NS/ Non-invasive stimulation technique probes deep into the human brain

Paradigm
Paradigm
Published in
28 min readJun 5, 2024

Neuroscience biweekly vol. 111, 22nd May — 5th June

TL;DR

  • Researchers at EPFL are developing a non-invasive technique called transcranial Temporal Interference Electric Stimulation (tTIS) to treat neurological disorders like addiction, depression, and OCD. tTIS uses low-level electrical stimulation on the scalp to specifically target deep brain regions, such as the striatum, involved in these conditions. This method is less invasive than traditional deep brain stimulation (DBS) and offers targeted, effective treatment with minimal side effects, showing promise for personalized therapies and improved understanding of brain functions.
  • A 3D model developed by West Virginia University neuroscientists shows how implantable stimulators — the same kind used to treat chronic pain — can target neurons that control specific muscles to provide rehabilitation for people with neurological disorders such as stroke and spinal cord injuries.
  • Research led by the University of Plymouth has shown that a new deep learning AI model can identify what happens and when during embryonic development, from video.
  • Low-level light therapy appears to affect healing in the brains of people who suffered significant brain injuries, according to a study published in Radiology, a journal of the Radiological Society of North America (RSNA).
  • A research team at Stanford’s Wu Tsai Neurosciences Institute has made a major stride in using AI to replicate how the brain organizes sensory information to make sense of the world, opening up new frontiers for virtual neuroscience.
  • Our willingness to help others is governed by a specific brain region pinpointed by researchers in a study of patients with brain damage to that region.
  • Researchers have found that a specific pattern of brain activity, known as ‘sharp-wave ripples,’ is associated with thoughts that wander from the present situation. This activity begins in the hippocampus, a crucial brain region for memory formation and recall, and is linked to more vivid and less desirable thoughts. A better understanding of the relationship between sharp-wave ripples and these kinds of thoughts might be helpful for treating related conditions.
  • Regular high caffeine consumption affects dopamine function in patients with Parkinson’s disease, according to a new international study. Caffeine consumption before undergoing diagnostic brain dopamine imaging may also affect the imaging results.
  • A substance naturally occurring in pomegranates and strawberries can improve memory and treatment of Alzheimer’s disease.
  • In a behavioral experiment, crows can learn to produce a set number of calls. This involves them planning in advance: from the sound of the first call in a numerical sequence it is possible to predict how many calls the crows will make. A research team from the Institute of Neurobiology at the University of Tübingen has established this. Their study has been published in Science.

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The global neuroscience market size was valued at USD 28.4 billion in 2016 and it is expected to reach USD 38.9 billion by 2027.

The latest news and research

Non-invasive stimulation of the human striatum disrupts reinforcement learning of motor skills

by Vassiliadis P, Beanato E, Popa T, et al. in Nat Hum Behav

Researchers at EPFL are developing a non-invasive technique called transcranial Temporal Interference Electric Stimulation (tTIS) to treat neurological disorders like addiction, depression, and OCD. tTIS uses low-level electrical stimulation on the scalp to specifically target deep brain regions, such as the striatum, involved in these conditions. This method is less invasive than traditional deep brain stimulation (DBS) and offers targeted, effective treatment with minimal side effects, showing promise for personalized therapies and improved understanding of brain functions.

Neurological disorders, such as addiction, depression, and obsessive-compulsive disorder (OCD) affect millions of people worldwide and are often characterized by complex pathologies involving multiple brain regions and circuits. These conditions are notoriously difficult to treat due to the intricate and poorly understood nature of brain functions and the challenge of delivering therapies to deep brain structures without invasive procedures.

In the rapidly evolving field of neuroscience, non-invasive brain stimulation is a new hope for understanding and treating a myriad of neurological and psychiatric conditions without surgical intervention or implants. Researchers, led by Friedhelm Hummel, who holds the Defitchech Chair of Clinical Neuroengineering at EPFL’s School of Life Sciences, and postdoc Pierre Vassiliadis, are pioneering a new approach in the field, opening frontiers in treating conditions like addiction and depression.

Their research, leveraging transcranial Temporal Interference Electric Stimulation (tTIS), specifically targets deep brain regions that are the control centers of several important cognitive functions and involved in different neurological and psychiatric pathologies. The research, published in Nature Human Behaviour, highlights the interdisciplinary approach that integrates medicine, neuroscience, computation, and engineering to improve our understanding of the brain and develop potentially life-changing therapies.

