Microscopy reveals how psychedelics light up brain’s neuropathways

 Alex Kwan, Ph.D. ‘09, associate professor in the Meinig School of Biomedical Engineering, is using optical microscopy and other tools to map the brain’s neural response to psychedelic drugs, an approach that could lead to the development of fast-acting antidepressants
Photo credit: Ryan Young/Cornell University.

What a long, strange trip it’s been for psychedelic drugs. From their use in ancient indigenous ceremonies, to their often-caricatured association with the 1960s counterculture, to their recent reemergence as a potential therapeutic, hallucinogens have been embraced by very different communities for very different reasons. But scientists have never fully understood how these drugs actually work on the brain.

Alex Kwan, Ph.D. ‘09, associate professor in the Meinig School of Biomedical Engineering in the College of Engineering, is using optical microscopy and other tools to map the brain’s neural response to these psychoactive chemicals, an approach that could eventually lead to the development of fast-acting antidepressants and treatments for substance-use disorders and cluster headaches.

“We know more about the pharmacology, how psychedelics work at the structural level, interacting with the brain receptors. But there has been a big void in terms of understanding what they do to the brain itself, at the neural circuit level,” Kwan said. “There’s a chain of events that happen that ultimately lead to acute and longer-lasting behavioral changes that might be useful for treatment. But in between a lot of that is a black box.”

Despite the renewed interest in the benefits of psychedelics from popular figures such as environmentalist and author Michael Pollan, much of the research into these drugs was conducted in the 1950s and 60s with fairly rudimentary methods, Kwan said.

Our brains use quantum computation

Scientists from Trinity believe our brains could use quantum computation after adapting an idea developed to prove the existence of quantum gravity to explore the human brain and its workings. The discovery may shed light on consciousness, the workings of which remain scientifically difficult to understand and explain. Quantum brain processes could also explain why we can still outperform supercomputers when it comes to unforeseen circumstances, decision making, or learning something new

Scientists from Trinity believe our brains could use quantum computation after adapting an idea developed to prove the existence of quantum gravity to explore the human brain and its workings.

The brain functions measured were also correlated to short-term memory performance and conscious awareness, suggesting quantum processes are also part of cognitive and conscious brain functions.

If the team’s results can be confirmed – likely requiring advanced multidisciplinary approaches –they would enhance our general understanding of how the brain works and potentially how it can be maintained or even healed. They may also help find innovative technologies and build even more advanced quantum computers.

Covid-19 is linked to increased degradation of connections between nerve cells in a new brain model

Postdoctoral fellow Samudyata and doctoral student Susmita Malwade.
Source: Karolinska Institutet

Researchers at Karolinska Institutet have used cellular reprogramming in a new study to create human three-dimensional brain models and infected them with SARS-CoV-2. In infected models, the brain's immune cells showed an excessive elimination of connections between the nerve cells. The gene expression of these cells also mimicked changes observed in neurodegenerative diseases. The results hope to identify new treatments for cognitive symptoms after Covid-19 infection.

Several studies have reported persistent cognitive symptoms following a covid-19 infection, but the underlying mechanisms for this are still unknown. The researchers behind the study, published in the journal Molecular Psychiatry, have created from human induced pluripotent stem cells (iPS) three-dimensional models of the brain in test tubes, so-called brain organoids. The model differs from previous organoid models in that they also contain microglia - the brain's immune cells. In the infected models, microglia regulated genes involved in phagocytosis, "cell-eating," the researchers could also see how microglia contained an increased amount of proteins from brain cell connections, so-called synapses. The developed model and results of the study can help guide future efforts to address cognitive symptoms in the aftermath of COVID-19 and other neuroinvasive viral infections.

Lack of biomarker profiles typical of Alzheimer's disease

Image credit: Gerd Altmann

A new study from Karolinska Institutet and Karolinska University Hospital shows that only a small proportion of patients who were examined for cognitive illness at the specialized memory reception at Karolinska Hospital in Solna had biomarker profiles typical of Alzheimer's disease and could be considered as potential candidates for new disease-modifying treatments. against amyloid.

