
- Taking a daily multivitamin supplement can slow age-related memory decline, finds a large study led by researchers at Columbia University and Brigham and Women’s Hospital/Harvard.
- And more!
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The latest news and research
Enabling ambulatory movement in wearable magnetoencephalography with matrix coil active magnetic shielding
by Niall Holmes, Molly Rea, Ryan M. Hill, James Leggett, Lucy J. Edwards, Peter J. Hobson, Elena Boto, Tim M. Tierney, Lukas Rier, Gonzalo Reina Rivero, Vishal Shah, James Osborne, T. Mark Fromhold, Paul Glover, Matthew J. Brookes, Richard Bowtell in NeuroImage
New research has demonstrated, for the first time, that a wearable brain scanner can measure brain function whilst people are standing and walking around. This breakthrough could help better understand and diagnose a range of neurological problems that affect movement, including Parkinson’s Disease, stroke and concussion.
To enable this novel technology, researchers from the University of Nottingham’s School of Physics have developed a new design of magnetic field control system. This allows a much greater degree of subject movement than has ever been possible previously.
The unique wearable brain scanner system uses small LEGO-brick-sized sensors — called optically pumped magnetometers (OPMs) — to measure magnetic fields generated by cellular activity in the brain — a technique called Magnetoencephalography, or MEG. These sensors are incorporated into a lightweight helmet. The unique design means the system can be adapted to fit anyone, from newborns to adults, and sensors can be placed much closer to the head, dramatically enhancing data quality. This is a step change from conventional brain scanners which are large and fixed and require the patient to stay very still during scanning.
However, OPMs must operate at precisely zero magnetic fields to become sensitive enough to measure brain signals, this means they must be operated inside a magnetically shielded room (MSR). This room must contain additional equipment that allows precise control of magnetic fields at a level 50,000 times smaller than the Earth’s magnetic field. Existing solutions to this problem used complex wire patterns to generate cancellation fields over small, fixed regions. This allowed people to move their heads whilst seated but was unable to allow ambulatory movement.
The Nottingham team has now designed a ‘matrix coil’ system formed from multiple simple square coils. The coil currents can be reconfigured in real-time to compensate magnetic fields over a moving region that can be flexibly placed within the coils, giving much greater scope for people to move during a scan.
Niall Holmes, a Research Fellow from the University of Nottingham, has led this study and said:
“By using the matrix coils to allow greater movement we can, for the first time, realize many scanning scenarios that would have previously been considered impossible, but that has the potential to significantly expand our understanding of exactly what is happening in the brain during movement, neurodevelopment and in a range of neurological issues.”
Professor Matt Brookes leads MEG research in Nottingham and said:
“Just 5 years ago, the idea of acquiring high-resolution images of human brain electrophysiology whilst people walk around a room would have seemed like something from science fiction. The matrix coil has made this a reality! The applications span a huge area, from basic neuroscientific questions like how young children learn to walk, to clinical challenges like why are older people prone to falling. It’s incredible to think how far this technology has come, and even more incredible to imagine where it’s going.”
The University launched the spin-out company Cerca Magnetics in 2020 to bring OPM-MEG research systems to the market. The wearable system has been installed in a number of research institutions across the globe, including Young Epilepsy’s Health and Research Centre in the UK. The team are currently working towards gaining clinical approval of the Cerca System to bring it closer to being used in clinical settings.
Niall adds: “We are excited to work with Cerca to incorporate this new coil design into the commercial systems and to see what new studies will be enabled by our work.”
Vitamin D: A potent regulator of dopaminergic neuron differentiation and function
by Renata Aparecida Nedel Pertile, Rachel Brigden, Vanshika Raman, Xiaoying Cui, Zilong Du, Darryl Eyles in Journal of Neurochemistry
Neuroscientists at The University of Queensland have uncovered how vitamin D deficiency affects developing neurons in schizophrenia, using new technology.
Professor Darryl Eyles has built on past research out of his laboratory at the Queensland Brain Institute linking maternal vitamin D deficiency and brain development disorders, such as schizophrenia, to understand the functional changes taking place in the brain.
Schizophrenia is associated with many developmental risk factors, both genetic and environmental. While the precise neurological causes of the disorder are unknown, what is known is that schizophrenia is associated with a pronounced change in the way the brain uses dopamine, the neurotransmitter often referred to as the brain’s ‘reward molecule’.