“Invasive deep brain stimulation (DBS) has already successfully been applied to the deeply seated neural control centers in order to curb addiction and treat Parkinson, OCD or depression,” says Hummel. “The key difference with our approach is that it is non-invasive, meaning that we use low-level electrical stimulation on the scalp to target these regions.”

Vassiliadis, lead author of the paper, a medical doctor with a joint PhD, describes tTIS as using two pairs of electrodes attached to the scalp to apply weak electrical fields inside the brain.

“Up until now, we couldn’t specifically target these regions with non-invasive techniques, as the low-level electrical fields would stimulate all the regions between the skull and the deeper zones — rendering any treatments ineffective. This approach allows us to selectively stimulate deep brain regions that are important in neuropsychiatric disorders,” he explains.

The innovative technique is based on the concept of temporal interference, initially explored in rodent models, and now successfully translated to human applications by the EPFL team. In this experiment, one pair of electrodes is set to a frequency of 2,000 Hz, while another is set to 2,080 Hz. Thanks to detailed computational models of the brain structure, the electrodes are specifically positioned on the scalp to ensure that their signals intersect in the target region.

It is at this juncture that the magic of interference occurs: the slight frequency disparity of 80 Hz between the two currents becomes the effective stimulation frequency within the target zone. The brilliance of this method lies in its selectivity; the high base frequencies (e.g., 2,000 Hz) do not stimulate neural activity directly, leaving the intervening brain tissue unaffected and focusing the effect solely on the targeted region.

The focus of this latest research is the human striatum, a key player in reward and reinforcement mechanisms.

“We’re examining how reinforcement learning, essentially how we learn through rewards, can be influenced by targeting specific brain frequencies,” says Vassiliadis. By applying stimulation of the striatum at 80 Hz, the team found they could disrupt its normal functioning, directly affecting the learning process.

The therapeutic potential of their work is immense, particularly for conditions like addiction, apathy and depression, where reward mechanisms play a crucial role.

“In addiction, for example, people tend to over-approach rewards. Our method could help reduce this pathological overemphasis,” Vassiliadis, who is also a researcher at UCLouvain’s Institute of Neuroscience, points out.

Furthermore, the team is exploring how different stimulation patterns can not only disrupt but also potentially enhance brain functions.

“This first step was to prove the hypothesis of 80 Hz affecting the striatum, and we did it by disrupting it’s functioning. Our research also shows promise in improving motor behavior and increasing striatum activity, particularly in older adults with reduced learning abilities,” Vassiliadis adds.

Hummel, a trained neurologist, sees this technology as the beginning of a new chapter in brain stimulation, offering personalized treatment with less invasive methods.

“We’re looking at a non-invasive approach that allows us to experiment and personalize treatment for deep brain stimulation in the early stages,” he says.

Another key advantage of tTIS is its minimal side effects. Most participants in their studies reported only mild sensations on the skin, making it a highly tolerable and patient-friendly approach.

Hummel and Vassiliadis are optimistic about the impact of their research. They envision a future where non-invasive neuromodulation therapies could be readily available in hospitals, offering a cost-effective and expansive treatment scope.

Muscle anatomy is reflected in the spatial organization of the spinal motoneuron pools

Taitano RI, Yakovenko S, Gritsenko V. . Commun Biol.

A 3D model developed by West Virginia University neuroscientists shows how implantable stimulators — the same kind used to treat chronic pain — can target neurons that control specific muscles to provide rehabilitation for people with neurological disorders such as stroke and spinal cord injuries.

The device, implanted on or near the spinal cord, works by delivering an electrical signal through a thin wire. To treat paralysis, stimulation targets specific parts of the spinal cord to help restore muscle function and movement. However, the effectiveness of the device has been constrained due to insufficient understanding of where motoneurons that connect to specific muscles are situated within the spinal cord.

“If we really want to maximize the usefulness of these implants, we want to be able to select specific motoneurons that would activate specific muscles and assist with the movement in the right way and at the right time,” said Valeriya Gritsenko, associate professor in the WVU School of Medicine, departments of Human Performance — Physical Therapy, Neuroscience and the Rockefeller Neuroscience Institute. “Scientists want to use a model to figure out where to implant this system.”

With further studies and testing, researchers are hopeful to gain a better understanding of the extent to which these devices can improve muscle function.

