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Some people have lost their eyesight, but they continue to "see." This phenomenon, a kind of vivid visual hallucination, is named after the Swiss doctor, Charles Bonnet, who described in 1769 how his completely blind grandfather experienced vivid, detailed visions of people, animals and objects. Charles Bonnet syndrome, which appears in those who have lost their eyesight, was investigated in a study led by scientists at the Weizmann Institute of Science. The findings, published today in Brain, suggest a mechanism by which normal, spontaneous activity in the visual centers of the brain can trigger visual hallucinations in the blind.
Prof. Rafi Malach and his group members of the Institute's Neurobiology Department research the phenomenon of spontaneous "resting-state" fluctuations in the brain. These mysterious slow fluctuations, which occur all over the brain, take place well below the threshold of consciousness. Despite a fair amount of research into these spontaneous fluctuations, their function is still largely unknown. The research group hypothesized that these fluctuations underlie spontaneous behaviors. However, it is typically difficult to investigate truly unprompted behaviors in a scientific manner for two reasons, since, for one, instructing people to behave spontaneously is usually a spontaneity-killer. Secondly, it is difficult to separate the brain's spontaneous fluctuations from other, task-related brain activity. The question was: How could they isolate a case of a truly spontaneous, unprompted, behavior in which the role of spontaneous brain activity could be tested?
Individuals experiencing Charles Bonnet visual hallucinations presented the group with a rare opportunity to investigate their hypothesis. This is because in Charles Bonnet syndrome, the hallucinations appear at random, in a truly unprompted fashion, and the visual centers of the brain do not process outside stimuli (because these individuals are blind), and are thus activated spontaneously. In a study led by Dr. Avital Hahamy, a former research student in Malach's lab who is now a postdoctoral research fellow at University College London, the relation between these hallucinations and the spontaneous brain activity has indeed been unveiled.
The researchers first invited to their lab five people who had lost their sight and reported occasionally experiencing clear visual hallucinations. These participants' brain activity was measured using an fMRI scanner while they described their hallucinations as these occurred. The scientists then created movies based on the participants' verbal descriptions, and they showed these movies to a sighted control group, also inside the fMRI scanner. A second control group consisted of blind people who had lost their sight but did not experience visual hallucinations. These were asked to imagine similar visual images while in the scanner.
The same visual areas in the brain were active in all three groups -- those that hallucinated, those that watched the films and those creating imagery in their minds' eye. But the researchers noted a difference in the timing of the neural activity between these groups. In both the sighted participants and those in the imagery group, the activity was seen to take place in response either to visual input or to the instructions set in the task. But in the group with Charles Bonnet syndrome, the scientists observed a gradually increasing wave of activity, reminiscent of the slow spontaneous fluctuations, that emerged just before the onset of the hallucinations. In other words, the hallucinations were not the result of external stimuli (eg., sensory images or instructions to imagine specific things), but were rather evoked internally by the slow, spontaneous, brain activity fluctuations.
"Our research clearly shows that the same visual system is active when we see the world outside of us, when we imagine it, when we hallucinate, and probably also when we dream," says Malach. "It also exemplifies the creative power of vision and the contribution of spontaneous brain activity to unprompted and creative behaviors," he adds.
In addition to the scientific value of the work, Hahamy hopes it may raise awareness of Charles Bonnet syndrome, which can be frightening to those who experience it. "These individuals may keep their visual hallucinations a secret -- even from doctors and family -- and we want them to understand that these visions are a natural product of a healthy brain, in which the visual centers remain intact, even if the eyes have ceased to send them sensory input," she says.
Also participating in this research were Dr. Meytal Wilf, formerly in Malach's lab, of Lausanne University Hospital, Switzerland; Dr. Boris Rosin, of the Ophthalmology Departments of Hadassah-Hebrew University Medical Center, Jerusalem, and University of of Pittsburgh Medical Center; and Prof. Marlene Behrmann of Carnegie Mellon University, Pittsburgh, Pennsylvania.
Prof. Rafael Malach's research is supported by the Dr. Lou Siminovitch Laboratory for Research in Neurobiology.
Peeking inside 'mini-brains' could boost understanding of the human brain
'Mini-brains' are pin-head sized collections of several different types of human brain cell. They are used as a tool, allowing scientists to learn about how the brain develops, study disease and test new medicines. Personalized 'mini-brains' can be grown from stem cells generated from a sample of human hair or skin and could shed light on how brain disease progresses in an individual and how this person may respond to drugs.