Professor Eyles has followed the mechanisms that might relate to abnormal dopamine release and discovered that maternal vitamin D deficiency affects the early development and later differentiation of dopaminergic neurons.
The team at the Queensland Brain Institute developed dopamine-like cells to replicate the process of differentiation into early dopaminergic neurons that usually take place during embryonic development.
They cultured the neurons both in the presence and absence of the active vitamin D hormone. In three different model systems they showed dopamine neurite outgrowth was markedly increased. They then showed alterations in the distribution of presynaptic proteins responsible for dopamine release within these neurites.
“What we found was the altered differentiation process in the presence of vitamin D not only makes the cells grow differently, but recruits machinery to release dopamine differently,” Professor Eyles said.
Using a new visualization tool known as false fluorescent neurotransmitters, the team could then analyze the functional changes in presynaptic dopamine uptake and release in the presence and absence of vitamin D.
They showed that dopamine release was enhanced in cells grown in the presence of the hormone compared to a control.
“This is conclusive evidence that vitamin D affects the structural differentiation of dopaminergic neurons.”
Leveraging advances in targeting and visualizing single molecules within presynaptic nerve terminals has enabled Professor Eyles and his team to further explore their long-standing belief that maternal vitamin D deficiency changes how early dopaminergic circuits are formed.
The team is now exploring whether other environmental risk factors for schizophrenia such as maternal hypoxia or infection similarly alter the trajectory of dopamine neuron differentiation.
Eyles and his team believe such early alterations to dopamine neuron differentiation and function may be the neurodevelopmental origin of dopamine dysfunction later in adults who develop schizophrenia.
SIK3–HDAC4 in the suprachiasmatic nucleus regulates the timing of arousal at the dark onset and circadian period in mice
by Fuyuki Asano, Staci J. Kim, Tomoyuki Fujiyama, Chika Miyoshi, Noriko Hotta-Hirashima, Nodoka Asama, Kanako Iwasaki, Miyo Kakizaki, Seiya Mizuno, Michihiro Mieda, Fumihiro Sugiyama, Satoru Takahashi, Shoi Shi, Arisa Hirano, Hiromasa Funato, Masashi Yanagisawa in Proceedings of the National Academy of Sciences
Most living creatures exhibit a circadian rhythm, an internal clock that repeats around every 24 hours. Now, researchers from Japan have found new details about the molecular processes that govern sleep/wake rhythms in mice.
In a recently published study, researchers from the University of Tsukuba have revealed that a key molecule involved in sleep homeostasis (called SIK3 or salt-inducible kinase 3) also plays a critical role in circadian behavior.
Animals are able to adapt to the 24-hour cycle of light and dark in terms of both behavior and physiology via changes in the suprachiasmatic nucleus (SCN), which is the brain’s master clock that synchronizes the various rhythms in the body. However, the biological activities within the SCN that induce time-specific wakefulness have not been fully characterized; the research team aimed to address this.
“Most animals show a peak in activity at a specific point in the circadian cycle,” explains lead author of the study Professor Masashi Yanagisawa. “Because the SCN has been found to regulate sleep and wakefulness at certain times of the day, we wanted to investigate the distinct neurons that control this process.”
To do this, the research team genetically manipulated levels of SIK3 in specific neuron groups in the SCN of mice. Then, they examined sleep and circadian behaviors in the mice, such as when and for how long the mice exhibited activity with respect to the light-dark cycle.
“We found that SIK3 in the SCN can influence circadian cycle length and the timing of peak arousal activity, without changing the daily sleep amount,” says Professor Yanagisawa.
The research team previously reported that SIK3 interacts with LKB1 (an upstream molecule of SIK3) and HDAC4 (an important target of SIK3) in glutamatergic neurons to regulate the amount and depth of sleep. Now, they have found that the SIK3-HDAC4 pathway modulates the length of the circadian period through NMS-producing neurons, and contributes to the sleep/wake rhythm.
The length of the behavioral period and the timing of peak activity are important components of the circadian rhythm. Given the similarities between the circadian systems of different mammals, new information about how this system works in mice could lead to new treatments for sleep and circadian rhythm disorders in humans.