To conduct the study, researchers first created a 3D model of the motoneuron locations in the macaque — an Old World monkey — spinal cord and compared it to the current knowledge of the human spinal cord. They also created 3D models of the musculoskeletal anatomy of the macaque and human right upper limb and compared those.

“We were looking at the differences and changes in muscle lengths across different postures in both the human model and the monkey model,” said Rachel Taitano, a doctoral student in medicine and neuroscience from Fairfax, Virginia, and lead author of the study. “The musculoskeletal model of the monkey shows that the biomechanics are similar to humans even though the species have differences in the muscles they use, the muscles they have, and different orientations and functionality.”

The study shows a close match in the distribution, or depth, of motoneuron pools along the spinal cord in macaques and humans. Those findings will allow scientists to gain precision in delivering treatment.

“Some of motoneuron pools are deeper inside the spinal cord and others are closer to the surface,” Gritsenko explained. “This model allows us to look in depth to where those motoneuron pools might be closest to the surface. That’s where you would want to stimulate to potentially activate those muscles.”

Gritsenko, who served as the primary investigator, explained that “knowing the spinal organization of motoneuron pools — groups of cells that connect to a single muscle — can reveal something fascinating. Our complex musculoskeletal system has evolved over time to enable the wide range of movements we see in all primates, including us humans. The team found that our spinal cords have built-in ‘maps’ that reflect this complex function. This ‘map’ helps simplify the control of our complex body by the spinal cord. It is like having an autopilot right inside the spine.”

Another colleague on the project, Sergiy Yakovenko, associate professor in the WVU School of Medicine, departments of Human Performance — Exercise Physiology, Neuroscience and RNI, has conducted similar studies on the spinal cord anatomy in quadrupedal animals. The new findings show how well the anatomy of the spinal cord is conserved across animals and how closely it reflects the actions of the muscles.

Results from an applied science study that can be used to benefit patients in a clinical setting is what Taitano said drew her to the project.

“I think we can get a lot of information from non-invasive studies,” said Taitano, who holds an undergraduate degree in biomedical engineering. “Now that we can apply these findings on the millimeter and the nanometer scale, we can fabricate devices to apply what we’re seeing in a model like this.”

With the project complete, Taitano moves on to the medical degree portion of her program this summer.

“Rachel’s background was very instrumental in making the study a success,” Gritsenko said. “I would definitely like to see more of this kind of interdisciplinary collaboration with graduate students working on projects with colleagues from medical and engineering departments.”

Gritsenko said in addition to her DOD grant, scientists at two other universities have expressed interest in using the model to explore how the stimulation technology can be improved. She also plans to collaborate with a primate researcher at another university to validate the study’s findings in animal models.

Dev-ResNet: automated developmental event detection using deep learning

by Ibbini Z, Truebano M, Spicer JI, McCoy JCS, Tills O. in J Experiment Biol.

Research led by the University of Plymouth has shown that a new deep learning AI model can identify what happens and when during embryonic development, from video.

Published in the Journal of Experimental Biology, the study highlights how the model, known as Dev-ResNet, can identify the occurrence of key functional developmental events in pond snails, including heart function, crawling, hatching and even death.

A key innovation in this study is the use of a 3D model that uses changes occurring between frames of the video, and enables the AI to learn from these features, as opposed to the more traditional use of still images.

The use of video means features ranging from the first heartbeat, or crawling behaviour, through to shell formation or hatching are reliably detected by Dev-ResNet, and has revealed sensitivities of different features to temperature not previously known.

While used in pond snail embryos for this study, the authors say the model has broad applicability across all species, and they provide comprehensive scripts and documentation for applying Dev-ResNet in different biological systems.

In future, the technique could be used to help accelerate understanding on how climate change, and other external factors, affect humans and animals.

The work was led by PhD candidate, Ziad Ibbini, who studied BSc Conservation Biology at the University, before taking a year out to upskill himself in software development, then beginning his PhD. He designed, trained and tested Dev-ResNet himself.

“The only real limitations are in creating the data to train the deep learning model — we know it works, you just need to give it the right training data.

We want to equip the wider scientific community with the tools that will enable them to better understand how a species’ development is affected by different factors, and thus identifying how we can protect them. We think that Dev-ResNet is a significant step in that direction.” — Ziad Ibbini, PhD candidate and the study’s lead author

“This research is important on a technological level, but it is also significant for advancing how we perceive organismal development — something that the University of Plymouth, within the Ecophysiology and Development research Group, has more than 20 years’ history of researching.

