TL;DR
- Elon Musk has unveiled a pig called Gertrude with a coin-sized computer chip in her brain to demonstrate his ambitious plans to create a working brain-to-machine interface.
- Subscalp brain monitoring devices could offer long-term, continuous, and reliable recording of neural activity at home and in the clinic.
- Researchers have developed a neurologically acting protein and tested it in laboratory studies. In mice, the experimental compound ameliorated symptoms of certain neurological injuries and diseases, while on the microscopic level it was able to establish and repair connections between neurons. This proof-of-principle study suggests that biologics, which act on neuronal connectivity, could be of clinical use in the long term.
- The new study finds that the fusiform face area is active when blind people touch 3D models of faces.
- ‘Jumping’ sequences of DNA, known as transposable elements, partner up with evolutionarily recent proteins to influence the differentiation and physiological functioning of human neurons.
- Scientists have made a breakthrough in understanding how the enteric nervous system forms, which could pave the way for new treatments for neurodegenerative diseases such as Parkinson’s.
- A new method of brain imaging analysis offers the potential to greatly improve the effectiveness of noninvasive brain stimulation treatment for Alzheimer’s, obsessive compulsive disorder, depression, and other conditions.
- Researchers have identified specific sub-populations of brain cells in the prefrontal cortex, a key part of the brain that regulates social behavior, that are required for normal sociability in adulthood and are profoundly vulnerable to juvenile social isolation in mice.
- Researchers at CHU Sainte-Justine Hospital and Université de Montréal have made a major discovery in understanding the mechanisms underlying learning and memory formation.
- Exercise fights off stress by increasing levels of the brain protein galanin, according to research in mice recently published in JNeurosci.
- An international research team now reports that problems in spatial navigation can also be detected in people with a genetic risk for Alzheimer’s. Their article was published in the journal Science Advances.
- In a new study from the Danish psychiatry project iPSYCH, researchers have identified genetic risk factors for developing bipolar disorder and psychoses among people with depression. In the longer term, the results may contribute to ensuring the correct diagnosis is made earlier, so that the patients can receive the correct treatment as quickly as possible.
- …And more!
Neuroscience market
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.
Latest news and researches
Neuralink: Elon Musk unveils pig with chip in its brain
Elon Musk has unveiled a pig called Gertrude with a coin-sized computer chip in her brain to demonstrate his ambitious plans to create a working brain-to-machine interface.
“It’s kind of like a Fitbit in your skull with tiny wires,” the billionaire entrepreneur said on a webcast.
His start-up Neuralink applied to launch human trials last year.
The interface could allow people with neurological conditions to control phones or computers with their mind.
Mr Musk argues such chips could eventually be used to help cure conditions such as dementia, Parkinson’s disease and spinal cord injuries.
But the long-term ambition is to usher in an age of what Mr Musk calls “superhuman cognition”, in part to combat artificial intelligence so powerful he says it could destroy the human race.
Gertrude was one of three pigs in pens that took part in Friday’s webcast demo. She took a while to get going, but when she ate and sniffed straw, the activity showed up on a graph tracking her neural activity. She then mostly ignored all the attention around her. The processor in her brain sends wireless signals, indicating neural activity in her snout when looking for food.
Mr Musk said the original Neuralink device, revealed just over a year ago, had been simplified and made smaller.
“It actually fits quite nicely in your skull. It could be under your hair and you wouldn’t know.”
Founded in 2017, Neuralink has worked hard to recruit scientists, something Mr Musk was still advertising for on Twitter last month and which he said was the purpose of Friday’s demo.
The device the company is developing consists of a tiny probe containing more than 3,000 electrodes attached to flexible threads thinner than a human hair, which can monitor the activity of 1,000 brain neurons.
Ahead of the webcast, Ari Benjamin, at the University of Pennsylvania’s Kording Lab, had told BBC News the real stumbling block for the technology could be the sheer complexity of the human brain.
“Once they have the recordings, Neuralink will need to decode them and will someday hit the barrier that is our lack of basic understanding of how the brain works, no matter how many neurons they record from.
“Decoding goals and movement plans is hard when you don’t understand the neural code in which those things are communicated.”
A new era in electroencephalographic monitoring? Subscalp devices for ultra–long-term recording
by Jukka Peltola Ivan C. Zibrandtsen Troels W. Kjaer et al. in Epilepsia
Subscalp brain monitoring devices could offer long-term, continuous, and reliable recording of neural activity at home and in the clinic.
Today, the way a physician gets an idea of how many seizures a person with epilepsy has had is through the patient’s own record of seizure activity in his day-to-day life. Despite all the technological advances in devices monitoring the human body, a patient’s seizure diary, as it is often called, remains the only means to record and count epileptic seizures outside the clinic. Any insights that such a diary can provide on the effects of medication, seizure frequency or seizure triggers depend on the reliability and detail of the patient’s reporting. Even accurate recognition of seizures is a problem since about half of seizures are not known to the patient.
A new generation of long-term brain monitoring technologies that continuously record brain activity in the clinic or at home is emerging and could greatly improve disease management for epilepsy patients. In an article published today in the journal Epilepsia, a team of scientists, engineers and clinicians from around the world describe how an innovative approach that records neural activity from beneath the scalp could provide a reliable alternative to subjective seizure diaries. These innovative devices are subscalp electroencephalography (EEG) systems that are minimally invasive and could remain underneath the scalp for long periods of time.