Research published today by a team of scientists and engineers from HEPIA and the Wyss Center for Bio and Neuroengineering, in the journal Frontiers in Bioengineering and Biotechnology, has revealed the detailed internal anatomy of 'mini-brains', for the first time.
"Despite advances in growing 'mini-brains', it has been difficult to understand in detail what is going on inside -- until now," said Professor Adrien Roux from the Tissue Engineering Laboratory, HEPIA, senior author on the paper.
"Typically, to look inside a 'mini-brain', we slice it thinly and view it on a slide under a microscope. This is a slow process that can damage the sample. Now, for the first time, we have produced high resolution 3D images of single neurons within intact 'mini-brains', revealing their remarkable complexity," added Dr Subashika Govindan, lead author on the paper, who carried out the work at HEPIA and is now Wellcome DBT early career fellow at the Indian Institute of Technology Madras (IITM).
The team combined a novel technique for labeling individual neurons with a method to make the whole sample completely transparent.
Leveraging the Wyss Center's microscopy capabilities, the team developed a state-of-the-art custom module, including a bespoke sample holder and sensitive imaging detectors, for capturing 3D images of entire intact 'mini-brains', without slicing them. They were then able to visualize and analyze the 3D morphology of specific neurons and their anatomical distribution inside the 'mini-brains'.
Dr Laura Batti, Microscopy Facility Manager at the Wyss Center said: "Human 'mini-brains' have a life span of more than a year and, with our new ability to visualize them in more detail, we can envision benefits such as reducing some animal testing."
The new approach could also enable imaging of large numbers of 'mini-brains', making it suitable for high-throughput screening for drug discovery or toxicity testing. It is reproducible and cost-effective and could potentially help accelerate personalized medicine studies.
Faulty metabolism of Parkinson's medication in the brain linked to severe side effects
Until now, the reason why the drug levodopa (L-Dopa), which reduces the motor symptoms of Parkinson's disease, declines in efficacy after a few years' use has been unknown. A side effect that then often occur is involuntary movements. A Swedish-French collaboration, led from Uppsala University, has now been able to connect the problems with defective metabolism of L-Dopa in the brain. The study is published in Science Advances.
"The findings may lead to new strategies for treating advanced Parkinson's," says Professor Per Andrén of the Department of Pharmaceutical Biosciences at Uppsala University. He and Dr Erwan Bézard of the University of Bordeaux, France, headed the study jointly.
Parkinson's disease (PD) is caused by the slow death of nerve cells that produce the key neurotransmitter dopamine. This results in the typical symptoms, such as rigidity and tremor. Treatment with L-Dopa, a precursor to dopamine, initially works very well as a rule; but after a few years, the effect of each dose becomes progressively more short-lived. Adverse side effects, such as rapid alternation between rigidity and uncontrolled movements that become increasingly severe over time, are very common. Finally, the benefits of L-Dopa treatment are jeopardised and the symptoms can become debilitating. Which neurochemical mechanisms cause these side effects is unknown. The involuntary movements are collectively known as "L-Dopa-induced dyskinesia."
Using a new method, "matrix-assisted laser desorption/ionisation mass spectrometry imaging" (MALDI-MSI), the researchers were able to map numerous neurotransmitters and other biomolecules directly in non-human primate brain tissue, which had not been possible before. The samples came from a French biobank.
Thus, they were able to compare in detail, and identify the differences between, the brains of two groups of parkinsonian animals. One group was suffering from motor complications caused by long-term L-Dopa treatment. In the second group were individuals who had PD symptoms to the same degree, and were receiving identical L-Dopa treatment, but in whom the medication had not caused the motor side effects.
In the group with motor disorders, abnormally elevated levels of both L-Dopa and 3-O-methyldopa were detected. The latter, a metabolite, is a product formed when L-Dopa is converted to dopamine. This was seen in all the brain regions examined, except -- to the researchers' surprise -- the particular part of the brain known as the striatum, which is thought to be involved in L-Dopa-induced movement disorders.
This suggests that brain mechanisms other than those that were previously recognised may underlie the motor disorders. Instead of originating in the striatum, these problems are most likely triggered by a direct effect of L-Dopa or dopamine, or a combination of the two, in some other part of the brain.
"Although there seems to be a direct connection between L-Dopa and motor complications, the mechanism that brings about the involuntary movements is still unclear and subject to further research. On the other hand, the new results show a direct role for L-Dopa in this motor disorder -- independently from dopamine. And this indicates that L-Dopa may also act on its own in the brain," Andrén says.