This milestone would not have been possible without deep learning, and it is exciting to think of where this new capability will lead us in the study of animals during their most dynamic period of life.” — Oliver Tills, UKRI Future Leaders Research Fellow and the study’s senior author.

Effects of low-level light therapy on resting-state connectivity following moderate traumatic brain injury: secondary analyses of a double-blinded placebo-controlled study

by Chan S tak, Mercaldo N, Figueir, Longo MG, et al. in Radiology.

Low-level light therapy appears to affect healing in the brains of people who suffered significant brain injuries, according to a study published in Radiology, a journal of the Radiological Society of North America (RSNA).

Lights of different wavelengths have been studied for years for their wound-healing properties. Researchers at Massachusetts General Hospital (MGH) conducted low-level light therapy on 38 patients who had suffered moderate traumatic brain injury, an injury to the head serious enough to alter cognition and/or be visible on a brain scan. Patients received light therapy within 72 hours of their injuries through a helmet that emits near-infrared light.

“The skull is quite transparent to near-infrared light,” said study co-lead author Rajiv Gupta, M.D., Ph.D., from the Department of Radiology at MGH. “Once you put the helmet on, your whole brain is bathing in this light.”

The researchers used an imaging technique called functional MRI to gauge the effects of the light therapy. They focused on the brain’s resting-state functional connectivity, the communication between brain regions that occurs when a person is at rest and not engaged in a specific task. The researchers compared MRI results during three recovery phases: the acute phase of within one week after injury, the subacute phase of two to three weeks post-injury and the late-subacute phase of three months after injury.

Of the 38 patients in the trial, 21 did not receive light therapy while wearing the helmet. This was done to serve as a control to minimize bias due to patient characteristics and to avoid potential placebo effects.

Patients who received low-level light therapy showed a greater change in resting-state connectivity in seven brain region pairs during the acute-to-subacute recovery phase compared to the control participants.

“There was increased connectivity in those receiving light treatment, primarily within the first two weeks,” said study coauthor Nathaniel Mercaldo, Ph.D., a statistician with MGH. “We were unable to detect differences in connectivity between the two treatment groups long term, so although the treatment appears to increase the brain connectivity initially, its long-term effects are still to be determined.”

The precise mechanism of the light therapy’s effects on the brain is also still to be determined. Previous research points to the alteration of an enzyme in the cell’s mitochondria (often referred to as the “powerhouse” of a cell), Dr. Gupta said. This leads to more production of adenosine triphosphate, a molecule that stores and transfers energy in the cells. Light therapy has also been linked with blood vessel dilation and anti-inflammatory effects.

“There is still a lot of work to be done to understand the exact physiological mechanism behind these effects,” said study coauthor Suk-tak Chan, Ph.D., a biomedical engineer at MGH.

While connectivity increased for the light therapy-treated patients during the acute to subacute phases, there was no evidence of a difference in clinical outcomes between the treated and control participants. Additional studies with larger cohorts of patients and correlative imaging beyond three months may help determine the therapeutic role of light in traumatic brain injury.

The researchers expect the role of light therapy to expand as more study results come in. The 810-nanometer-wavelength light used in the study is already employed in various therapeutic applications. It’s safe, easy to administer and does not require surgery or medications. The helmet’s portability means it can be delivered in settings outside of the hospital. It may have applications in treating many other neurological conditions, according to Dr. Gupta.

“There are lots of disorders of connectivity, mostly in psychiatry, where this intervention may have a role,” he said. “PTSD, depression, autism: these are all promising areas for light therapy.”

A unifying framework for functional organization in early and higher ventral visual cortex

by Margalit E, Lee H, Finzi D, DiCarlo JJ, Grill-Spector K, Yamins DLK. in Neuron

A research team at Stanford’s Wu Tsai Neurosciences Institute has made a major stride in using AI to replicate how the brain organizes sensory information to make sense of the world, opening up new frontiers for virtual neuroscience.

Watch the seconds tick by on a clock and, in visual regions of your brain, neighboring groups of angle-selective neurons will fire in sequence as the second hand sweeps around the clock face. These cells form beautiful “pinwheel” maps, with each segment representing a visual perception of a different angle. Other visual areas of the brain contain maps of more complex and abstract visual features, such as the distinction between images of familiar faces vs. places, which activate distinct neural “neighborhoods.”

