Posts Tagged ‘research’

by PETER DOCKRILL

Scientists think they’ve identified a previously unknown form of neural communication that self-propagates across brain tissue, and can leap wirelessly from neurons in one section of brain tissue to another – even if they’ve been surgically severed.

The discovery offers some radical new insights about the way neurons might be talking to one another, via a mysterious process unrelated to conventionally understood mechanisms, such as synaptic transmission, axonal transport, and gap junction connections.

“We don’t know yet the ‘So what?’ part of this discovery entirely,” says neural and biomedical engineer Dominique Durand from Case Western Reserve University.

“But we do know that this seems to be an entirely new form of communication in the brain, so we are very excited about this.”

Before this, scientists already knew there was more to neural communication than the above-mentioned connections that have been studied in detail, such as synaptic transmission.

For example, researchers have been aware for decades that the brain exhibits slow waves of neural oscillations whose purpose we don’t understand, but which appear in the cortex and hippocampus when we sleep, and so are hypothesised to play a part in memory consolidation.

“The functional relevance of this input‐ and output‐decoupled slow network rhythm remains a mystery,” explains neuroscientist Clayton Dickinson from the University of Alberta, who wasn’t involved in the new research but has discussed it in a perspective article.

“But [it’s] one that will probably be solved by an elucidation of both the cellular and the inter‐cellular mechanisms giving rise to it in the first place.”

To that end, Durand and his team investigated slow periodic activity in vitro, studying the brain waves in hippocampal slices extracted from decapitated mice.

What they found was that slow periodic activity can generate electric fields which in turn activate neighbouring cells, constituting a form of neural communication without chemical synaptic transmission or gap junctions.

“We’ve known about these waves for a long time, but no one knows their exact function and no one believed they could spontaneously propagate,” Durand says.

“I’ve been studying the hippocampus, itself just one small part of the brain, for 40 years and it keeps surprising me.”

This neural activity can actually be modulated – strengthened or blocked – by applying weak electrical fields and could be an analogue form of another cell communication method, called ephaptic coupling.

The team’s most radical finding was that these electrical fields can activate neurons through a complete gap in severed brain tissue, when the two pieces remain in close physical proximity.

“To ensure that the slice was completely cut, the two pieces of tissue were separated and then rejoined while a clear gap was observed under the surgical microscope,” the authors explain in their paper.

“The slow hippocampal periodic activity could indeed generate an event on the other side of a complete cut through the whole slice.”

If you think that sounds freaky, you’re not the only one. The review committee at The Journal of Physiology – in which the research has been published – insisted the experiments be completed again before agreeing to print the study.

Durand et al. dutifully complied, but sound pretty understanding of the cautiousness, all things considered, given the unprecedented weirdness of the observation they’re reporting.

“It was a jaw-dropping moment,” Durand says, “for us and for every scientist we told about this so far.”

“But every experiment we’ve done since to test it has confirmed it so far.”

It’ll take a lot more research to figure out if this bizarre form of neural communication is taking place in human brains – let alone decoding what exact function it performs – but for now, we’ve got new science that’s shocking in all kinds of ways, as Dickson adroitly observes.

“While it remains to be seen if the [findings] are relevant to spontaneous slow rhythms that occur in both cortical and hippocampal tissue in situ during sleep and sleep‐like states,” Dickson writes, “they should probably (and quite literally) electrify the field.”

The findings are reported in The Journal of Physiology.

https://www.sciencealert.com/neuroscientists-say-they-ve-found-an-entirely-new-form-of-neural-communication

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by Ruth Williams

The brains of people in vegetative, partially conscious, or fully conscious states have differing profiles of activity as revealed by functional magnetic resonance imaging (fMRI), according to a report today (February 6) in Science Advances. The results of the study indicate that, compared with patients lacking consciousness, the brains of healthy individuals exhibit highly dynamic and complex connectivity.

“This new study provides a substantial advance in characterizing the ‘fingerprints’ of consciousness in the brain” Anil Seth, a neuroscientist at the University of Sussex, UK, who was not involved in the project, writes in an email to The Scientist. “It opens new doors to determining conscious states—or their absence—in a range of different conditions.”