Cognitive dissonance increases spine loading in the neck and low back
by Eric B. Weston, Afton L. Hassett, Safdar N. Khan, Tristan E. Weaver, William S. Marras in Ergonomics
The mental distress of cognitive dissonance — encountering information that conflicts with how we act or what we believe — can lead to added pressure on the neck and low back during lifting and lowering tasks, new research suggests.
When study participants were told they were performing poorly in a precision lowering experiment in the lab, after initially being told they were doing well, their movements were linked to increased loads on vertebrae in their neck and low back.
Results showed that the higher the cognitive dissonance score, the greater the extent of loading on the upper and lower parts of the spine.
The finding suggests cognitive dissonance may be a previously unidentified risk factor for neck and low back pain, which could have implications for risk prevention in the workplace, according to researchers.
“This increased spine loading occurred under just one condition with a fairly light load — you can imagine what this would be like with more complex tasks or higher loads,” said senior author William Marras, executive director of the Spine Research Institute at The Ohio State University. “Basically, the study scratched the surface of showing there’s something to this.”
Marras’ lab has been studying daily living and occupational forces on the spine for decades. About 20 years ago, he found that psychological stress could influence spine biomechanics, using a study design that involved having a fake argument with a graduate student in front of research participants.
“We found that in certain personality types, the loads in the spine increased by up to 35%,” Marras said. “We ended up finding that when you’re under that kind of psychosocial stress, what you tend to do is what we call co-activate muscles in your torso. It creates this tug of war in the muscles because you’re always tense.
“In this study, to get at that mind-body connection, we decided to look at the way people think and, with cognitive dissonance, when people are disturbed by their thoughts.”
Seventeen research participants — nine men and eight women aged 19–44 — completed three phases of an experiment in which they placed a light-weight box within a square on a surface that was moved left and right, up and down. After a short practice run, researchers gave almost exclusively positive feedback during the first of two 45-minute trial blocks. During the second, the feedback increasingly suggested participants were performing in an unsatisfactory way.
To arrive at a cognitive dissonance score for each participant, changes during the experiment to blood pressure and heart rate variability were combined with responses to two questionnaires assessing discomfort levels as well as positive and negative affect — feeling strong and inspired versus distressed and ashamed.
Wearable sensors and motion-capture technology were used to detect peak spinal loads in the neck and low back: both compression of vertebrae and vertebral movement, or shear, from side to side (lateral) and forward and back (A/P).
Statistical modeling showed that, on average, peak spinal loads on cervical vertebrae in the neck were 11.1% higher in compression, 9.4% higher in A/P shear and 19.3% higher in lateral shear during the negative-feedback trial block compared to the baseline measures from the practice run. Peak loading in the lumbar region of the low back — an area that bears the brunt of any spinal loading — increased by 1.7% in compression and 2.2% in shear during the final trial block.
“Part of the motivation here was to see whether cognitive dissonance can manifest itself not only in the low back — we thought we’d find it there, but we didn’t know what we’d find in the neck. We did find a pretty strong response in the neck,” said Marras, a professor of integrated systems engineering with College of Medicine academic appointments in neurosurgery, orthopaedics and physical medicine and rehabilitation.
“Our tolerance to shear is much, much lower than it is to compression, so that’s why that’s important,” he said. “A small percentage of load is no big deal for one time. But think about when you’re working day in and day out, and you’re in a job where you’re doing this 40 hours a week — that could be significant, and be the difference between a disorder and not having a disorder.”
Marras is also principal investigator on a federally funded multi-institution clinical trial assessing different treatments for low back pain that range from medication to exercise to cognitive behavioral therapy.
“We’re trying to unravel this onion and understand all the different things that affect spine disorders because it’s really, really complex,” he said. “Just like the whole system has got to be right for a car to run correctly, we’re learning that that’s the way it is with the spine. You could be in physically great shape, but if you’re not thinking correctly or appropriately, or you have all these mental irregularities, like cognitive dissonance, that will affect the system. And until you get that right, you’re not going to be right.
“We’re looking for causal pathways. And now we can say cognitive dissonance plays a role and here’s how it works.”