This study was done in collaboration between Karolinska Institutet and Janssen Pharmaceutica NV (part of Janssen Pharmaceutical Companies of Johnson & Johnson), and was published online in the journal Neurology, the medical journal of the American Academy of Neurology.

Biomarkers that reflect typical changes in brain pathology in Alzheimer's disease are an important support in the diagnosis, as well as finding which patient group is suitable for which new disease-modifying treatment, when such drugs become available in the market. At present, however, there is only limited data on the proportion of patients in regular clinics and memory clinics (ie who are not participants in research studies) who have Alzheimer's-type biomarkers and who could thus be the right patient group for these new drugs.

Large patient base at the Solna memorial reception

In this study, the research team led by Professor Miia Kivipelto, MD PhD, has examined biomarker profiles in a well-characterized patient group at the memorial reception at Karolinska University Hospital in Solna. The clinical investigation process at the newly started clinic (which opened in 2018) has given rise to a large amount of well-documented information. The memory reception receives patients with memory problems from primary care in the reception area as well as younger patients under 70 years from the entire Stockholm region. The investigation process follows a "fast track model" where a majority of all investigations are done within a week. Most patients undergo lumbar puncture for spinal cord fluid collection, magnetic camera examination of the brain, and most neuropsychological tests. These survey results are then compiled into a diagnosis. All patients are also asked for permission to participate in the hospital's research database and biobank (GEDOC).

Too much motivation affects our decision-making

Sami El-Boustani, Assistant Professor in the Department of Basic Neurosciences at the Faculty of Medicine of the UNIGE
Credit: Sami El-Boustani

In a good or a bad mood, focused or distracted, in dire or no need: our internal states directly influence our perceptions and decision- making. While the role of motivation on the performance of behavioral tasks has been known for more than a century - thanks to the work of psychologists Robert Yerkes and John Dilligham Dodson - its precise effect on the brain remains unclear. A team from the University of Geneva (UNIGE), in collaboration with the EPFL, has revealed how motivation alters the neural circuits responsible for sensory perception preceding decision-making in mice. This study reveals why a level of motivation that is too high or too low can affect our perception and therefore our choices. These results, featured in the journal Neuron, open up new perspectives in learning methods. 

Going to work early in the morning, choosing a restaurant at lunchtime: many of our decisions are motivated by needs, such as earning a living or satisfying our hunger. However, decision-making is a complex process, which can also be influenced by external factors, such as the environment or other individuals, and by our internal states, such as our mood, our level of attention or our degree of motivation. 

Study explores links between people taking multiple medications and dementia

Photo credit: Ksenia Yakovleva

People with dementia are likely to have taken more than three medications for other health conditions in the five years directly before their diagnosis, according to new research.

The study is the first to provide an in-depth exploration of the links between evolving polypharmacy – which involves a patient being prescribed more than one drug at any given time – and a dementia diagnosis.

Published in the Aging and Disease journal, it is based on an analysis of the records of more than 33,000 dementia patients in Wales between 1990 to 2015.

Experts in e-health used machine learning techniques to identify potentially damaging patterns in a patient’s medicine usage, and how these patterns evolve in the run-up to diagnosis.

They found that in the 20 years leading up to them being diagnosed, the proportion of patients taking three or more medications rose from 5.5% (for the period 16 to 20 years prior to diagnosis) to 82.16% among those less than five years from a diagnosis.

Team uses digital cameras, machine learning to predict neurological disease

From left, Richard Sowers, Rachneet Kaur and Manuel Hernandez led the development of a new approach for identifying people with multiple sclerosis or Parkinson’s disease. Their method involves videotaping the hips and lower extremities of individuals walking on a treadmill and allowing a machine-learning algorithm to differentiate gait abnormalities associated with each of these neurological conditions.
Photo credit: Fred Zwicky

In an effort to streamline the process of diagnosing patients with multiple sclerosis and Parkinson’s disease, researchers used digital cameras to capture changes in gait – a symptom of these diseases – and developed a machine-learning algorithm that can differentiate those with MS and PD from people without those neurological conditions.