Such functional maps can be found across the brain, both delighting and confounding neuroscientists, who have long wondered why the brain should have evolved a map-like layout that only modern science can observe.

To address this question, the Stanford team developed a new kind of AI algorithm — a topographic deep artificial neural network (TDANN) — that uses just two rules: naturalistic sensory inputs and spatial constraints on connections; and found that it successfully predicts both the sensory responses and spatial organization of multiple parts of the human brain’s visual system.

After seven years of extensive research, the findings were published in a new paper — “A unifying framework for functional organization in the early and higher ventral visual cortex” — in the journal Neuron.

The research team was led by Wu Tsai Neurosciences Institute Faculty Scholar Dan Yamins, an assistant professor of psychology and computer science; and Institute affiliate Kalanit Grill-Spector, a professor in psychology.

Unlike conventional neural networks, the TDANN incorporates spatial constraints, arranging its virtual neurons on a two-dimensional “cortical sheet” and requiring nearby neurons to share similar responses to sensory input. As the model learned to process images, this topographical structure caused it to form spatial maps, replicating how neurons in the brain organize themselves in response to visual stimuli. Specifically, the model replicated complex patterns such as the pinwheel structures in the primary visual cortex (V1) and the clusters of neurons in the higher ventral temporal cortex (VTC) that respond to categories like faces or places.

Eshed Margalit, the study’s lead author, who completed his PhD working with Yamins and Grill-Spector, said the team used self-supervised learning approaches to help the accuracy of training models that simulate the brain.

“It’s probably more like how babies are learning about the visual world,” Margalit said. “I don’t think we initially expected it to have such a big impact on the accuracy of the trained models, but you really need to get the training task of the network right for it to be a good model of the brain.”

The fully trainable model will help neuroscientists better understand the rules of how the brain organizes itself, whether for vision, like in this study, or other sensory systems such as hearing.

“When the brain is trying to learn something about the world — like seeing two snapshots of a person — it puts neurons that respond similarly in proximity in the brain and maps form,” said Grill-Spector, who is the Susan S. and William H. Hindle Professor in the School of Humanities and Sciences. “We believe that principle should be translatable to other systems, as well.”

This innovative approach has significant implications for both neuroscience and artificial intelligence. For neuroscientists, the TDANN provides a new lens to study how the visual cortex develops and operates, potentially transforming treatments for neurological disorders. For AI, insights derived from the brain’s organization can lead to more sophisticated visual processing systems, akin to teaching computers to ‘see’ as humans do.

The findings could also help explain how the human brain operates with such stellar energy efficiency. For example, the human brain can compute a billion-billion math operations with only 20 watts of power, compared with a supercomputer that requires a million times more energy to do the same math.

The new findings emphasize that neuronal maps — and the spatial or topographic constraints that drive them — likely serve to keep the wiring connecting the brain’s 100 billion neurons as simple as possible. These insights could be key to designing more efficient artificial systems inspired by the elegance of the brain.

More energy-efficient AI could help grow virtual neuroscience, where experiments could be done more quickly and at a larger scale. In their study, the researchers demonstrated as a proof of principle that their topographical deep artificial neural network reproduced brain-like responses to a wide range of naturalistic visual stimuli, suggesting that such systems could, in the future, be used as fast, inexpensive playgrounds for prototyping neuroscience experiments and rapidly identifying hypotheses for future testing.

Virtual neuroscience experiments could also advance human medical care. For example, better training an artificial visual system in the same way a baby visually learns about the world might help an AI see the world like a human, where the center of gaze is sharper than the rest of a field of view. Another application could help develop prosthetics for vision or simulate exactly how diseases and injuries affect parts of the brain.

Human ventromedial prefrontal cortex is necessary for prosocial motivation

by Patricia L. Lockwood, Jo Cutler, Daniel Drew, Ayat Abdurahman, Deva Sanjeeva Jeyaretna, Matthew A. J. Apps, Masud Husain, Sanjay G. Manohar. in Nature Human Behaviour

Our willingness to help others is governed by a specific brain region pinpointed by researchers in a study of patients with brain damage to that region.

Learning about where in the brain ‘helping’ decisions are made is important for understanding how people might be motivated to tackle large global challenges, such as climate change, infectious disease and international conflict. It is also essential for finding new approaches to treating disorders of social interactions.

The study, published in Nature Human Behaviour, was carried out by researchers at the University of Birmingham and the University of Oxford, and shows for the first time how a region called the ventromedial prefrontal cortex (vmPFC) has a critical role in helping, or ‘prosocial’ behaviours.