Maxime Baud, MD, PhD, epileptologist at Bern University Hospital, Wyss Center Staff Neurologist and co-author of the paper said: “Our current epilepsy treatment plans are primarily based on short-term brain activity data from EEG caps during a hospital visit. Epileptic seizures can occur months apart and come in cycles, so we need ways to, continuously and accurately, monitor brain activity in the home environment. With the Wyss Center’s Epios system, we are excited to be part of the movement developing such new technologies, that can ultimately enable us to optimize and personalize treatment for each patient.”
Six new technologies, commercially available or under development, are described in the paper each with a different primary value including seizure counting and recording, seizure forecasting and alerting, and neuro-stimulation. These minimally invasive techniques may help avoid some of the risks linked to directly intervening in the brain.
One of these subscalp devices is Minder, being developed by the Australian company Epi-Minder. Currently in clinical trials, the device’s multichannel electrode is placed across the skull so that both brain hemispheres are covered. “Through long-term and continuous EEG measurements, Minder aims to provide accurate knowledge of brain activity and seizures to help people with epilepsy take back control of their lives,” said Professor Mark Cook, MD, PhD, Chair of Medicine at the University of Melbourne, Director of Neurology at St Vincent’s Hospital, Melbourne and co-author of the paper.
Another technology reviewed in the paper is the Wyss Center’s EpiosTM system, designed to offer flexible subscalp configurations, from focal or bitemporal electrode layouts to broad head coverage and high-channel-count neural recording, through a series of thin sensing electrodes connected to a miniature implant, all inserted beneath the skin. The neural signals are wirelessly transmitted to an external (behind-the-ear) receiver, while a wearable data processor enhances brain data with heart rate, accelerometry and audio data and uploads it to the Epios Cloud, which offers secure and centralized data storage, annotation and visualization.
“In parallel to the recording devices, we are constantly optimizing our high performance analytics software with algorithms that could help clinicians draw meaningful conclusions from the vast amount of data recorded by these long-term systems,” George Kouvas, MBA, Chief Technology Officer at the Wyss Center and co-author of the paper said. “We are already working towards adapting these new technologies to help patients with other brain disorders manage their daily life, such as with tinnitus and stroke,” Kouvas added.
Future uses for long-term, subscalp brain monitoring include biomarker detection and efficacy monitoring of pharmaceuticals as well as well as closed-loop neuromodulation applications.
A synthetic synaptic organizer protein restores glutamatergic neuronal circuits
by Kunimichi Suzuki, Jonathan Elegheert, Inseon Song, Hiroyuki Sasakura, Oleg Senkov, Keiko Matsuda, Wataru Kakegawa, Amber J. Clayton, Veronica T. Chang, Maura Ferrer-Ferrer, Eriko Miura, el al. Science
Researchers from the German Center for Neurodegenerative Diseases (DZNE), UK and Japan have developed a neurologically acting protein and tested it in laboratory studies. In mice, the experimental compound ameliorated symptoms of certain neurological injuries and diseases, while on the microscopic level it was able to establish and repair connections between neurons. This proof-of-principle study suggests that biologics, which act on neuronal connectivity, could be of clinical use in the long term. The results are published in the journal Science.
The human brain’s neuronal network undergoes life-long changes in order to be able to assimilate information and store it in a suitable manner. This applies in particular to the generation and recalling of memories. So-called synapses play a central role in the brain’s ability to adapt. They are junctions through which nerve signals are passed from one cell to the next. A number of specific molecules — known as “synaptic organizing proteins” — make sure that synapses are formed and reconfigured whenever necessary.
An artificial protein
An international team of researchers has now combined various structural elements of such naturally occurring molecules into an artificial protein called CPTX and tested its effect in different disease models. To this end, the compound was administered to mice with neurological deficits that occur in similar fashion in humans. Specifically, the tests focused on Alzheimer’s disease, spinal cord injury and cerebellar ataxia — a disease that is characterized primarily by a failure of muscle coordination. All these conditions are associated with damage to the synapses or their loss. The study was a collaborative effort by experts from several research institutions, including the DZNE’s Magdeburg site, MRC Laboratory of Molecular Biology in UK, Keio University School of Medicine in Tokyo, and, also in Japan, Aichi Medical University.
Easing symptoms of disease
“In our lab we studied the effect of CPTX on mice that exhibited certain symptoms of Alzheimer’s disease,” said Prof. Alexander Dityatev, a senior researcher at the DZNE, who has been investigating synaptic proteins for many years. “We found that application of CPTX improved the mice’s memory performance.” The researchers also observed normalization of several important neuronal parameters that are compromised in Alzheimer’s disease, as well as in the studied animal model. Namely, CPTX increased the ability of synapses to change, which is considered as a cellular process associated with memory formation. Furthermore, CPTX was shown to elevate what is called “excitatory transmission.” This is to say that the protein acted specifically on synapses that promoted activity of the contacted cell. And finally, CPTX increased the density of so-called dendritic spines. These are tiny bulges in the cell’s membrane that are essential for establishing excitatory synaptic connections.
Further research by the study partners in the UK and Japan revealed that application of CPTX to mice with motor dysfunction — caused either by spinal cord injury or pathological conditions similar to cerebellar ataxia — improved the rodent’s mobility. And at the cellular level, the drug was shown to repair and promote excitatory synaptic connections.
A molecular connector
CPTX combines functional domains present in natural synaptic organizing proteins in a unique way. The compound was designed to act as a universal bridge builder for excitatory connections between nerve cells. Where two neurons meet, either in adhesive contact or actually in synaptic connection, CPTX links to specific molecules on the surfaces of both involved cells, and thereby either triggers the formation of new synapses or strengthens already existing ones.