Their findings are reported in the IEEE Journal of Biomedical and Health Informatics.

The goal of the research was to make the process of diagnosing these diseases more accessible, said Manuel Hernandez, a University of Illinois Urbana-Champaign professor of kinesiology and community health who led the work with graduate student Rachneet Kaur and industrial and enterprise systems engineering and mathematics professor Richard Sowers.

Currently, patients must wait – sometimes for years – to get an appointment with a neurologist to make a diagnosis, Hernandez said. And people in rural communities often must travel long distances to a facility where their condition can be assessed. To be able to gather gait information using nothing more than a digital camera and have that data assessed online could allow clinicians to do a quick screening that sends to a specialist only those deemed likely to have a neurological condition.

Researchers advance efforts to develop a protein-based treatment therapy for individuals with ALS

Photo Credit: Michal Jarmoluk

Researchers at the USF Health Morsani College of Medicine, located at the University of South Florida, successfully tested a protein that has the potential to aid in the development of a protein-based therapy for patients with ALS, a progressive nervous system disease, also known as Lou Gehrig’s disease, that affects nerve cells in the brain and spinal cord.

Published in eNeuro, the study examines the effects of apolipoprotein A1, a “good cholesterol” on endothelial cells, the lining in blood vessels that provides a barrier between the brain, spinal cord tissues and blood circulation.

In a petri dish under an environmental condition reminiscent of ALS, the team found that the protein activates a unique pathway inside cells that increases survival and protects endothelial cells from toxic substances in the blood. This pathway can enhance the survival of cells and prevent further vascular damage by ALS.

“With a functional barrier, the hope is that the environment in the central nervous system will become less toxic and disease progression can be slowed,” said Svitlana Garbuzova-Davis, professor at the Department of Neurosurgery and Brain Repair and lead investigator.

While the protein has been proven to protect endothelial cells in diseases such as diabetes and atherosclerosis, the effects on ALS-damaged endothelial cells were previously unknown.

Mouse-human comparison shows unimagined functions of the Thalamus

With mathematical models, Bochum and US researchers have simulated processes in the brain of mice and humans.
Credit: RUB, Marquard

Researchers have reproduced the brain functions of the mouse and human in the computer. Artificial intelligence could learn from this.

For a long time, the thalamus was considered a brain region that is primarily responsible for processing sensory stimuli. Current studies have increased the evidence that it is a central switch in cognitive processes. Researchers of neuroscience around Prof. Dr. Burkhard Pleger in Collaborative Research Center 874 of the Ruhr University Bochum and a team from the Massachusetts Institute of Technology (MIT, USA) observed learning processes in the brains of mice and humans and reproduced them in mathematical models. They were able to show that the region of the mediodoral nucleus in the thalamus has a decisive share in cognitive flexibility. They report in the journal PLOS Computational Biology.

Traumatic brain injury ‘remains a major global health problem’ say experts

Photo Credit: Ian Valerio

The report – the 2022 Lancet Neurology Commission – has been produced by world-leading experts, including co-lead author Professor David Menon from the Division of Anesthesia at the University of Cambridge.

 "Over the last decade, large international collaborations have provided important information to improve understanding and care of TBI. However, significant problems remain, especially in low- and middle-income countries"

David Menon

The Commission documents traumatic brain injury (TBI) as a global public health problem, which afflicts 55 million people worldwide, costs over US$400 billion per year, and is a leading cause of injury-related death and disability.

TBI is not only an acute condition but also a chronic disease with long-term consequences, including an increased risk of late-onset neurodegeneration, such as Parkinson’s disease and dementia. Road traffic incidents and falls are the main causes, but while in low- and middle-income countries, road traffic accidents account for almost three times the number of TBIs as falls, in high-income countries falls cause twice the number of TBIs compared to road traffic accidents. These data have clear consequences for prevention.

Over 90% of TBIs are categorized as ‘mild’, but over half of such patients do not fully recover by six months after injury. Improving outcome in these patients would be a huge public health benefit. A multidimensional approach to outcome assessment is advocated, including a focus on mental health and post-traumatic stress disorder. Outcome after TBI is poorer in females compared with males, but reasons for this are not clear.