A person can lose consciousness temporarily, such as during sleep or anesthesia, or more permanently as is the case with certain brain injuries. But while unconsciousness manifests behaviorally as a failure to respond to stimuli, such behavior is not necessarily the result of unconsciousness.

Some seemingly unresponsive patients, for example, can display brain activities similar to those of fully conscious individuals when asked to imagine performing a physical task such as playing tennis. Such a mental response in the absence of physical feedback is a condition known as cognitive-motor dissociation.

Researchers are therefore attempting to build a better picture of what is happening in the human brain during consciousness and unconsciousness. In some studies, electroencephalography (EEG) recordings of the brain’s electrical activities during sleep, under anesthesia, or after brain injury have revealed patterns of brain waves associated with consciousness. But, says Jacobo Sitt of the Institute of Brain and Spinal Cord in Paris, such measurements do not provide good spatial information about brain activity. With fMRI, on the other hand, “we know where the activity is coming from.”

Sitt and colleagues performed fMRI brain scans on a total of 47 healthy individuals and 78 patients who either had unresponsive wakefulness syndrome (UWS)—a vegetative state in which the patient’s eyes open, but they never exhibit voluntary movement—or were in a minimally conscious state (MCS)—having more complex behaviors, such as the ability to follow an object with their eyes, but remaining unable to communicate thoughts or feelings. The scans were performed by an international team of collaborators at three different facilities in Paris, New York, and Liège, Belgium.

Data from the fMRI scans, which generated roughly 400 images in approximately 20 minutes for each patient, was computationally analyzed for identifiable patterns of activity. Four patterns were reproducibly detected within the data from each facility. And, for two of these patterns, the likelihood of their occurrence in a given individual’s scan depended on diagnosis.

Healthy individuals, for example, were more likely than patients to display pattern 1—characterized by high spatial complexity and interregional connectivity indicating brain-wide coordination. Patients with UWS, on the other hand, rarely displayed pattern 1, most often displaying pattern 4—characterized by low complexity and reduced interregional connectivity. Generally speaking, MCS patients fell somewhere between. The occurrence of patterns 2 and 3 were equally likely across all groups.

The team went on to analyze a second set of 11 patients at a facility in Ontario, Canada. Again the four distinct patterns were detected within the fMRI images. Six of these patients had UWS and predominantly displayed pattern 4, while the remaining five, who had cognitive-motor dissociation, had higher rates of pattern 1, supporting previous evidence for consciousness in these patients.

With such a mix of patients, facilities, scanners, and researchers, the study “had every possibility of failing,” says neuroscientist Tristan Bekinschtein of the University of Cambridge, UK, who did not participate in the research. However, the results were “brutally consistent,” he says.

Having identifiable signatures of consciousness and unconsciousness might ultimately help doctors and families make difficult decisions about continuing life support for vegetative patients, says anesthesiology researcher Anthony Hudetz of the University of Michigan who was not involved with the work. It might also provide insight into whether particular rehabilitation methods or other treatments are working.

“All that hinges on a better understanding of what goes on in the brains of these patients versus healthy or aware [people],” Hudetz says. To that end, this paper “makes a major step forward.”

A. Demertzi et al., “Human consciousness is supported by dynamic complex patterns of brain signal coordination,” Sci Adv, 5: eaat7603, 2019.

https://www.the-scientist.com/news-opinion/neural-patterns-of-consciousness-identified-65433

To determine whether someone is a psychopath, they have to score highly on tests like the Hare Psychopathy Checklist, answering questions about superficial charm, impulsive behaviour, and pathological lies.

But there could be a simpler test: yawning.

It’s hard not to yawn when someone else does, because yawning is so contagious. Even dogs can catch them. But according to a study from 2015, published in the journal Personality and Individual Differences, psychopaths aren’t so susceptible.

The researchers from Baylor University recruited 135 students and measured their personalities for psychopathic traits. They then subjected them to a contagious yawning experiment.

Those who scored highly on the psychopathic scale were much less likely to catch a yawn.

In previous research, yawning has been linked to empathy. For example, in one study, children with autism were less likely to catch yawns, possibly because they find it harder to read other people. Babies don’t catch yawns either, and won’t until they are at least 4 years old, when they have more emotional awareness.

The researchers suggest empathy could be at play in their experiment, as psychopaths tend to lack it.