Induction of a torpor-like hypothermic and hypometabolic state in rodents by ultrasound
by Yaoheng Yang, Jinyun Yuan, Rachael L. Field, Dezhuang Ye, Zhongtao Hu, Kevin Xu, Lu Xu, Yan Gong, Yimei Yue, Alexxai V. Kravitz, Michael R. Bruchas, Jianmin Cui, Jonathan R. Brestoff, Hong Chen in Nature Metabolism
Some mammals and birds have a clever way to preserve energy and heat by going into torpor, during which their body temperature and metabolic rate drop to allow them to survive potentially fatal conditions in the environment, such as extreme cold or lack of food. While a similar condition was proposed for scientists making flights to space in the 1960s or for patients with life-threatening health conditions, safely inducing such a state remains elusive.
Hong Chen, an associate professor at Washington University in St. Louis, and a multidisciplinary team induced a torpor-like state in mice by using ultrasound to stimulate the hypothalamus preoptic area in the brain, which helps to regulate body temperature and metabolism. In addition to the mouse, which naturally goes into torpor, Chen and her team induced torpor in a rat, which does not. Their findings show the first noninvasive and safe method to induce a torpor-like state by targeting the central nervous system.
Chen, associate professor of biomedical engineering in the McKelvey School of Engineering and of radiation oncology at the School of Medicine, and her team, including Yaoheng (Mack) Yang, a postdoctoral research associate, created a wearable ultrasound transducer to stimulate the neurons in the hypothalamus preoptic area. When stimulated, the mice showed a drop in body temperature of about 3 degrees C for about one hour. In addition, the mice’s metabolism showed a change from using both carbohydrates and fat for energy to only fat, a key feature of torpor, and their heart rates fell by about 47%, all while at room temperature.
The team also found that as the acoustic pressure and duration of the ultrasound increased, so did the depth of the lower body temperature and slower metabolism, known as ultrasound-induced hypothermia and hypometabolism (UIH).
“We developed an automatic closed-loop feedback controller to achieve long-duration and stable ultrasound-induced hypothermia and hypometabolism by controlling of the ultrasound output,” Chen said. “The closed-loop feedback controller set the desired body temperature to be lower than 34C, which was previously reported as critical for natural torpor in mice. This feedback-controlled UIH kept the mouse body temperature at 32.95C for about 24 hours and recovered to normal temperature after ultrasound was off.”
To learn how ultrasound-induced hypothermia and hypometabolism is activated, the team studied the dynamics of the activity of neurons in the hypothalamus preoptic area in response to ultrasound. They observed a consistent increase in neuronal activity in response to each ultrasound pulse, which aligned with the changes in body temperature in the mice.
“These findings revealed that UIH was evoked by ultrasound activation of hypothalamus preoptic area neurons,” Yang said. “Our finding that transcranial stimulation of the hypothalamus preoptic area was sufficient to induce UIH revealed the critical role of this area in orchestrating a torpor-like state in mice.”
Chen and her team also wanted to find the molecule that allowed these neurons to activate with ultrasound. Through genetic sequencing, they found that ultrasound activated the TRPM2 ion channel in the hypothalamus preoptic area neurons. In a variety of experiments, they showed that TRPM2 is an ultrasound-sensitive ion channel and contributed to the induction of UIH.
In the rat, which does not naturally go into torpor or hibernation, the team delivered ultrasound to the hypothalamus preoptic area and found a decrease in skin temperature, particularly in the brown adipose tissue region, as well as about a 1-degree C drop in core body temperature, resembling natural torpor.
This multidisciplinary team consists of Jonathan R. Brestoff, MD, PhD, assistant professor of pathology & immunology at the School of Medicine; Alexxai V. Kravitz, associate professor of psychiatry, of anesthesiology and of neuroscience at the School of Medicine, and Jianmin Cui, professor of biomedical engineering in the McKelvey School of Engineering, all at Washington University in St. Louis. The team also includes Michael R. Bruchas, professor of anesthesiology and pharmacology at the University of Washington.
“UIH has the potential to address the long sought-after goal of achieving noninvasive and safe induction of the torpor-like state, which has been pursued by the scientific community at least since the 1960s,” Chen said. “Ultrasound stimulation possesses a unique capability to noninvasively reach deep brain regions with high spatial and temporal precision in animal and human brains.”