Making lab-grown brain organoids ‘brainier

 Slices of mini–brain organoids with neural stem cells (red) and cortical neurons (green).
Credit: Hajime Ozaki, Watanabe lab/UCI

By using stem cells to grow miniature brain-like organs in the lab, scientists have opened a new avenue for studies of neurological development, disease and therapies that can’t be conducted in living people. But not all mini–brain organoids are created equal and getting them to precisely mimic the human brain tissues they’re modeling has been a persistent challenge.

“Right now, it’s like the Wild West because there is no standard method for generating mini–brain organoids,” said Bennett Novitch, a member of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA and the senior author of a new paper on the topic. “Every neuroscientist wants to make a brain organoid model of their favorite disease, and yet everyone’s organoids do not always look alike.”

In fact, because there is no common protocol for their production and a lack of quality-control guidelines, organoids can vary from lab to lab — and even from batch to batch — which means that a finding made in one organoid may not hold true in another.

“If my lab and another lab down the hall were to conduct drug screens using mini–brain organoid models of the same disorder, we could still get different results,” said Momoko Watanabe, the new paper’s first author and an assistant professor of anatomy and neurobiology at UC Irvine. “We won’t know whose findings are correct because the differences we’re seeing could be reflections of how our models differ rather than reflections of the disease.”

Neurodegenerative disease can progress in newly identified patterns

Neurodegenerative diseases — like amyotrophic lateral sclerosis (ALS, or Lou Gehrig's disease), Alzheimer’s, and Parkinson’s — are complicated, chronic ailments that can present with a variety of symptoms, worsen at different rates, and have many underlying genetic and environmental causes, some of which are unknown. ALS, in particular, affects voluntary muscle movement and is always fatal, but while most people survive for only a few years after diagnosis, others live with the disease for decades. Manifestations of ALS can also vary significantly; often slower disease development correlates with onset in the limbs and affecting fine motor skills, while the more serious, bulbar ALS impacts swallowing, speaking, breathing, and mobility. Therefore, understanding the progression of diseases like ALS is critical to enrollment in clinical trials, analysis of potential interventions, and discovery of root causes.

However, assessing disease evolution is far from straightforward. Current clinical studies typically assume that health declines on a downward linear trajectory on a symptom rating scale, and use these linear models to evaluate whether drugs are slowing disease progression. However, data indicate that ALS often follows nonlinear trajectories, with periods where symptoms are stable alternating with periods when they are rapidly changing. Since data can be sparse, and health assessments often rely on subjective rating metrics measured at uneven time intervals, comparisons across patient populations are difficult. These heterogenous data and progression, in turn, complicate analyses of invention effectiveness and potentially mask disease origin.

A potential new treatment for brain tumors

Featured photo at top of Pankaj Desai, left, and senior graduate research assistant Aniruddha Karve, right, in the lab.
Photo credit: Andrew Higley | University of Cincinnati

A research question posed in Pankaj Desai’s lab has led to a decade of research, a clinical trial and major national funding to further investigate a potential new treatment for the deadliest form of brain tumors.

Desai, PhD, and his team at the University of Cincinnati recently received a $1.19 million grant from the National Institutes of Health/National Institute of Neurological Disorders and Stroke to continue research into the use of a drug called letrozole to treat glioblastomas (GBM).

Research progression

GBMs are aggressive brain tumors that patients often are unaware of until symptoms emerge and the tumor is substantial. Current treatments include immediate surgery to safely remove as much tumor as possible, radiation and chemotherapy, but the tumor often recurs or becomes resistant to treatments. The average patient survives no more than 15 months after diagnosis.

The medication letrozole was approved by the U.S. Food and Drug Administration as a treatment for postmenopausal women with breast cancer in 2001. The drug works by targeting an enzyme called aromatase that is present in breast cancer cells and helps the cancer grow.