“At present, this drug is experimental and its synthesis, the credit for which goes to our UK partners, is quite demanding. We are far off from application in humans,” Dityatev emphasized, who in addition to his research at the DZNE is also a member of the Medical Faculty of the University Magdeburg. “However, our study suggests that CPTX can even do better than some of its natural analogs in building and strengthening nerve connections. Thus, CPTX could be the prototype for a new class of drugs with clinical potential.” Application would be in disorders that are associated with impaired neuronal connectivity. “Much of the current therapeutic effort against neurodegeneration focuses on stopping disease progression and offers little prospect of restoring lost cognitive abilities. Our approach could help to change this and possibly lead to treatments that actually regenerate neurological functions. Based on the principles we have used in designing CPTX, we thus intend to develop further compounds. In future studies, we want to refine their properties and explore possible therapeutic applications.”
Retinoic Acid Accelerates the Specification of Enteric Neural Progenitors from In-Vitro-Derived Neural Crest
by Thomas J.R. Frith, Antigoni Gogolou, James O.S. Hackland, Zoe A. Hewitt, Harry D. Moore, Ivana Barbaric, Nikhil Thapar, Alan J. Burns, Peter W. Andrews, Anestis Tsakiridis, Conor J. McCann in Stem Cell Reports
Scientists have made a breakthrough in understanding how the enteric nervous system forms, which could pave the way for new treatments for neurodegenerative diseases such as Parkinson’s.
The findings, published in the journal Stem Cell Reports, pave the way for using stem cells to understand and treat a range of diseases linked to the enteric nervous system — which is embedded in the walls of the esophagus, stomach, small and large intestines, pancreas, gallbladder and biliary tree.
Researchers from the University of Sheffield and University College London (UCL) identified a key stage in the formation of the enteric nervous system using pluripotent stem cells, which can generate any cell type in the body, and were able to generate enteric neurons in the lab.
The enteric nervous system contains between 400–600 million nerves and is crucial for everyday functions such as digestion, fluid absorption and communicating with the immune system.
Faults in the enteric nervous system are often linked to life-threatening digestive disorders such as Hirschprung’s disease, where nerves in the system are missing. Ongoing research has also suggested that Parkinson’s disease is initiated in the enteric nervous system before reaching the brain.
Dr Anestis Tsakiridis,Group Leader of the Study from the University of Sheffield’s Centre for Stem Cell Biology, said: “Our findings show new promise for using stem cells to treat a range of diseases. We now plan to utilise these findings as the basis for developing stem cell-based approaches to treat and model diseases caused by dysfunction of the enteric nervous system.”
Dr Tom Frith, from the Francis Crick Institute who led the study said: “This work was the result of an exciting collaboration with experts from the UCL Great Ormond Street Institute of Child Health.
“These results are a key first step into generating cells in a dish that may one day be used to help treat patients.”
(A) Schematic of NC differentiation protocol and time points corresponding to addition of all-trans RA.
(B) FACS plots showing SOX10:GFP and p75 expression at day 5 after RA addition at indicated time points during NC differentiation.
(C ) Percentage of cells expressing SOX10 in three hPSC lines following FACS or immunofluorescence. Graphs show percentage of SOX10+ cells normalized to cells not treated with RA. Bars = mean; error = SD. N = 4 independent differentiations for SOX10:GFP. N = 3 independent differentiations for H7 and MasterShef7. ∗p < 0.05, ∗∗p < 0.01; one-way ANOVA.
A prefrontal–paraventricular thalamus circuit requires juvenile social experience to regulate adult sociability in mice
by Kazuhiko Yamamuro, Lucy K. Bicks, Michael B. Leventhal, Daisuke Kato, Susanna Im, Meghan E. Flanigan, Yury Garkun, Kevin J. Norman, Keaven Caro, Masato Sadahiro, Klas Kullander, Schahram Akbarian, Scott J. Russo, Hirofumi Morishita Nature Neuroscience
Researchers have identified specific sub-populations of brain cells in the prefrontal cortex, a key part of the brain that regulates social behavior, that are required for normal sociability in adulthood and are profoundly vulnerable to juvenile social isolation in mice.
A research team from the Icahn School of Medicine at Mount Sinai has now identified specific sub-populations of brain cells in the prefrontal cortex, a key part of the brain that regulates social behavior, that are required for normal sociability in adulthood and are profoundly vulnerable to juvenile social isolation in mice. The study findings, which appear in the August 31 issue of Nature Neuroscience, shed light on a previously unrecognized role of these cells, known as medial prefrontal cortex neurons projecting to the paraventricular thalamus, the brain area that relays signals to various components of the brain’s reward circuitry. If the finding is replicated in humans, it could lead to treatments for psychiatric disorders connected to isolation.
“In addition to identifying this specific circuit in the prefrontal cortex that is particularly vulnerable to social isolation during childhood, we also demonstrated that the vulnerable circuit we identified is a promising target for treatments of social behavior deficits,” says Hirofumi Morishita, MD, PhD, Associate Professor of Psychiatry, Neuroscience, and Ophthalmology at the Icahn School of Medicine at Mount Sinai, a faculty member of The Friedman Brain Institute and the Mindich Child Health and Development Institute, and senior author of the paper. “Through stimulation of the specific prefrontal circuit projecting to the thalamic area in adulthood, we were able to rescue the sociability deficits caused by juvenile social isolation.”