Dynamic prospect theory: Two core decision theories coexist in the gambling behavior of monkeys and humans
by Agnieszka Tymula, Xueting Wang, Yuri Imaizumi, Takashi Kawai, Jun Kunimatsu, Masayuki Matsumoto, Hiroshi Yamada in Science Advances
How do humans make decisions when the outcomes are uncertain? One possible way would be to calculate the expected value of each option by multiplying each possible outcome amount by its probability and then choosing the option with the highest expected value. While this strategy would maximize the payoff in expectation, this is not what people tend to do. In particular, people seem to be irrationally influenced by past outcomes of their decisions when making subsequent choices.
Researchers from the University of Tsukuba have developed and validated a model (“dynamic prospect theory”) that integrates the most popular model in behavioral economics to describe decision-making under uncertainty — prospect theory, and a well-established model of learning from neuroscience — reinforcement learning theory. This model more accurately described the decisions that people and monkeys made while facing risk than prospect theory or reinforcement learning theory alone.
Specifically, the researchers asked 70 people to repeatedly choose between two lotteries in which they could gain some reward with some probability. The lotteries varied in the size of the reward, the probability of receiving it, and the amount of risk involved. The results showed that immediately after experiencing an outcome that was bigger than the expected value of the selected option, participants behaved as if the probability of winning in the next lottery increased. Senior author of the study Assistant Professor Hiroshi Yamada says “This behavior is surprising because winning probabilities were clearly described to the participants (participants did not have to learn them from experience) and these probabilities were also completely independent of previous outcomes.” Using their dynamic prospect theory model, the researchers were able to determine that the change in behavior is driven by a change in the perception of probabilities rather than by a change in valuation of rewards.
Yamada also says: “Such learning from unexpected events underlies reinforcement learning theory and is a well-known algorithm that occurs when people need to learn the rewards from experience. It is interesting that it occurs even if learning is not necessary.”
In similar experiments with macaque monkeys, whose brains closely resemble those of humans, essentially the same results were observed. Researchers commented that the similarity in human and monkey behavior was remarkable in this study.
Based on the results of this research, it is expected that the investigation of the monkey brain will lead to an understanding of the brain mechanisms involved in the perception of rewards and probability that all of us use when making risky decisions, as well as the joy we feel when we succeed.
Ultrastructural Axon–Myelin Unit Alterations in Multiple Sclerosis Correlate with Inflammation
by Aletta M. R. van den Bosch, Sophie Hümmert, Anna Steyer, Torben Ruhwedel, Jörg Hamann, Joost Smolders, Klaus‐Armin Nave, Christine Stadelmann, Maarten H. P. Kole, Wiebke Möbius, Inge Huitinga in Annals of Neurology
Patients with MS show structural abnormalities in their white matter even before MS inflammation develops. This is the conclusion of a new study by the Netherlands Institute for Neuroscience (NIN) in Amsterdam and the Max Planck Institute for Multidisciplinary Sciences in Göttingen (MPI). Could this finding be a target for a new treatment to prevent MS inflammation?
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system. In early, as well as advanced progressive MS, lesions arise along with the substantial inflammatory activity. Lesions are the inflammatory sites where the myelin is broken down and taken up by microglial cells (our brain’s immune cells). But do we see something in the tissue even before these inflammation spots appear?
To answer this question, Aletta van den Bosch of the research team of Inge Huitinga (NIN) and Wiebke Moebius (MPI) looked into human post-mortem brains of MS patients and controls that have been donated to the Dutch Brain Bank. Their focus was particularly on the so-called ‘normal-appearing white matter’. As the name suggests, these are areas where lesions have not formed yet, and so still appear normal. How is it possible that people with MS develop lesions here later and people without MS do not?
The team took a detailed look at myelin to see if there are early changes in people with MS. Myelin is an insulating white, fatty substance that is wrapped up to 150 times around the nerve fibers. At regular distances from each other there are interruptions of the myelin, these are the Nodes of Ranvier. During the transmission of electrical signals, the signal jumps from one Node or Ranvier to the next, allowing a myelin-containing fiber to transmit a signal 100 times faster than without myelin. In people with MS, myelin is damaged and signal transmission in the central nervous system is disrupted, which can impair functions such as walking and vision. What kinds of changes in brain tissue can we observe in the early stages of MS?