New research reveals the relationship between particular brain circuits and different aspects of mental wellbeing

Brain circuits and wellbeing
Credit: Miriam Klein-Flugge 

Associate Professor Miriam Klein-Flügge and colleagues looked at brain connectivity and mental health data from nearly 500 people. In particular, they looked at the connectivity of the amygdala – a brain region well known for its importance in emotion and reward processing. The researchers used functional magnetic resonance imaging to consider seven small subdivisions of the amygdala and their associated networks rather than combining the whole region together as previous studies have done.

The team also adopted a more precise approach to the data on mental wellbeing, looking at a large group of healthy people and using questionnaires that captured information about wellbeing in the social, emotional, sleep, and anger domains. This generated more precise data than many investigations which still use broad diagnoses such as depression or anxiety, which involve many different symptoms.

The paper, published in Nature Human Behavior, shows how the improved level of detail about both brain connectivity and wellbeing made it possible to characterize the exact brain networks that relate to these distinct aspects of mental health. The brain connections that mattered most for discerning whether an individual was struggling with sleep problems, for example, looked very different from those that carried information about their social wellbeing.

A new understanding of the neurobiology of impulsivity News

Photo Credit: Vitolda Klein

While not all impulsive behavior speaks of mental illness, a wide range of mental health disorders which often emerge in adolescence, including depression and substance abuse, have been linked to impulsivity. So, finding a way to identify and treat those who may be particularly vulnerable to impulsivity early in life is especially important.

A group of researchers, led by scholars at McGill University, have developed a genetically based score which could help identify, with a high degree of accuracy (greater than that of any impulsivity scores currently in use), the young children who are most at risk of impulsive behavior.

Their findings are especially compelling because the score they have developed was able to detect those at a higher risk of impulsivity within three ethnically diverse community samples of children, from a cohort of close to 6,000 children.

This discovery of a novel score for impulsivity in early life can inform prevention strategies and programs for children and adolescents who are at risk for psychiatric disorders. In addition, by describing the function of the gene networks comprising the score, the study can stimulate the development of new therapies in the future.

Statin use is not justified for healthy people with high cholesterol

Professor David Diamond, Department of Psychology
Credit: University of South Florida

About 40 million adults in the United States regularly take statins to lower their cholesterol levels and reduce their risk of heart disease and stroke, according to American Heart Association data from 2020.

However, many of them don’t stand to benefit from these drugs based on new research from David Diamond, a neuroscientist and cardiovascular disease researcher in the Department of Psychology at the University of South Florida.

Diamond and his co-authors reviewed literature from medical trials involving patients taking either a statin or placebo. They then narrowed their review to look at study participants with elevated levels of low-density lipoprotein-cholesterol (LDL), the so-called “bad cholesterol,” which can be reduced with a statin. Some individuals with high LDL also had high triglycerides (fat in the blood) and low high-density lipoprotein (HDL), the “good cholesterol,” which put them at the highest risk of having a heart attack.

But others with high LDL were very different. They had low triglycerides and high HDL, which meant they were healthier. People with optimal triglycerides and HDL levels typically exercise, have low blood pressure and low blood sugar, and are at a low risk of a heart attack.

Diamond and his co-authors asked two questions: If people are at a low risk of a heart attack based on having optimal triglycerides and HDL, but they also have high LDL, does that raise their risk? Further, would these people benefit from lowering their LDL with a statin?

Even the smartest AI models don’t match human visual processing

The study employed novel visual stimuli called “Frankensteins
Source/Credit: York University

Deep convolutional neural networks (DCNNs) don’t see objects the way humans do – using configural shape perception – and that could be dangerous in real-world AI applications, says Professor James Elder, co-author of a York University study.

Published in the Cell Press journal iScience, Deep learning models fail to capture the configural nature of human shape perception is a collaborative study by Elder, who holds the York Research Chair in Human and Computer Vision and is Co-Director of York’s Centre for AI & Society, and Assistant Psychology Professor Nicholas Baker at Loyola College in Chicago, a former VISTA postdoctoral fellow at York.