Specifically, the team found that, in male mice, two weeks of social isolation immediately following weaning leads to a failure to activate medial prefrontal cortex neurons projecting to the paraventricular thalamus during social exposure in adulthood. Researchers found that juvenile isolation led to both reduced excitability of the prefrontal neurons projecting to the paraventricular thalamus and increased inhibitory input from other related neurons, suggesting a circuit mechanism underlying sociability deficits caused by juvenile social isolation. To determine whether acute restoration of the activity of prefrontal projections to the paraventricular thalamus is sufficient to ameliorate sociability deficits in adult mice that underwent juvenile social isolation, the team employed a technique known as optogenetics to selectively stimulate the prefrontal projections to paraventricular thalamus. The researchers also used chemogenetics in their study. While optogenetics enables researchers to stimulate particular neurons in freely moving animals with pulses of light, chemogenetics allows non-invasive chemical control over cell populations. By employing both of these techniques, the researchers were able to quickly increase social interaction in these mice once light pulses or drugs were administered to them.
“We checked the presence of social behavior deficits just prior to stimulation and when we checked the behavior while the stimulation was ongoing, we found that the social behavior deficits were reversed,” said Dr. Morishita.
Given that social behavior deficits are a common dimension of many neurodevelopmental and psychiatric disorders, such as autism and schizophrenia, identification of these specific prefrontal neurons will point toward therapeutic targets for the improvement of social behavior deficits shared across a range of psychiatric disorders. The circuits identified in this study could potentially be modulated using techniques like transcranial magnetic stimulation and/or transcranial direct current stimulation.
Unmasking selective path integration deficits in Alzheimer’s disease risk carriers
by Anne Bierbrauer, Lukas Kunz, Carlos A. Gomes, Maike Luhmann, Lorena Deuker, Stephan Getzmann, Edmund Wascher, Patrick D, et al. in Science Advances
An international research team now reports that problems in spatial navigation can also be detected in people with a genetic risk for Alzheimer’s. Their article was published in the journal Science Advances.
Finding paths without external cues
Animals and humans have the ability to follow their own position in space through self-motion cues, even in the absence of any other sensory information. “If you get up at night and want to find your way to the bathroom in the dark, you need — in addition to knowing the arrangement of your own home — a mechanism that tracks your own position in the room without using external cues,” illustrates Anne Bierbrauer. This ability is known as path integration.
Researchers assume that the activity of so-called grid cells in the entorhinal cortex is responsible for this ability. When navigating a spatial environment, these cells display a unique, regular activity pattern. It has long been known that the entorhinal cortex is crucial for spatial navigation. It is also one of the first regions of the brain affected by Alzheimer’s disease.
Previous study showed changes in grid cell activity
In a previous study, the researchers had shown that grid cells exhibit altered functioning in people at genetic risk for developing Alzheimer’s disease. However, the test persons did not show any obvious navigation problems. “We assume that they used compensatory mechanisms to find their way,” explains Nikolai Axmacher, “presumably via external cues in their surroundings. In Bochum, for example, the winding tower of the Bergbau-Museum can be seen in many places, as it is often visible over the rooftops of other buildings.”
Alzheimer’s risk and navigation problems go hand in hand
In the current study, the team therefore used a computerized navigation task in which the participants couldn’t use external landmarks to find their way. The researchers compared the navigation performance of 202 volunteers without genetic Alzheimer’s risk and 65 volunteers with increased genetic risk. The latter had a specific expression of the gene for apolipoprotein E, the APOE-ε4 allele.
Participants with a genetic risk of Alzheimer’s disease didn’t perform as well as the control group.
Insights into grid cell activity
An additional group of test persons performed the same task while the researchers recorded their brain activity with functional magnetic resonance imaging. The objective of this experiment was to find out which brain processes play a role in path integration. The team found grid cell representations in the entorhinal cortex to be specifically associated with navigation without external cues, which highlights the role of this brain region for path integration.
“In this study, we demonstrated a very specific deficit in healthy people with a genetically increased risk for Alzheimer’s,” concludes Lukas Kunz. “In the future, such behavioural changes might perhaps help diagnose Alzheimer’s disease earlier, before any serious symptoms appear.” Researchers believe that drug therapies for Alzheimer’s disease have so far failed, because the diagnosis is made too late.
Funding
The study was funded by the Federal Ministry of Education and Research (funding code 01GQ1705A), the National Institutes of Health (NIH, grant 563386), the National Science Foundation (grant BCS-1724243), the NIH in collaboration with the National Institute of Neurological Disorders and Stroke (grant U01 NS1113198–01), the German Research Foundation (EXC 1086, SFB 874, SFB 1280), the Emma and Ernesto Rulfo Foundation for Medical Genetics, the Spanish Ministry of Economy and Competitiveness (funding codes SAF2017–85310-R and PSI2017–85311-P), the Regional Ministry of Innovation, Science and Enterprise, Junta de Andalucia (P12-CTS-2327 to JLC), the International Center on Aging (0348_CIE_6_E) and Ciberned.