Lead author Professor Patricia Lockwood said: “Prosocial behaviours are essential for addressing global challenges. Yet helping others is often effortful and humans are averse to effort. Understanding how effortful helping decisions are processed in the brain is extremely important.”

In the study, the researchers focused on the vmPFC, a region located right at the front of the brain, which is known to be important for decision-making and other executive functions. Previous studies using magnetic resonance imaging (MRI scanning) have linked the vmPFC to choices that involve a trade-off between the rewards available and the effort required to obtain rewards. However, these techniques cannot show whether a part of the brain is essential for these functions.

Three groups of participants were recruited for the study. 25 patients had vmPFC damage, 15 patients had damage elsewhere in the brain, and 40 people were healthy age and gender-matched control participants. These groups allowed the researchers to test the impact of damage to vmPFC specifically.

Each participant attended an experiment where they met another person anonymously. They then completed a decision-making task that measured how willing they were to exert physical effort (squeezing a grip force device) to earn rewards (bonus money) for themselves and for the other person.

By enabling participants to meet — but not see — the person they were ‘working’ for in advance, researchers were able to convey the sense that participants’ efforts would have real consequences, but hide any information about the other person that could affect decision-making.

Each choice the participants made varied in how much bonus money for them or the other person was available, and how much force they would have to exert to obtain the reward. This allowed the researchers to measure the impact of reward and effort separately, and to use advanced mathematical modelling to precisely quantify people’s motivation.

The results of the study clearly showed that the vmPFC was necessary for motivation to help others. Patients with vmPFC damage were less willing to choose to help others, exerted less force on even after they did decide to help, and earned less money to help others compared to the control groups.

In a further step, the researchers used a technique called lesion symptom mapping which enabled them to identify even more specific subregions of the vmPFC where damage made people particularly antisocial and unwilling to exert effort for the other person. Surprisingly, damage to a nearby but different subregion made people relatively more willing to help.

Co-lead author Dr Jo Cutler said: “As well as better understanding prosocial motivation, this study could also help us to develop new treatments for clinical disorders such as psychopathy, where understanding the underlying neural mechanisms can give us new insights into how to treat these conditions.”

“This region of the brain is particularly interesting because we know that it undergoes late development in teenagers, and also changes as we get older,” added Professor Lockwood. “It will be really interesting to see whether this area of the brain can also be influenced by education — can we learn to be better at helping others?”

Hippocampal sharp-wave ripples correlate with periods of naturally occurring self-generated thoughts in humans

by Takamitsu Iwata, Takufumi Yanagisawa, Yuji Ikegaya, Jonathan Smallwood, Ryohei Fukuma, Satoru Oshino, Naoki Tani, Hui Ming Khoo, Haruhiko Kishima in Nature Communications

Part of what makes us human is our ability to think about people, places, or events that aren’t currently present — but we still don’t know exactly how our brains do this. Now, researchers from Osaka University have identified a specific kind of brain activity linked with these kinds of thoughts, such as when we daydream or let our minds wander.

When we think about things that aren’t actually happening, like when we daydream, the brain is essentially making up information rather than receiving and processing it — for this reason, researchers classify it as a “self-generated” brain state. In a recent study published in Nature Communications, researchers from Japan have identified that these self-generated states are associated with a specific pattern of brain activity known as “sharp-wave ripples.” These ripples start in the hippocampus, a brain region that is essential for making and retrieving memories.

To study the relationship between these sharp-wave ripples and different kinds of thoughts, the research team made use of the information that’s collected when patients with drug-resistant epilepsy are about to undergo surgery (to remove the starting point of the epileptic activity in the brain). Intracranial electrodes are implanted in the hippocampus in these patients and the activity in the brain is continuously tracked, so that the surgeons can identify the epileptic region and be sure that they aren’t removing a part of the brain that will have unexpected consequences.

“We asked patients undergoing this electroencephalographic brain monitoring for 10 days to complete an hourly questionnaire relating to their thoughts and emotions,” says lead author of the study Takamitsu Iwata. “We mainly wanted to see if we could identify any links between the recorded brain activity and how the patients were feeling and thinking at the time.”

In general, the sharp-wave ripples from the hippocampus were generated in patients at night (presumably during sleep). Furthermore, the research team noticed a link between increased sharp-wave activity and thoughts that were more vivid or imaginative and less desirable or task-related, i.e. when their minds wandered.