Aletta van den Bosch: ‘To be able to study myelin properly, we looked at the optic nerve. In this area, all nerve fibers and their myelin follow the same direction very nicely, so that we can visualize the myelin well. We did this by using electron microscopy. With this technique we zoomed in 5,000 to 30,000 times on a cross-section of a nerve-fiber.’
‘In MS, myelin was found to be less tightly wrapped around the nerve-fiber. This means that the fiber is not properly insulated which has major consequences: the signal can’t be transmitted as fast as it used to be. We saw that where myelin was less attached to the fiber, there was a disruption of the nodes of Ranvier combined with increased levels of T-cells and activated microglia. Furthermore, there were more mitochondria. Mitochondria are the energy factories of the cell, so this phenomenon may indicate that more energy is needed for signal movement and maintenance of the fibers.’
‘Although mitochondria are generally good for energy production, they also produce many by-products, such as oxygen radicals. We suspect this to be an amplifying factor for myelin breakdown: the myelin is already in a bad state, more mitochondria develop to provide more energy, which then makes conditions even worse. The theory is that a threshold value is needed to initiate the breakdown. It is also possible that the body recognizes the detached myelin as ‘abnormal’, which could be the start of breakdown by immune cells.’
‘We haven’t been able to look at human tissue in such detail before, meaning that almost all the research so far has been done in laboratory animals. Although this is very valuable research, it could sometimes be more difficult to translate the results directly to humans. This is the first glimpse into what happens at the ultrastructural level in people with MS and what exactly leads to the lesions. You need very good tissue to do this which is why the brain bank is so crucial for our research.”
‘The next step is to see if we can prevent the myelin from winding so loosely around nerve endings. First, we want to experiment in culture dishes to see if we can make the wrapping of myelin stronger. Subsequently, we will have perform tests in laboratory animals, and eventually we will be able to take the step to humans. It would be great if we could find something to prevent myelin detachment. While this will not prevent the damage of the lesions that are already there, it might prevent the development of new lesions. This would provide a whole new target for MS treatment.”
Targeted neurostimulation reverses a spatiotemporal biomarker of treatment-resistant depression
by Anish Mitra, Marcus E. Raichle, Andrew D. Geoly, Ian H. Kratter, Nolan R. Williams in Proceedings of the National Academy of Sciences
Powerful magnetic pulses applied to the scalp to stimulate the brain can bring fast relief to many severely depressed patients for whom standard treatments have failed. Yet it’s been a mystery exactly how transcranial magnetic stimulation, as the treatment is known, changes the brain to dissipate depression. Now, research led by Stanford Medicine scientists has found that the treatment works by reversing the direction of abnormal brain signals.
The findings also suggest that backward streams of neural activity between key areas of the brain could be used as a biomarker to help diagnose depression.
“The leading hypothesis has been that TMS could change the flow of neural activity in the brain,” said Anish Mitra, MD, PhD, a postdoctoral fellow in psychiatry and behavioral sciences. “But to be honest, I was pretty skeptical. I wanted to test it.”
Mitra had just the tool to do it. As a graduate student at Washington University in Saint Louis, in the lab of Mark Raichle, MD, he developed a mathematical tool to analyze functional magnetic resonance imaging, or fMRI — commonly used to locate active areas in the brain. The new analysis used minute differences in timing between the activation of different areas to also reveal the direction of that activity.
In the new study, Mitra and Raichle teamed up with Nolan Williams, MD, associate professor of psychiatry and behavioral sciences, whose team has advanced the use of magneticstimulation, personalized to each patient’s brain anatomy, to treat profound depression. The FDA-cleared treatment, known as Stanford Neuromodulation Therapy, incorporatesadvanced imaging technologies to guide stimulation with high-dose patterns of magnetic pulses that can modify brain activity related to major depression. Compared with traditional TMS, which requires daily sessions over several weeks or months, SNT works on an accelerated timeline of 10 sessions each day for just five days.
“This was the perfect test to see if TMS has the ability to change the way that signals flow through the brain,” said Mitra, who is lead author of the study. “If this doesn’t do it, nothing will.”
Raichle and Williams are senior authors of the study.
The researchers recruited 33 patients who had been diagnosed with treatment-resistant major depressive disorder. Twenty-three received SNT treatment, and 10 received a sham treatment that mimicked SNT but without magnetic stimulation. They compared data from these patients with that of 85 healthy controls without depression.