(A) Participants performed a novel PI task (the Apple Game) in a virtual environment. The task comprised three subtasks that differed with regard to the presence or absence of supportive spatial cues: the PPI subtask without any supportive cue, the BPI subtask with a circular boundary, and the LPI subtask with an intramaze landmark (lighthouse) close to the center of the environment. (B) In each trial, participants collected a basket (start phase) and tried to remember its location (goal location). After navigating toward a variable number of trees (1 to 5; outgoing phase), which disappeared after having been reached, participants had to find their way back to the goal location (incoming phase). Last, they received feedback via different numbers of stars, depending on response accuracy. (C ) Outgoing distance refers to the cumulated distance during the outgoing phase, and incoming distance refers to the Euclidean distance between retrieval location (tree with apple) and goal location (basket). (D) PI performance was assessed as the distance between the correct goal location and the response location (drop error). The drop error can be separated into the distance error (i.e., the difference between the retrieval-to-goal distance and the retrieval-to-response distance) and the rotation error (i.e., the difference between the retrieval-to-goal rotation and the retrieval-to-response rotation). (E) The behavioral task comprised 8 practice trials followed by 16 trials in each subtask (short version; in the long version, all subtasks were performed twice, resulting in 32 trials in each subtask). (F) The fMRI task consisted of up to nine practice trials during the structural scan, followed by two functional runs with six blocks of four trials each. See also fig. S1 and movie S1.
Primate-restricted KRAB zinc finger proteins and target retrotransposons control gene expression in human neurons
by Priscilla Turelli, Christopher Playfoot, Dephine Grun, Charlène Raclot, Julien Pontis, Alexandre Coudray, Christian Thorball, Julien Duc, Eugenia V. Pankevich, Bart Deplancke, Volker Busskamp, Didier Trono in Science Advances
‘Jumping’ sequences of DNA, known as transposable elements, partner up with evolutionarily recent proteins to influence the differentiation and physiological functioning of human neurons.
Now, an international team of scientists led by Didier Trono at EPFL has discovered that transposable elements play a significant role in influencing the development of the human brain. The study is published in Science Advances.
The scientists found that transposable elements regulate the brain’s development by partnering up with two specialized proteins from the family of proteins known as “Krüppel-associated box-containing zinc finger proteins, or KZFPs. In 2019, another study led by Trono showed that KZFPs tamed the regulatory activity of transposable elements in the first few days of the fetus’s life. However, they suspected that these regulatory sequences were subsequently re-ignited to orchestrate the development and function of adult organs.
The researchers identified two KZFPs as specific only to primates, and found that they are expressed in specific regions of the human developing and adult brain. They further observed that these proteins kept controlling the activity of transposable elements — at least in neurons and brain organoids cultured in the lab. As a result, these two KZFPs influenced the differentiation and neurotransmission profile of neurons, as well as guarded these cells against inflammatory responses that were otherwise triggered if their target transposable elements were left to be expressed.
“These results reveal how two proteins that appeared only recently in evolution have contributed to shape the human brain by facilitating the co-option of transposable elements, these virus-like entities that have been remodeling our ancestral genome since the dawn of times,” says Didier Trono. “Our findings also suggest possible pathogenic mechanisms for diseases such as amyotrophic lateral sclerosis or other neurodegenerative or neurodevelopmental disorders, providing leads for the prevention or treatment of these problems.”
(A) Expression from a PGK-GFP cassette cloned downstream of KAP1-restricted (R) or nonrestricted (NR) HERVK PBS sequences in control (Ctrl) or ZNF417/587 KD hESC (average and SD values of duplicates). unT, untransduced. (B) LoF mutations for ZNF417/587 with numbers of most frequent alleles among >140,000 individuals (in red homozygous LoF mutations). Dark and light purple boxes indicate intact and degenerated ZFs. (C ) ZNF417/587 expression in brain development and substructures according to BrainSpan Atlas of the Developing Human Brain. pcw, post-conception weeks; FTS, forebrain fetal transient structures; D, diencephalon; My, myelencephalon; Me, metencephalon; M1C_S1C, primary motor sensory cortex; PCx, parietal cortex; TCx, temporal neocortex; LGE, lateral ganglionic eminence; MGE, medial ganglionic eminence; URL, upper rhombic lip; CB, cerebellum; CBC, cerebellar cortex. (D) Percentage of integrants from indicated TE families and subfamilies overlapping with ZNF417 and ZNF587 peaks as obtained by ChIP-seq triplicates in hESC. Only families with at least five bound integrants are shown. (***P < 0.001 and **P < 0.01, hypergeometric test). (E) Top: PBS consensus sequences of bound LTR/ERVs and SVAs compared with PBSLys1.2 and R- and NR-HERVK14C sequences. Bottom: Predicted binding motifs according to Rsat.
Chronic environmental or genetic elevation of galanin in noradrenergic neurons confers stress resilience in mice
by Rachel P. Tillage, Genevieve E. Wilson, L. Cameron Liles, Philip V. Holmes, David Weinshenker in The Journal of Neuroscience
Exercise fights off stress by increasing levels of the brain protein galanin, according to research in mice recently published in JNeurosci.
Going on a run during a stressful time does wonders for mental and emotional health. But the stress-relief benefits of exercise go beyond the anecdotal: exercise increases the brain’s resilience to stress. This happens through elevated levels of the neuromodulator galanin, a protein that influences stress and mood and has been implicated in stress-related psychiatric disorders.
In examining the relationship between exercise and stress relief, Tillage et al. measured anxious behaviors in mice 24 hours after a stressful event. Mice that had access to an exercise wheel for three weeks displayed fewer anxious behaviors compared to mice that didn’t exercise. The exercising mice also had elevated galanin levels in the locus coeruleus, a cluster of neurons in the brainstem involved in the stress response. The amount of time the mice spent exercising in the third week correlated with the amount of galanin in the locus coeruleus, which in turn correlated with their degree of stress resilience. Genetically increasing locus coeruleus galanin in sedentary mice recapitulated the beneficial effects of exercise. The increased galanin did not alter other aspects of the animal’s behavior, suggesting galanin may be recruited only during periods of high stress.