“Notably, although our study was conducted entirely on people with epilepsy, we did our best to remove epilepsy-related data so that the results are applicable to healthy populations,” explains Takufumi Yanagisawa, senior author of the study. “The similarities between many of our results and those of previous studies, using other species or methods, indicate that our approach worked well.”

There is increasing evidence that self-generated brain states, including mind wandering and intrusive thoughts, have complex links with intelligence, autism, attention deficit disorder, and happiness/well-being. A better understanding of the brain regions and activity that cause these states may therefore help people with a range of different conditions.

Dietary Caffeine and Brain Dopaminergic Function in Parkinson Disease

by Emmi K Saarinen, Tomi Kuusimäki, Kari Lindholm, Kalle Niemi, Emma A Honkanen, Tommi Noponen, Marko Seppänen, Toni Ihalainen, Kirsi Murtomäki, Tuomas Mertsalmi, Elina Jaakkola, Elina Myller, Mikael Eklund, Simo Nuuttila, Reeta Levo, Kallol Ray Chaudhuri, Angelo Antonini, Tero Vahlberg, Marko Lehtonen, Juho Joutsa, Filip Scheperjans, Valtteri Kaasinen in Annals of Neurology

Regular high caffeine consumption affects dopamine function in patients with Parkinson’s disease, shows a new international study led by the University of Turku and Turku University Hospital in Finland. Caffeine consumption before undergoing diagnostic brain dopamine imaging may also affect the imaging results.

Previous research has shown that regular caffeine intake is associated with a reduced risk of developing Parkinson’s disease. However, there is limited research on the effects of caffeine on disease progression in patients who have already been diagnosed.

A follow-up study led by the University of Turku and Turku University Hospital (Tyks) in Finland examined how caffeine consumption affects brain dopamine function over an extended period in patients diagnosed with Parkinson’s disease. The dopamine function of the brain was assessed with single photon emission computed tomography (SPECT) to measure dopamine transporter (DAT) binding.

“The association between high caffeine consumption and a reduced risk for Parkinson’s disease has been observed in epidemiological studies. However, our study is the first to focus on the effects of caffeine on disease progression and symptoms in relation to dopamine function in Parkinson’s disease,” says Valtteri Kaasinen, Professor of Neurology at the University of Turku and principal investigator of the study.

A clinical study compared 163 patients with early-stage Parkinson’s disease to 40 healthy controls. The examinations and imaging were conducted on two occasions for a subsample, with an average interval of six years between the first and second imaging session. Changes in brain dopamine transporter binding were compared with patients’ caffeine consumption, which was assessed both by a validated questionnaire and by determining concentrations of caffeine and its metabolites in blood samples.

The findings revealed that patients with a high caffeine consumption exhibited a 8.3–15.4% greater decrease in dopamine transporter binding compared to those with a low caffeine consumption. However, the observed decline in dopamine function is unlikely to be due to a greater reduction in dopamine neurons following caffeine consumption. Rather, it is more likely to be a downregulatory compensatory mechanism in the brain that has also been observed in healthy individuals following caffeine and other stimulant use.

“While caffeine may offer certain benefits in reducing risk of Parkinson’s disease, our study suggests that high caffeine intake has no benefit on the dopamine systems in already diagnosed patients. A high caffeine intake did not result in reduced symptoms of the disease, such as improved motor function,” says Kaasinen.

Another significant finding of the study was the observation that a recent dose of caffeine, for example in the morning of the imaging session, temporarily increases the person’s DAT binding values. This could potentially complicate the interpretation of clinically commonly used brain DAT imaging results. The research results suggest that patients should refrain from consuming coffee and caffeine for 24 hours before undergoing diagnostic DAT imaging.

Urolithin A improves Alzheimer’s disease cognition and restores mitophagy and lysosomal functions

by Hou Y, Chu X, Park J, et al. in Alzheimer’s & Dementia.

Forgetfulness, difficulty finding words and confusion about time and place. These are some of the most common symptoms of Alzheimer’s disease. Now researchers at the University of Copenhagen have discovered that an ordinary fruit can help.

Alzheimer’s disease is an incurable disease of the brain and the most frequently occurring type of dementia. About two thirds of people with dementia are diagnosed with Alzheimer’s disease. Dementia often leads to functional impairment and eventually affects the parts of the brain responsible for motor control and breathing.