This isn’t to say if someone doesn’t yawn when you do they must be a psychopath. It’s just an intriguing symptom of the people who struggle to connect with other people’s emotions.

Also, people can catch yawns to different degrees. For some, it’s just reading the word “yawn” is enough to set them off. So if you yawned the whole way through reading this article, you might be able to conclude that your empathy is pretty high.

https://www.thisisinsider.com/psychopaths-dont-catch-yawns-2018-10

by Debora MacKenzie

We may finally have found a long-elusive cause of Alzheimer’s disease: Porphyromonas gingivalis, the key bacteria in chronic gum disease. That’s bad, as gum disease affects around a third of all people. But the good news is that a drug that blocks the main toxins of P. gingivalis is entering major clinical trials this year, and research published this week shows it might stop and even reverse Alzheimer’s. There could even be a vaccine.

Alzheimer’s is one of the biggest mysteries in medicine. As populations have aged, dementia has skyrocketed to become the fifth biggest cause of death worldwide. Alzheimer’s constitutes some 70 per cent of these cases and yet, we don’t know what causes it. The disease often involves the accumulation of proteins called amyloid and tau in the brain, and the leading hypothesis has been that the disease arises from defective control of these two proteins. But research in recent years has revealed that people can have amyloid plaques without having dementia. So many efforts to treat Alzheimer’s by moderating these proteins have failed, and the hypothesis has now been seriously questioned.

Indeed, evidence has been growing that the function of amyloid proteins may be as a defence against bacteria, leading to a spate of recent studies looking at bacteria in Alzheimer’s, particularly those that cause gum disease, which is known to be a major risk factor for the condition.

Bacteria involved in gum disease and other illnesses have been found after death in the brains of people who had Alzheimer’s, but until now, it hasn’t been clear whether these bacteria caused the disease or simply got in via brain damage caused by the condition.

Gum disease link

Multiple research teams have been investigating P. gingivalis, and have so far found that it invades and inflames brain regions affected by Alzheimer’s; that gum infections can worsen symptoms in mice genetically engineered to have Alzheimer’s; and that it can cause Alzheimer’s-like brain inflammation, neural damage, and amyloid plaques in healthy mice.

“When science converges from multiple independent laboratories like this, it is very compelling,” says Casey Lynch of Cortexyme, a pharmaceutical firm in San Francisco, California.

In the new study, Cortexyme have now reported finding the toxic enzymes – called gingipains – that P. gingivalis uses to feed on human tissue in 96 per cent of the 54 Alzheimer’s brain samples they looked at, and found the bacteria themselves in all three Alzheimer’s brains whose DNA they examined.

“This is the first report showing P. gingivalis DNA in human brains, and the associated gingipains, co-lococalising with plaques,” says Sim Singhrao, of the University of Central Lancashire, UK. Her team previously found that P. gingivalis actively invades the brains of mice with gum infections. She adds that the new study is also the first to show that gingipains slice up tau protein in ways that could allow it to kill neurons, causing dementia.

The bacteria and its enzymes were found at higher levels in those who had experienced worse cognitive decline, and had more amyloid and tau accumulations. The team also found the bacteria in the spinal fluid of living people with Alzheimer’s, suggesting that this technique may provide a long-sought after method of diagnosing the disease.

When the team gave P. gingivalis gum disease to mice, it led to brain infection, amyloid production, tangles of tau protein, and neural damage in the regions and nerves normally affected by Alzheimer’s.

Cortexyme had previously developed molecules that block gingipains. Giving some of these to mice reduced their infections, halted amyloid production, lowered brain inflammation and even rescued damaged neurons.

The team found that an antibiotic that killed P. gingivalis did this too, but less effectively, and the bacteria rapidly developed resistance. They did not resist the gingipain blockers. “This provides hope of treating or preventing Alzheimer’s disease one day,” says Singhrao.

New treatment hope

Some brain samples from people without Alzheimer’s also had P. gingivalis and protein accumulations, but at lower levels. We already know that amyloid and tau can accumulate in the brain for 10 to 20 years before Alzheimer’s symptoms begin. This, say the researchers, shows P. gingivalis could be a cause of Alzheimer’s, but it is not a result.