Structural controllability predicts functional patterns and brain stimulation benefits associated with working memory
by Lysianne Beynel, Lifu Deng, Courtney A. Crowell, Moritz Dannhauer, Hannah Palmer, Susan Hilbig, Angel V. Peterchev, Bruce Luber, Sarah H. Lisanby, Roberto Cabeza, Lawrence G. Appelbaum, Simon W. Davis in The Journal of Neuroscience
A new method of brain imaging analysis offers the potential to greatly improve the effectiveness of noninvasive brain stimulation treatment for Alzheimer’s, obsessive compulsive disorder, depression, and other conditions.
The study has direct implications for improving the benefits of transcranial magnetic stimulation, which is currently used for major depression and obsessive compulsive disorder, and may soon lead to therapeutic treatment for memory disorders such as Alzheimer’s and dementia.
Researchers at the Duke Brain Stimulation Research Center (BSRC) developed a method of analysis that relies on the concept of controllability, a network principle that helps to predict how one area of the brain influences a whole network involved in regulating behavior.
The authors measured controllability using functional magnetic resonance imaging (fMRI) to determine how much change TMS would induce as participants did a working memory task. In this task, individuals had to keep bits of information briefly in their memory and manipulate this information in their mind before answering questions about it. This task was used because of the importance of working memory in everyday life (like ordering your shopping list in your mind before walking through the grocery store) and because it is highly impacted by aging, particularly in conditions like Alzheimer’s and dementia.
“Essentially, we look at the brain not as a set of discrete islands, but as a dense web of connections that have lots of mutual influence,” said lead researcher Dr. Simon Davis, PhD, Assistant Professor of Neurology at Duke. “Controllability allows us a framework for identifying which nodes in this web are most likely to be influenced by brain stimulation, and for that reason likely to show plasticity and improvement after TMS treatments.”
The controllability measure, which is based on a static, structural image of the brain, was used to predict dynamic activity. “Brain activity is like the spatial pattern of traffic in a city. Although the traffic pattern is ever-changing, it is always confined by the topology of the road network,” said Lifu Deng, a Duke graduate student in the Department of Psychology and Neuroscience, and co-lead on the paper. “Controllability links the stimulation at one location to the global pattern of brain activity. In our study, for instance, this is the activation patterns signifying better working memory.”
Previously, there has not been a systematic way to identify which brain areas are the most likely to produce global chances, because most studies have focused on just one region. This study, however, advanced the field by considering the whole brain network.
While healthy adults participated in the study, the research likely has implications for memory disorders. “Memory dysfunction as a network phenomenon that relies on multiple brain regions operating under coordinated dynamics. The typical focus on the TMS response at a single site represents a fundamental limitation in the approach of neurostimulation therapies because it neglects global impairments in whole network that underlies memory dysfunction,” said Lysianne Beynel, PhD, a postdoctoral associate in the BSRC and first author on the study.
Ultimately, this non-invasive brain stimulation method will be used to promote healthy brain activity patterns and eventually enhance memory function, which has potential to enhance the efficacy of brain stimulation treatments for a range of cognitive disorders.
A spike-timing-dependent plasticity rule for dendritic spines
by Sabrina Tazerart, Diana E. Mitchell, Soledad Miranda-Rottmann, Roberto Araya in Nature Communications
Researchers at CHU Sainte-Justine Hospital and Université de Montréal have made a major discovery in understanding the mechanisms underlying learning and memory formation.
Led by Professor Roberto Araya, the team studied the function and morphological transformation of dendritic spines, tiny protrusions located on the branches of neurons, during synaptic plasticity, thought to be the underlying mechanism for learning and memory.
“We are very excited because this is the first time that the rules of synaptic plasticity, a process directly related to memory formation in the brain, have been discovered in a way that allows us to better understand plasticity and ultimately how memories are formed when neurons of the cerebral neocortex receive single and/or multiple streams of sensory information” said Professor Araya.
A neuronal “tree”
The brain is made up of billions of excitable nerve cells better known as neurons. They specialize in communication and information processing.
“Imagine a tree,” said Araya. “The roots are represented by the axon, the central trunk by the cell body, the peripheral branches by the dendrites and finally, the leaves by the dendritic spines. These thousands of small leaves act as a gateway by receiving excitatory information from other cells. They will decide whether this information is significant enough to be amplified and circulated to other neurons.
“This is a key concept,” he added, “in the processing, integration and storage of information and therefore in memory and learning.”
Neurons amplify the “volume”
Dendritic spines serve as a contact zone between neurons by receiving inputs (information) of varying strength. If an input is persistent, a mechanism by which neurons amplify the “volume” is triggered so that it can better “hear” that particular piece of information.
Otherwise, information of a low “volume” will be further turned down so that it goes unnoticed. This phenomenon corresponds to synaptic plasticity, which involves the potentiation or depression of synaptic input strength.
“This is the fundamental law of time-dependent plasticity, or Spike-timing-dependent plasticity (STDP), which adjusts the strength of connections between neurons in the brain and is believed to contribute to learning and memory,” said Sabrina Tazerart, co-author of the study.
While the scientific literature shows this phenomenon and how neurons connect, the precise structural organization of dendritic spines and the rules that control the induction of synaptic plasticity have remained unknown.
“Laws of connections”
Araya’s team has succeeded in shedding light onto the mechanisms underlying STDP.