When they analyzed fMRI data across the whole brain, one connection stood out. In the normal brain, the anterior insula, a region that integrates bodily sensations, sends signals to a region that governs emotions, the anterior cingulate cortex.
“You could think of it as the anterior cingulate cortex receiving this information about the body — like heart rate or temperature — and then deciding how to feel on the basis of all these signals,” Mitra said.
In three-quarters of the participants with depression, however, the typical flow of activity was reversed: The anterior cingulate cortex sent signals to the anterior insula. The more severe the depression, the higher the proportion of signals that traveled the wrong way.
“What we saw is that who’s the sender and who’s the receiver in the relationship seems to really matter in terms of whether someone is depressed,” Mitra said. “It’s almost as if you’d already decided how you were going to feel, and then everything you were sensing was filtered through that,” he said. “The mood has become primary. That’s consistent with how a lot of psychiatrists see depression,” he added. “Even things that are quite joyful to a patient normally are suddenly not bringing them any pleasure.”
When depressed patients were treated with SNT, the flow of neural activity shifted to the normal direction within a week, coinciding with a lifting of their depression.
Those with the most severe depression — and the most misdirected brain signals — were the most likely to benefit from the treatment.
“We’re able to undo the spatio-temporal abnormality so that people’s brains look like those of normal, healthy controls,” Williams said.
A challenge in treating depression has been the lack of insight into its biological mechanisms. If a patient has a fever, there are various tests — for a bacterial or viral infection, for example — that could determine the appropriate treatment. But for a patient with depression, there are no analogous tests.
“This is the first time in psychiatry where this particular change in a biology — the flow of signals between these two brain regions — predicts the change in clinical symptoms,” Williams said.
Not everyone with depression has this abnormal flow of neural activity, and it may be rare in less severe cases of depression, Williams said, but it could serve as an important biomarker for triaging treatment for the disorder.
“The fMRI data that allows precision treatment with SNT can be used both as a biomarker for depression and a method of personalized targeting to treat its underlying cause,” he said. “When we get a person with severe depression, we can look for this biomarker to decide how likely they are to respond well to SNT treatment,” Mitra said.
“Behavioral conditions like depression have been difficult to capture with imaging because, unlike an obvious brain lesion, they deal with the subtlety of relationships between various parts of the brain,” said Raichle, who has studied brain imaging for more than four decades. “It’s incredibly promising that the technology now is approaching the complexity of the problems we’re trying to understand.”
The researchers plan to replicate the study in a larger group of patients. They also hope others will adopt their analytic technique to uncover more clues about the direction of brain activity hidden in fMRI data.
“As long as you have good clean fMRI data, you can study this property of the signals,” Mitra said.
Superior Global Cognition in Oldest-Old Is Associated with Resistance to Neurodegenerative Pathologies: Results from The 90+ Study
by Roshni Biswas, Claudia Kawas, Thomas J. Montine, Syed A. Bukhari, Luohua Jiang, Maria M. Corrada in Journal of Alzheimer’s Disease
A University of California, Irvine-led team of researchers has discovered that the oldest-old, those who live to be 90+ and have superior cognitive skills, have similar levels of brain pathology as Alzheimer’s patients, however, they also have less brain pathology of other neurodegenerative diseases that cause memory and thinking problems.
“People who are 90+ and still have a good memory and thinking abilities tend to have similar levels of Alzheimer’s pathology in their brains,” Roshni Biswas, post-doctoral scholar with The 90+ Study. “Our findings indicate that while Alzheimer’s Disease neuropathological changes and vascular changes are common in their brains, these individuals are less susceptible to other types of neurodegenerative changes such as Lewy body disease.”
Age is the primary risk factor for cognitive issues, such as Alzheimer’s, Lewy body disease and other related dementias. Over the past 30 years, the number of people aged 90 and older in the U.S. has nearly tripled, and this number is projected to quadruple in the next four decades.
With this rise in age, many people see increased problems with memory and brain function. However, little data is available on the changes in the brains of 90+ people who maintain superior cognitive abilities, despite their age.
The objective of the study was to examine the brain features of people without cognitive impairment and their relation to superior cognitive skills and reasoning in those that are 90+.