Gum disease is far more common than Alzheimer’s. But “Alzheimer’s strikes people who accumulate gingipains and damage in the brain fast enough to develop symptoms during their lifetimes,” says Lynch. “We believe this is a universal hypothesis of pathogenesis.”

Cortexyme reported in October that the best of their gingipain blockers had passed initial safety tests in people, and entered the brain. It also seemed to improve participants with Alzheimer’s. Later this year the firm will launch a larger trial of the drug, looking for P. gingivalis in spinal fluid, and cognitive improvements, before and after.

They also plan to test it against gum disease itself. Efforts to fight that have led a team in Melbourne to develop a vaccine for P. gingivalis that started tests in 2018. A vaccine for gum disease would be welcome – but if it also stops Alzheimer’s the impact could be enormous.

Journal reference: Science Advances

https://www.newscientist.com/article/2191814-we-may-finally-know-what-causes-alzheimers-and-how-to-stop-it/


Coloured positron emission tomography (PET, centre) and computed tomography (CT, left) scans of the brain of a 62-year-old woman with Alzheimer’s disease.

By Pam Belluck

In dementia research, so many paths have led nowhere that any glimmer of optimism is noteworthy.

So some experts are heralding the results of a large new study, which found that people with hypertension who received intensive treatment to lower their blood pressure were less likely than those receiving standard blood pressure treatment to develop minor memory and thinking problems that often progress to dementia.

The study, published Monday in JAMA, is the first large, randomized clinical trial to find something that can help many older people reduce their risk of mild cognitive impairment — an early stage of faltering function and memory that is a frequent precursor to Alzheimer’s disease and other dementias.

The results apply only to those age 50 or older who have elevated blood pressure and who do not have diabetes or a history of stroke. But that’s a condition affecting a lot of people — more than 75 percent of people over 65 have hypertension, the study said. So millions might eventually benefit by reducing not only their risk of heart problems but of cognitive decline, too.

“It’s kind of remarkable that they found something,” said Dr. Kristine Yaffe, a professor of psychiatry and neurology at University of California San Francisco, who was not involved in the research. “I think it actually is very exciting because it tells us that by improving vascular health in a comprehensive way, we could actually have an effect on brain health.”

The research was part of a large cardiovascular study called Sprint, begun in 2010 and involving more than 9,000 racially and ethnically diverse people at 102 sites in the United States. The participants had hypertension, defined as a systolic blood pressure (the top number) from 130 to 180, without diabetes or a history of stroke.

These were people who could care for themselves, were able to walk and get themselves to doctors’ appointments, said the principal investigator, Dr. Jeff D. Williamson, chief of geriatric medicine and gerontology at Wake Forest School of Medicine.

The primary goal of the Sprint study was to see if people treated intensively enough that their blood pressure dropped below 120 would do better than people receiving standard treatment which brought their blood pressure just under 140. They did — so much so that in 2015, the trial was stopped because the intensively treated participants had significantly lower risk of cardiovascular events and death that it would have been unethical not to inform the standard group of the benefit of further lowering their blood pressure.

But the cognitive arm of the study, called Sprint Mind, continued to follow the participants for three more years even though they were no longer monitored for whether they continued with intensive blood pressure treatment. About 8,500 participants received at least one cognitive assessment.

The primary outcome researchers measured was whether patients developed “probable dementia.” Fewer patients did so in the group whose blood pressure was lowered to 120. But the difference — 149 people in the intensive-treatment group versus 176 people in the standard-treatment group — was not enough to be statistically significant.

But in the secondary outcome — developing mild cognitive impairment or MCI — results did show a statistically significant difference. In the intensive group, 287 people developed it, compared to 353 people in the standard group, giving the intensive treatment group a 19 percent lower risk of mild cognitive impairment, Dr. Williamson said.

Because dementia often develops over many years, Dr. Williamson said he believes that following the patients for longer would yield enough cases to definitively show whether intensive blood pressure treatment helps prevent dementia too. To find out, the Alzheimer’s Association said Monday it would fund two more years of the study.

“Sprint Mind 2.0 and the work leading up to it offers genuine, concrete hope,” Maria C. Carrillo, the association’s chief science officer, said in a statement. “MCI is a known risk factor for dementia, and everyone who experiences dementia passes through MCI. When you prevent new cases of MCI, you are preventing new cases of dementia.”