In Denmark, about 85,000–90,000 people have been diagnosed with dementia, and 50,000 of these are affected by Alzheimer’s disease. Every year, approx. 8,000 Danes are diagnosed with dementia.

“Our study on mouse models with AD shows that urolithin A, which is a naturally occurring substance in i.a. pomegranates, can alleviate memory problems and other consequences of dementia,” says Vilhelm Bohr, who is Affiliate Professor at the Department of Cellular and Molecular Medicine at the University of Copenhagen and prevoiusly Department Chair at the US National Institute on Aging.

This is good news for patients with dementia — a disease that is difficult to treat.

“Even though the study was conducted on mouse models, the prospects are positive. So far, research has shown promising results for the substance in the muscles, and clinical trials on humans are being planned.”

The researchers previously discovered that a specific molecule, nicotinamide riboside (NAD supplement), plays a key role in neurodegenerative diseases such as Alzheimer’s and Parkinson’s, as it actively helps remove damaged mitochondria from the brain.

“Many patients with neurodegenerative diseases experience mitochondrial dysfunction, also known as mitophagy. This means that the brain has difficulties removing weak mitochondria, which thus accumulate and affect brain function. If you are able to stimulate the mitophagy process, removing weak mitochondria, you will see some very positive results,” Vilhelm Bohr explains.

The results of the new study show that a substance found in pomegranates, urolithin A, removes weak mitochondria from the brain just as effectively as NAD supplement.

The researchers still don’t know how much urolithin A is needed to improve memory and alleviate symptoms of i.a. Alzheimer’s.

“We still cannot say anything conclusive about the dosage. But I imagine that it is more than a pomegranate a day. However, the substance is already available in pill form, and we are currently trying to find the right dosage,” Vilhelm Bohr says.

He also hopes the substance can be used for preventive purposes with no significant side effects.

“The advantage of working with a natural substance is the reduced risk of side effects. Several studies so far show that there are no serious side effects of NAD supplementation. Our knowledge of urolithin A is more limited, but as I mentioned, clinical trials with Urolithin A have been effective in muscular disease, and now we need to look at Alzheimers disease. ,” he says and adds:

“If we are going to eat something in the future to reduce the risk of Alzheimer’s, which we talk a lot about, we have to make sure there are no significant side effects.”

Crows “count” the number of self-generated vocalizations

by Liao DA, Brecht KF, Veit L, Nieder A. in Science.

In a behavioral experiment crows can learn to produce a set number of calls. This involves them planning in advance: from the sound of the first call in a numerical sequence it is possible to predict how many calls the crows will make.

A research team consisting of Dr. Diana A. Liao, Dr. Katharina F. Brecht and assistant professor Lena Veit led by Professor Andreas Nieder from the Institute of Neurobiology at the University of Tübingen has established this. Their study has been published in Science.

Carrion crows, which belong to the group of songbirds, are not known for the beauty of their song but for their formidable learning ability. For instance, earlier studies have shown that birds understand counting. “In addition, they have very good vocal control. They can control precisely whether they want to emit a call or not,” reports Andreas Nieder. Together with his team he undertook behavioral experiments with three carrion crows to study whether they can apply these abilities in combination.

The birds were given the following task: on seeing a selection of Arabic numerals or on hearing specific sounds they had to produce one to four calls as appropriate and then conclude their call sequence by pecking on an enter key.

“All three birds succeeded in this. They were able to count their calls in sequence,” says Nieder. The response time between presentation of the stimulus and emitting the first call in the answer was relatively long and became longer the more calls were required. The length of the delay was unaffected by the nature of the stimulus, visual or auditory. “This indicates that, from the information presented to them, the crows form an abstract numerical concept which they use to plan their vocalizations before emitting the calls,” Nieder explains.

This finding is reinforced by analysis of the individual crows’ calls in a sequence.

“Using the acoustic properties of the first call in a numerical sequence we could predict how many calls the crow would make,” reports Nieder. The crows’ behavior was not however entirely without errors. “Counting errors, such as one call too many or one too few, arose through the bird losing track of the calls already made or still to be produced. We are also able to read out these types of errors from the acoustic properties of the individual calls.”

The ability to produce a volitional number of vocalizations demands a highly-developed combination of numerical competence and vocal control.

“Our results show that humans are not the only ones who can do this. In principle it also opens up sophisticated communication to the crows,” says Nieder.

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