Where antibiotic resistance comes from
By comparing thousands of bacterial genomes, scientists in Gothenburg, Sweden have traced back the evolutionary history of antibiotic resistance genes. In almost all cases where an origin could be determined, the gene started to spread from bacteria that, themselves, can cause disease.
While human DNA is only passed down from parent to child, bacteria also have the habit of sharing some of their genes across species. This often applies to genes that make the bacteria resistant to antibiotics.
The use and overuse of antibiotics provide an advantage to those bacteria that have acquired resistance genes, thus further promoting the spread of resistance and making it more difficult to treat infections. This development threatens large parts of modern healthcare.
The rapid advances in DNA sequencing during the last decade has made it possible to study bacterial evolution much more effectively than ever before. This is an important background to the new study, published in the scientific journal Communications Biology.
The team from Gothenburg explored the scientific literature for claims of recent origins for antibiotic resistance genes, added information from public DNA-sequence-databases, and scrutinized the evidence at hand. While antibiotic-producing bacteria often are speculated to be the source for antibiotic resistance genes (as self-defence), this was not what the scientists found. None of the origin species found are known antibiotic producers. Strikingly, all verified origin species, except one, are known to cause disease, at least from time to time.
Professor Joakim Larsson, senior author of the study and director of the Centre for Antibiotic Resistance Research at University of Gothenburg, CARe, comments on the finding:
"Given that the overwhelming majority of bacteria are harmless to us, it was quite surprising that these genes almost exclusively came from bacteria causing disease. On the other hand, it makes some sense since such bacteria often trigger antibiotic use when we become infected, and other pathogens are often nearby, ready to engage in gene-transfer. These findings underscores the microbial-rich gut flora humans and domestic animals given antibiotics as arenas for resistance evolution" he says.
Knowing where resistance genes come from can inform measures to delay the emergence of additional resistance genes in the clinics. Importantly, the authors conclude that the origin is still unknown for more than 95% of all known resistance genes.
"Most likely, most of them come from un-sequenced bacterial species. We know the majority of the species that frequently tend to reside in the gut or on the skin of ourselves and of domestic animals. Therefore, this points to an important role of a much less explored gene reservoir -- the environmental microbiota. The role of the environment as a likely source for antibiotic resistance also stress the need reduce risks for resistance development in the environment, for example by limiting discharges of antibiotics though wastewaters," says Larsson.
The oldest hominins of Olduvai Gorge persisted across changing environments
Olduvai (now Oldupai) Gorge, known as the Cradle of Humankind, is a UNESCO World Heritage site in Tanzania, made famous by Louis and Mary Leakey. New interdisciplinary field work has led to the discovery of the oldest archaeological site in Oldupai Gorge as reported in Nature Communications, which shows that early humans used a wide diversity of habitats amidst environmental changes across a 200,000 year-long period.
Located in the heart of eastern Africa, the Rift System is a prime region for human origins research, boasting extraordinary records of extinct human species and environmental records spanning several million years. For more than a century, archaeologists and human palaeontologists have been exploring the East African Rift outcrops and unearthing hominin fossils in surveys and excavations. However, understanding of the environmental contexts in which these hominins lived has remained elusive due to a dearth of ecological studies in direct association with the cultural remains.
In the new study, published in Nature Communications, researchers from the Max Planck Institute for for the Science of Human History teamed up with lead partners from the University of Calgary, Canada, and the University of Dar es Salaam, Tanzania, to excavate the site of 'Ewass Oldupa' (meaning on 'the way to the Gorge' in the local Maa language, as the site straddles the path that links the canyon's rim with its bottom). The excavations uncovered the oldest Oldowan stone tools ever found at Oldupai Gorge, dating to ~2 million years ago. Excavations in long sequences of stratified sediments and dated volcanic horizons indicated hominin presence at Ewass Oldupai from 2.0 to 1.8 million years ago.
Fossils of mammals (wild cattle and pigs, hippos, panthers, lions, hyena, primates), reptiles and birds, together with a range of multidisciplinary scientific studies, revealed habitat changes over 200,000 years in riverine and lake systems, including fern meadows, woodland mosaics, naturally burned landscapes, lakeside palm groves and dry steppe habitats. The uncovered evidence shows periodic but recurrent land use across a subset of environments, punctuated with times when there is an absence of hominin activity.