Dr. Yaffe said the study had several limitations and left many questions unanswered. It’s unclear how it applies to people with diabetes or other conditions that often accompany high blood pressure. And she said she would like to see data on the participants older than 80, since some studies have suggested that in people that age, hypertension might protect against dementia.

The researchers did not specify which type of medication people took, although Dr. Williamson said they plan to analyze by type to see if any of the drugs produced a stronger cognitive benefit. Side effects of the intensive treatment stopped being monitored after the main trial ended, but Dr. Williamson said the biggest negative effect was dehydration.

Dr. Williamson said the trial has changed how he treats patients, offering those with blood pressure over 130 the intensive treatment. “I’ll tell them it will give you a 19 percent lower chance of developing early memory loss,” he said.

Dr. Yaffe is more cautious about changing her approach. “I don’t think we’re ready to roll it out,” she said. “It’s not like I’m going to see a patient and say ‘Oh my gosh your blood pressure is 140; we need to go to 120.’ We really need to understand much more about how this might differ by your age, by the side effects, by maybe what else you have.”

Still, she said, “I do think the take-home message is that blood pressure and other measures of vascular health have a role in cognitive health,” she said. “And nothing else has worked.”

Levels of a protein called neurofilament light chain increase in the blood and spinal fluid of some Alzheimer’s patients 16 years before they develop symptoms, according to a study published January 21 in Nature Medicine.

The results suggest that neurofilament light chain (NfL), which is part of the cytoskeleton of neurons and has previously been tied to brain damage in mice, could serve as a biomarker to noninvasively track the progression of the disease. “This is something that would be easy to incorporate into a screening test in a neurology clinic,” coauthor Brian Gordon, an assistant professor of radiology at Washington University, says in a press release.

Gordon and his colleagues measured NfL in nearly 250 people carrying an Alzheimer’s-risk allele and more than 160 of their relatives who did not carry the variant. They found that those at risk of developing the disease had higher levels of the protein early on, and that NfL levels in both the blood and spinal fluid were on the rise well before the patients began to show signs of neurodegeneration, more than 16 years before disease onset.

Examining a subset of the patients more closely, the team saw that the rate of increase in NfL correlated with the shrinkage of a brain region called the precuneus, and patients whose NfL levels were rising rapidly tested worse on cognitive tests. “It is not necessarily the absolute levels which tell you your neurodegeneration is ongoing, it is the rate of change,” coauthor Mathias Jucker, a professor of cellular neurology at the German Center for Neurodegenerative Diseases in Tübingen, tells The Guardian.

The Alzheimer’s-linked mutation carried by patients examined in this study only affects about 1 percent of people who get the neurodegenerative disease, so the approach must be validated in a broader patient population, James Pickett, the head of research at the Alzheimer’s Society, tells The Guardian.

“We validated it in people with Alzheimer’s disease because we know their brains undergo lots of neurodegeneration, but this marker isn’t specific for Alzheimer’s,” Gordon says in the release. “I could see this being used in the clinic in a few years to identify signs of brain damage in individual patients.”

Meanwhile, a research team at Seoul National University in South Korea described another potential blood test for Alzheimer’s, focusing on the tau and amyloid proteins known to be associated with the disease. According to their study published today in Brain, blood levels of tau and amyloid correlate with how much tau has accumulated in the brain, as well as other markers of neurodegeneration such as hippocampal volume. “These results indicate that combination of plasma tau and amyloid-β1–42 levels might be potential biomarkers for predicting brain tau pathology and neurodegeneration,” the researchers write in their report.

https://www.the-scientist.com/news-opinion/protein-changes-detected-in-blood-years-before-alzheimers-onset-65347

Bringing the filtering abilities of a fuel cell into the blood vessels of living organisms, a new device could cut down on toxic effects of cancer treatment.

At the heart of this approach — recently tested in pigs — is a tiny, cylindrical “sponge” created by 3-D printing. Wedged inside a vein near a tumor being treated with chemotherapy, the sponge could absorb excess drug before it spreads through the body — thus lessening chemotherapy’s harmful side effects, including vomiting, immune suppression or even heart failure.