“There are some individuals who can maintain high levels of cognitive function well into advanced ages,” said María M. Corrada, ScD, co-principal investigator of the study and professor in the Department of Neurology at UCI School of Medicine. “Further research into the factors that enable these individuals to maintain their cognitive function could provide insights into how to preserve cognitive health despite advanced age.”
The study results were derived by analyzing autopsy data from 102 cognitively normal individuals who died at a mean age of 97.6 years. They also used cognitive test scores from people taken between two to twelve months before death. The average age of study participants at the time of their last visit was 97.1 years of age.
“In our future research, we will examine how lifestyle habits and health conditions are associated with superior cognition in individuals who are 90+ and the factors that contribute to maintaining stable cognitive function over time,” said Biswas.
The 90+ Study is a longitudinal study on aging and dementia that was initiated in 2003 to study the oldest-old population, which is the fastest-growing age group in the United States.
With more than 2000 participants enrolled, it is now one of the largest studies of its kind in the world. The project has produced several significant findings regarding cognitive function, health and lifestyle habits in the oldest-old population information obtained during life.
Multivitamin supplementation improves memory in older adults: a randomized clinical trial
by Lok-Kin Yeung, Daniel M. Alschuler, Melanie Wall, Heike Luttmann-Gibson, Trisha Copeland, Christiane Hale, Richard P. Sloan, Howard D. Sesso, JoAnn E. Manson, Adam M. Brickman in The American Journal of Clinical Nutrition
Taking a daily multivitamin supplement can slow age-related memory decline, finds a large study led by researchers at Columbia University and Brigham and Women’s Hospital/Harvard.
“Cognitive aging is a top health concern for older adults, and this study suggests that there may be a simple, inexpensive way to help older adults slow down memory decline,” says study leader Adam M. Brickman, PhD, professor of neuropsychology at Columbia University Vagelos College of Physicians and Surgeons.
Many older people take vitamins or dietary supplements under the assumption that they will help maintain general health. But studies that have tested whether they improve memory and brain function have been mixed, and very few large-scale, randomized trials have been done.
In the current study, more than 3,500 adults (mostly non-Hispanic white) over age 60 were randomly assigned to take a daily multivitamin supplement or placebo for three years. At the end of each year, participants performed a series of online cognitive assessments at home designed to test the memory function of the hippocampus, an area of the brain that is affected by normal aging. The COSMOS-Web study is part of a large clinical trial led by Brigham & Women’s Hospital and Harvard called the COcoa Supplement and Multivitamin Outcomes Study (COSMOS).
By the end of the first year, memory improved for people taking a daily multivitamin, compared with those taking a placebo. The researchers estimate the improvement, which was sustained over the three-year study period, was equivalent to about three years of age-related memory decline. The effect was more pronounced in participants with underlying cardiovascular disease.
The results of the new study are consistent with another recent COSMOS study of more than 2,200 older adults that found that taking a daily multivitamin improved overall cognition, memory recall, and attention, effects that were also more pronounced in those with underlying cardiovascular disease.
“There is evidence that people with cardiovascular disease may have lower micronutrient levels that multivitamins may correct, but we don’t really know right now why the effect is stronger in this group,” says Brickman.
Though the researchers did not look at whether any specific component of the multivitamin supplement was linked to the improvement in memory, the findings support growing evidence that nutrition is important for optimizing brain health as we age.
“Our study shows that the aging brain may be more sensitive to nutrition than we realized, though it may not be so important to find out which specific nutrient helps slow age-related cognitive decline,” says Lok-Kin Yeung, PhD, a postdoctoral researcher in Columbia’s Taub Institute for Research on Alzheimer’s Disease and the Aging Brain and first author of the study.
“The finding that a daily multivitamin improved memory in two separate cognition studies in the COSMOS randomized trial is remarkable, suggesting that multivitamin supplementation holds promise as a safe, accessible, and affordable approach to protecting cognitive health in older adults,” says co-author JoAnn Manson, MD, chief of the Division of Preventive Medicine at Brigham and Women’s Hospital.
“Supplementation of any kind shouldn’t take the place of more holistic ways of getting the same micronutrients,” adds Brickman. “Though multivitamins are generally safe, people should always consult a physician before taking them.”
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