Dr. Pastory Bushozi of Dar es Salaam University, Tanzania, notes, "the occupation of varied and unstable environments, including after volcanic activity, is one of the earliest examples of adaptation to major ecological transformations."
Hominin occupation of fluctuating and disturbed environments is unique for this early time period and shows complex behavioural adaptations among early human groups. In the face of changing habitats, early humans did not substantially alter their toolkits, but instead their technology remained stable over time. Indicative of their versatility, typical Oldowan stone tools, consisting of pebble and cobble cores and sharp-edged flakes and polyhedral cobbles, continued to be used even as habitats changed. The implication is that by two million years ago, early humans had the behavioural capacity to continually and consistently exploit a multitude of habitats, using reliable stone toolkits, to likely process plants and butcher animals over the long term.
Though no hominin fossils have yet been recovered from Ewass Oldupa, hominin fossils of Homo habilis were found just 350 metres away, in deposits dating to 1.82 million years ago. While it is difficult to know if Homo habilis was present at Ewass Oldupa, Professor Julio Mercader of the University of Calgary asserts that "these early humans were surely ranging widely over the landscape and along shores of the ancient lake." Mercader further notes that this does not discount the possibility that other hominin species, such as the australopithecines, were also using and making stone tools at Ewass Oldupa, as we know that the genus Paranthropus was present in Oldupai Gorge at this time.
Not just a guys' club: Resistance training benefits older women just as much as older men
Men and women aged over 50 can reap similar relative benefits from resistance training, a new study led by UNSW Sydney shows.
While men are likely to gain more absolute muscle size, the gains relative to body size are on par to women's.
The findings, recently published in Sports Medicine, consolidated the results of 30 different resistance training studies involving over 1400 participants. This paper specifically compared the results of men and women aged 50 and over.
"Historically, people tended to believe that men adapted to a greater degree from resistance training compared to women," says Dr Amanda (Mandy) Hagstrom, exercise science lecturer at UNSW Medicine & Health and senior author of the study.
"The differences we found primarily relate to how we look at the data -- that is, absolutely or relatively. 'Absolute' looks at the overall gains, while 'relative' is a percentage based on their body size."
The paper is the first systematic review and meta-analysis to examine whether older men and women reap different resistance training results. The findings add to past research on differences in younger adults (18-50), which suggested that men and women can achieve similar relative muscle size gains.
The researchers compared muscle mass and strength gains in 651 older men and 759 older women across the 30 studies. The participants were aged between 50 and 90, with most having no prior resistance training experience.
While 50 is not typically considered an 'older adult', it was selected as the threshold for this study given the potential for menopausal hormone changes to influence resistance training outcomes.
"We found no sex differences in changes in relative muscle size or upper body strength in older adults," says Dr Hagstrom.
"It's important for trainers to understand that women benefit just as much as men in terms of relative improvement compared to their baseline."
Sex-specific workout tips
Older men tended to build bigger muscles when looking at absolute gains, the researchers found. They were also more likely to see greater absolute improvements to upper and lower body strength.
But when it came to relative lower body strength, older women saw the biggest increases.
"Our study sheds light on the possibility that we should be programming differently for older men and women to maximise their training benefits," says Dr Hagstrom.
The team conducted a sub-analysis of the literature to see what resistance training techniques gave the best results for each sex.
"Older men might benefit from higher intensity programs to improve their absolute upper and lower body strength," says Dr Hagstrom.
"But older women might benefit from higher overall exercise volumes -- that is, more weekly repetitions -- to increase their relative and absolute lower body strength."
Longer training durations could also help increase relative and absolute muscle size (for older men) or absolute upper body strength (for older women).
"Changes to exercise regimes should be made safely and with professional consultation," says Dr Hagstrom.
Strengthening future health
Feeling stronger and having bigger muscles aren't the only benefits to resistance training.
Resistance training can offer other health benefits, like increasing a person's stamina, balance, flexibility and bone density. It has also been shown to help improve sleep, sense of wellbeing, and decrease the risk of injury.
"Strength training is very important and beneficial to our health -- especially for older people," says Dr Hagstrom.
"It can help prevent and treat many age-related chronic diseases, like diabetes, heart disease and arthritis."
Dr Hagstrom hopes her future research can identify more best-practice prescriptions for resistance training exercises.
"Learning more about resistance training and its benefits could help improve overall health outcomes for Australia's ageing population," she says.