“Until now, no one knew how synaptic inputs (incoming information) were arranged in the ‘neural tree’ and what precisely causes a dendritic spine to increase or decrease the strength, or loudness, of information it passes on,” the professor said. “Our goal was to extract “laws of synaptic connectivity” responsible for building memories in the brain.’”
For their study, his team employed preclinical models at a juvenile stage, a critical period for learning and memory in the brain.
Using advanced techniques in two-photon microscopy that mimic synaptic contacts between two neurons, the researchers discovered an important law related to the arrangement of information received by dendritic spines.
Their work shows that depending on the number of inputs received (synapses) and their proximity, the information will be taken into account and stored differently.
“We found that if more than one input occurs within a small piece of tree branch, the cell will always consider this information important and will increase its volume,” said co-first author Diana E. Mitchell.
“A major discovery”
“This is a major discovery,” added Araya.
“Structural and functional alterations of dendritic spines, the major recipients of inputs from other neurons, are often associated with neurodegenerative conditions, such as Fragile X syndrome or autism, as the patient can no longer process or store information properly,” he said.
“This disrupts the logic of memory construction. Now, by understanding the mechanisms underlying the dynamics of dendritic spines and how they impact the nervous system, we will be able to develop new and better-adapted therapeutic approaches.”
a Experimental protocol for t-LTP induction in single dendritic spines (sp). b Representative experiment where a spine was activated with t-LTP pre–post pairing protocol of +13 ms. Traces correspond to average of ten uEPSPs recorded in the soma and generated by 2P uncaging before (control, black trace) and after t-LTP induction (red trace) over the indicated spine (red dot). c Time course of uEPSP amplitude, neck length, and spine head volume (P < 0.001, P < 0.001, and P = 0.25, respectively, n = 9 spines, one-way repeated-measures ANOVA) following STDP induction with pre–post timing of +13 ms. n.s. not significant; *P < 0.05; ***P < 0.001, post hoc Dunnet’s test. d Changes in uEPSP amplitude, neck length, and head volume of the activated spine 15–25 min after t-LTP induction with a pre–post timing of +13 ms (uEPSP = 121.00 ± 6.98%, P = 0.039, neck length = 71.88 ± 8.29%, P = 0.019, spine head volume = 109.63 ± 8.84%, P = 0.38; n = 9 spines, two-sided Wilcoxon test; *P < 0.05). e Time course of uEPSP amplitude, neck length, and spine head volume (P = 0.45, 0.09, and 0.36 respectively, n = 8 spines, one-way repeated-measures ANOVA) changes following STDP induction with pre–post timing of +7 ms. n.s. not significant, post hoc Dunnet’s test. f Changes in uEPSP amplitude, neck length, and head volume of the activated spine 15–25 min after t-LTP induction with a pre–post timing of +7 ms (uEPSP = 90.06 ± 5.00%, P = 0.15; neck length = 92.10 ± 7.15%, P = 0.38; spine head volume = 95.67 ± 7.25%, P = 0.84; n = 8 spines, two-sided Wilcoxon test). Shaded area and error bars represent SEM and Time 0 represents the end of the STDP induction protocol. Lines, bars, and dots in c–f: uEPSP = black, neck length = red, and head volume = blue.
Face-specific brain area responds to faces even in people born blind
The new study finds that the fusiform face area is active when blind people touch 3D models of faces.
More than 20 years ago, neuroscientist Nancy Kanwisher and others discovered that a small section of the brain located near the base of the skull responds much more strongly to faces than to other objects we see. This area, known as the fusiform face area, is believed to be specialized for identifying faces.
Now, in a surprising new finding, Kanwisher and her colleagues have shown that this same region also becomes active in people who have been blind since birth, when they touch a three-dimensional model of a face with their hands. The finding suggests that this area does not require visual experience to develop a preference for faces.
“That doesn’t mean that visual input doesn’t play a role in sighted subjects — it probably does,” she says. “What we showed here is that visual input is not necessary to develop this particular patch, in the same location, with the same selectivity for faces. That was pretty astonishing.”
Kanwisher, the Walter A. Rosenblith Professor of Cognitive Neuroscience and a member of MIT’s McGovern Institute for Brain Research, is the senior author of the study. N. Apurva Ratan Murty, an MIT postdoc, is the lead author of the study, which appears this week in the Proceedings of the National Academy of Sciences. Other authors of the paper include Santani Teng, a former MIT postdoc; Aude Oliva, a senior research scientist, co-director of the MIT Quest for Intelligence, and MIT director of the MIT-IBM Watson AI Lab; and David Beeler and Anna Mynick, both former lab technicians.
Selective for faces
Studying people who were born blind allowed the researchers to tackle longstanding questions regarding how specialization arises in the brain. In this case, they were specifically investigating face perception, but the same unanswered questions apply to many other aspects of human cognition, Kanwisher says.
“This is part of a broader question that scientists and philosophers have been asking themselves for hundreds of years, about where the structure of the mind and brain comes from,” she says. “To what extent are we products of experience, and to what extent do we have built-in structure? This is a version of that question asking about the particular role of visual experience in constructing the face area.”
The new work builds on a 2017 study from researchers in Belgium. In that study, congenitally blind subjects were scanned with functional magnetic resonance imaging (fMRI) as they listened to a variety of sounds, some related to faces (such as laughing or chewing), and others not. That study found higher responses in the vicinity of the FFA to face-related sounds than to sounds such as a ball bouncing or hands clapping.
In the new study, the MIT team wanted to use tactile experience to measure more directly how the brains of blind people respond to faces. They created a ring of 3D-printed objects that included faces, hands, chairs, and mazes, and rotated them so that the subject could handle each one while in the fMRI scanner.