A human study could launch “in a couple of years, if all the stars are aligned,” says Steve Hetts, a neuroradiologist at the University of California, San Francisco who came up with the drug-capture concept. He worked with engineers at UC Berkeley and elsewhere to create and test prototypes.

A test of the most recent prototype showed that the absorber captured nearly two-thirds of a common chemotherapy drug infused into a nearby vein, without triggering blood clots or other obvious problems in the pig, Hetts and his colleagues report January 9 in ACS Central Science.

The study addresses a major need, says Eleni Liapi, a radiologist at Johns Hopkins University School of Medicine not involved with the new work. Existing methods for controlling chemotherapy delivery do not fully block drug escape, she notes. “A technological advancement to reduce unwanted circulating drug is always welcome.”


This image shows a cross-sectional view of a new 3-D printed cylindrical device that could cut down on toxic side effects from cancer treatment. Resin coatings (gold) bind to a chemo drug used to treat liver cancer, experiments show.

Chemo is often delivered intravenously in the hope that some treatment reaches the cancer site. In a more localized form of chemotherapy used to treat hard-to-remove tumors, the drug travels through catheter wires snaked into arteries going straight to the tumor. Although this technique, known as transarterial chemo embolization, or TACE, is given to tens of thousands of people each year, typically some of the injected drug bypasses the tumor site and slips into general circulation where it can wreak havoc elsewhere.

Hetts uses the transarterial method to treat babies with a rare eye tumor called retinoblastoma – and it was those experiences that birthed the “sponge” idea in the first place. After the chemotherapy ran its course through transarterial catheters, the infants’ eye tumors shrank. However, several weeks later, their blood cell counts tanked, suggesting to Hetts that some of the chemo drugs were escaping the eye and affecting other cells. Those observations eight years ago led Hetts to think that “if only I had a device I could put into the vein to bind up the excess drug, then maybe these little babies wouldn’t get the side effect” of immune suppression.

Heart surgeons use a similar “filter” to remove bits of cholesterol plaque from arteries of people with atherosclerosis, a disease characterized by the clogging and hardening of arteries. Hetts envisioned a similar device for chemotherapy treatment — “but not just a dumb, inert membrane to capture debris,” he says. “I wanted a ‘smart’ membrane that chemically binds to a drug.”

Instead of trying to develop a drug-trap device for a super rare tumor — retinoblastoma has just 300 new cases per year in the United States — Hetts’ team focused on a chemo drug for liver cancer, which is estimated to strike more than 40,000 Americans this year and kill three-quarters of them.

Anand Patel, a trainee in the Hetts’ lab with a bioengineering background, tested a batch of resins and found several that could bind to this drug, known as doxorubicin. To optimize the resins and get them onto the tips of guide wires, Patel sought help with “cold call” e-mails to local professors. Nitash Balsara — a UC Berkeley chemical engineer with expertise in polymer chemistry and membranes — “was actually crazy enough to return my e-mail with interest,” says Patel, who now works as an interventional radiologist in the Los Angeles area.

Balsara’s lab develops materials to regulate ion flow in batteries and fuel cells. As it turns out, these filtration processes are “very similar to those that we needed to capture excess chemotherapy drugs from the blood,” Patel says. The team worked with Carbon, Inc., a 3-D printing company in the San Francisco Bay area, to get the drug-binding material onto a 30-millimeter-long, cylinder-shaped “sponge” about as wide as a drinking straw. Hee Jeung Oh of UC Berkeley spent more than a year working out how to attach the drug-binding material to the 3-D printed cylinder with crisscrossing struts.

In experiments, the team injected the liver cancer drug through the pigs’ leg and pelvic veins — which are similar in width to human liver veins, Hetts says. Before infusing the chemotherapy drug, the researchers inserted the 3-D printed sponge a few centimeters from the infusion site — as well as catheters above and below the sponge for collecting blood samples to measure drug absorption over time. Within a half hour, the device absorbed, on average, 64 percent of the liver cancer drug.

The next round of studies will monitor the capture of doxorubicin by drug sponges inserted directly into the pigs’ liver veins.

https://www.sciencenews.org/article/new-3d-printed-sponge-sops-excess-chemo-cancer-drugs