The study employed novel visual stimuli called “Frankensteins” to explore how the human brain and DCNNs process holistic, configural object properties.

“Frankensteins are simply objects that have been taken apart and put back together the wrong way around,” says Elder. “As a result, they have all the right local features, but in the wrong places.”

The investigators found that while the human visual system is confused by Frankensteins, DCNNs are not – revealing an insensitivity to configural object properties.

Exercise may be key to developing treatments for rare movement disorders

Spinal cerebellar ataxia 6 (SCA6) is an inherited neurological condition which has a debilitating impact on motor coordination. Affecting around 1 in 100,000 people, the rarity of SCA6 has seen it attract only limited attention from medical researchers. To date, there is no known cure and only limited treatment options exist.

Now, a team of McGill University researchers specializing in SCA6 and other forms of ataxia, have published findings that not only offer hope for SCA6 sufferers but may also open the way to developing treatments for other movement disorders.

Exercise in a pill

In mice affected by SCA6, the McGill team, led by biology professor Alanna Watt, found that exercise restored the health of cells in the cerebellum, the part of the brain implicated in SCA6 and other ataxias. The reason for the improvement, the researchers found, was that exercise increased levels of brain-derived neurotrophic factor (BDNF), a naturally occurring substance in the brain which supports the growth and development of nerve cells. Importantly for patients with a movement disorder, for whom exercise may not always be feasible, the team demonstrated that a drug that mimicked the action of BDNF could work just as well as exercise, if not better.

Brain Injury Model Created to Find New Medication

The experiments on the fish were conducted non-invasively, using a laser machine.
Photo credit: Danil Lomovskikh

Scientists from Russia and Taiwan (China) have developed and successfully tested a new model of traumatic brain injury (TBI) in zebradanio fish (Danio rerio). The method is based on irradiating the brains of adult individuals of these popular aquarium and laboratory fish with a unique laser system with precise aiming, which was specially developed by scientists. The application of this model allowed the researchers to simulate the TBI and identify molecular targets promising for the treatment of neurotrauma and its consequences. This paves the way for preclinical zebrafish testing of new neuroprotective medications.

The work was financially supported by the Russian Science Foundation (grant № 20-65-46006). An article describing the research was published in the highly rated scientific journal Pharmaceutics. The subject of the research was explained by Alan Kaluev, professor of the Russian Academy of Sciences, member of the European Academy, leading researcher of the Research Institute of Neuroscience and Medicine, professor of the St. Petersburg State University and Sirius Scientific-Technological University, leading researchers of the Ural Federal University and the Moscow Institute of Physics and Technology. Professor Kaluev is a leading scientist within the framework of research conducted at the Scientific Novosibirsk Research Institute of Neuroscience and Medicine (laboratory of Tamara Amstislavskaya and Maria Tikhonova).

The most common experimental models of brain injury in both rodents and zebrafish, such as mechanical blows to the head or needle piercing of the brain, involve penetrating brain tissue damage. However, these models do not correctly reproduce TBI. In the created model, due to the fact that the skin and skull of the used zebradanio species are transparent, it was possible to hit directly the brain, and non-invasively.

Study links length of REM sleep to body temperature

Credit: Lancet Neurology

Warm-blooded animal groups with higher body temperatures have lower amounts of rapid eye movement (REM) sleep, while those with lower body temperatures have more REM sleep, according to new research from UCLA professor Jerome Siegel, who said his study suggests that REM sleep acts like a “thermostatically controlled brain heater.”

The study in Lancet Neurology suggests a previously unobserved relationship between body temperature and REM sleep, a period of sleep when the brain is highly active, said Siegel, who directs the Center for Sleep Research at the Jane and Terry Semel Institute for Neuroscience and Human Behavior at UCLA.

Birds have the highest body temperature of any warm-blooded, or homeotherm, animal group at 41 degrees while getting the least REM sleep at 0.7 hours per day. That’s followed by humans and other placental mammals (37 degrees, 2 hours of REM sleep), marsupials (35 degrees, 4.4 hours of REM sleep), and monotremes (31 degrees, 7.5 hours of REM sleep).