They began with normally sighted subjects and found that when they handled the 3D objects, a small area that corresponded to the location of the FFA was preferentially active when the subjects touched the faces, compared to when they touched other objects. This activity, which was weaker than the signal produced when sighted subjects looked at faces, was not surprising to see, Kanwisher says.
“We know that people engage in visual imagery, and we know from prior studies that visual imagery can activate the FFA. So the fact that you see the response with touch in a sighted person is not shocking because they’re visually imagining what they’re feeling,” she says.
The researchers then performed the same experiments, using tactile input only, with 15 subjects who reported being blind since birth. To their surprise, they found that the brain showed face-specific activity in the same area as the sighted subjects, at levels similar to when sighted people handled the 3D-printed faces.
“When we saw it in the first few subjects, it was really shocking, because no one had seen individual face-specific activations in the fusiform gyrus in blind subjects previously,” Murty says.
Patterns of connection
The researchers also explored several hypotheses that have been put forward to explain why face-selectivity always seems to develop in the same region of the brain. One prominent hypothesis suggests that the FFA develops face-selectivity because it receives visual input from the fovea (the center of the retina), and we tend to focus on faces at the center of our visual field. However, since this region developed in blind people with no foveal input, the new findings do not support this idea.
Another hypothesis is that the FFA has a natural preference for curved shapes. To test that idea, the researchers performed another set of experiments in which they asked the blind subjects to handle a variety of 3D-printed shapes, including cubes, spheres, and eggs. They found that the FFA did not show any preference for the curved objects over the cube-shaped objects.
The researchers did find evidence for a third hypothesis, which is that face selectivity arises in the FFA because of its connections to other parts of the brain. They were able to measure the FFA’s “connectivity fingerprint” — a measure of the correlation between activity in the FFA and activity in other parts of the brain — in both blind and sighted subjects.
They then used the data from each group to train a computer model to predict the exact location of the brain’s selective response to faces based on the FFA connectivity fingerprint. They found that when the model was trained on data from sighted patients, it could accurately predict the results in blind subjects, and vice versa. They also found evidence that connections to the frontal and parietal lobes of the brain, which are involved in high-level processing of sensory information, may be the most important in determining the role of the FFA.
“It’s suggestive of this very interesting story that the brain wires itself up in development not just by taking perceptual information and doing statistics on the input and allocating patches of brain, according to some kind of broadly agnostic statistical procedure,” Kanwisher says. “Rather, there are endogenous constraints in the brain present at birth, in this case, in the form of connections to higher-level brain regions, and these connections are perhaps playing a causal role in its development.”
Polygenic Risk and Progression to Bipolar or Psychotic Disorders Among Individuals Diagnosed With Unipolar Depression in Early Life
by Katherine L. Musliner, Morten D. Krebs et al. in American Journal of Psychiatry
In a new study from the Danish psychiatry project iPSYCH, researchers have identified genetic risk factors for developing bipolar disorder and psychoses among people with depression. In the longer term, the results may contribute to ensuring the correct diagnosis is made earlier, so that the patients can receive the correct treatment as quickly as possible.
Bipolar disorder and psychoses such as schizophrenia are serious mental disorders, which often have a great impact on a person’s life and well-being. In a number of cases, bipolar disorder and schizophrenia are first diagnosed several years after the onset of the disorder. This is associated with unfavourable prognosis for the course of the disorders. The sooner the patient gets the correct diagnosis and begins targeted treatment, the better the prognosis. For this reason, researchers are aiming at identifying risk factors that will aid psychiatrists to reach the correct diagnosis as early as possible.
Depression often precedes bipolar disorder and psychoses
Many people who develop bipolar disorder or psychoses initially come into contact with the mental health services due to depression. A research team from iPSYCH therefore set out to examine a dataset consisting of 16,949 people aged 10–35 who had been treated for depression at a psychiatric hospital in Denmark.
“Our goal with the study was to investigate whether genetic factors are associated with an increased risk of developing bipolar disorder or psychosis among patients with depression. This knowledge can potentially be used in clinical practice to identify patients who should be monitored even more closely,” explains the lead author of the research article based on the study, Senior Researcher Katherine Musliner from the National Centre for Register-based Research.
Among the factors the researchers looked into in the study was whether the genetic risk scores for bipolar disorder and schizophrenia — i.e. a person’s individual genetic risk of developing these disorders — could possibly help psychiatrists determine which of their patients with depression was at greatest risk of subsequently developing bipolar disorder or a psychosis.
“One thing we discovered was that the genetic risk score for bipolar disorder is associated with an increased risk of developing bipolar disorder, and that the genetic risk score for schizophrenia is associated with an increased risk of developing a psychosis among patients who have been diagnosed with depression,” says Katherine Musliner, stressing that the effect of the genetic risk scores were relatively small.
Family history weighs heavily
Another member of the research group behind the study, Professor Søren Dinesen Østergaard from the Department of Clinical Medicine and Aarhus University Hospital — Psychiatry, emphasises that caution is needed when interpreting the results.
“At present, the genetic risk scores cannot contribute to early diagnosis of bipolar disorder and psychoses in clinical practice, but it cannot be ruled out that this could be the future scenario. On the other hand, our study confirms that having a parent with bipolar disorder or a psychosis is a strong predictor for the development of these particular disorders after depression. This underlines the importance of getting information about mental disorders in the family as part of the assessment of people suffering from depression,” he explains.
MISC
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