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In addition to the featured articles posted in the blog, links to other research news articles are posted on the Brain Science News page.

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Alpha-beta rhythms in deeper layers of prefrontal cortex regulate gamma rhythms in superficial layers during working memory tasks

From MIT News:

 

 

Study: Rhythmic interactions between cortical layers underlie working memory

MIT neuroscientists suggest a model for how we gain volitional control of what we hold in our mind

David Orenstein | Picower Institute for Learning and Memory
January 15, 2018

Working memory is a sort of “mental sketchpad” that allows you to accomplish everyday tasks such as calling in your hungry family’s takeout order and finding the bathroom you were just told “will be the third door on the right after you walk straight down that hallway and make your first left.” It also allows your mind to go from merely responding to your environment to consciously asserting your agenda.

“Working memory allows you to choose what to pay attention to, choose what you hold in mind, and choose when to make decisions and take action,” says Earl K. Miller, the Picower Professor in MIT’s Picower Institute for Learning and Memory and the Department of Brain and Cognitive Sciences. “It’s all about wresting control from the environment to your own self. Once you have something like working memory, you go from being a simple creature that’s buffeted by the environment to a creature that can control the environment.”

For years Miller has been curious about how working memory — particularly the volitional control of it — actually works. In a new study in the Proceedings of the National Academy of Sciences led by Picower Institute postdoc Andre Bastos, Miller’s lab shows that the underlying mechanism depends on different frequencies of brain rhythms synchronizing neurons in distinct layers of the prefrontal cortex (PFC), the area of the brain associated with higher cognitive function. As animals performed a variety of working memory tasks, higher-frequency gamma rhythms in superficial layers of the PFC were regulated by lower-frequency alpha/beta frequency rhythms in deeper cortical layers.

The findings suggest not only a general model of working memory, and the volition that makes it special, but also new ways that clinicians might investigate conditions such as schizophrenia where working memory function appears compromised.

Layers of waves

To conduct the study, Bastos worked from several lines of evidence and with some relatively new technology. Last year, for example, co-author and Picower Institute postdoc Mikael Lundqvist led a study showing that gamma waves perked up in power when sensory (neuroscientists call it “bottom-up”) information was loaded into and read out from working memory. In previous work, Miller, Bastos, and their colleagues had found that alpha/beta rhythms appeared to carry “top-down” information about goals and plans within the cortex. Top-down information is what we use to make volitional decisions about what to think about or how to act, Miller says.

The current study benefitted from newly improved multilayer electrode brain sensors that few groups have applied in cognitive, rather than sensory, areas of the cortex. Bastos realized that if he made those measurements, he and Miller could determine whether deep alpha/beta and superficial gamma might interact for volitional control of working memory.

In the lab Bastos and his co-authors, including graduate students Roman Loonis and Simon Kornblith, made multilayer measurements in six areas of the PFC as animals performed three different working memory tasks.

In different tasks, animals had to hold a picture in working memory to subsequently choose a picture that matched it. In another type of task, the animals had to remember the screen location of a briefly flashed dot. Overall, the tasks asked the subjects to store, process, and then discard from working memory the appearance or the position of visual stimuli.

“Combining data across the tasks and the areas does lead to additional weight for the evidence,” Bastos says.

A mechanism for working memory

Across all the PFC areas and all tasks, the data showed the same thing: When sensory information was loaded into working memory, the gamma rhythms in superficial layers increased and the alpha/beta rhythms in deep layers that carried the top-down information decreased. Conversely, when deep-layer alpha/beta rhythms increased, superficial layer gamma waned. Subsequent statistical analysis suggested that gamma was being controlled by alpha and beta rhythms, rather than the other way around.

“This suggests mechanisms by which the top-down information needed for volitional control, carried by alpha/beta rhythms, can turn on and off the faucet of bottom-up sensory information, carried by gamma, that reaches working memory and is held in mind,” Miller says.

With these insights, the team has since worked to directly test this multilayer, multifrequency model of working memory dynamics more explicitly, with results in press but not yet published.

Charles Schroeder, research scientist and section head in the Center for Biomedical Imaging and Neuromodulation at the Nathan S. Kline Institute for Psychiatric Research, describes two contributions of the study as empirically important.

“First, the paper clearly shows that critical cognitive operations (in this case working memory) are underlain by periodic (oscillatory) network activity patterns in the brain, and that these must be addressed by single trial analysis,” Schroeder says. “This provides an important conceptual alternative to the idea that working memory must involve continuous neural activation. Secondly, the findings strongly reinforce the notion that dynamic coupling across high- and low-frequency ranges performs a clear mechanistic function: Lower frequency activity dominant in the lower layers of the prefrontal area network controls the temporal patterning of higher frequency information representation in the superficial layers of the same network of areas. The important conceptual innovation in this case lies in allowing lower frequency control operations to act directly on higher frequency information representation within each cortical area.”

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Sleep boosts communication between hippocampus and sensory neocortex involved in memory formation

From NINDS Press Releases:

Study shows how memories ripple through the brain

Monday, October 30, 2017

NIH-funded study suggests increased communication between key brain areas during sleep

 

Neuronal cross-talk in the sleeping brain

Neuronal cross-talk in the sleeping brain:  NIH-funded research suggests that increased communication between two brain areas during sleep may play a role in memory formation. Image courtesy of György Buzsáki, M.D., Ph.D., NYU School of Medicine.

Using an innovative “NeuroGrid” technology, scientists showed that sleep boosts communication between two brain regions whose connection is critical for the formation of memories. The work, published in Science, was partially funded by the Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative, a project of the National Institutes of Health devoted to accelerating the development of new approaches to probing the workings of the brain.

“Using new technologies advanced by the BRAIN Initiative, these researchers made a fundamental discovery about how the brain creates and stores new memories,” said Nick Langhals, Ph.D., program director at NIH’s National Institute of Neurological Disorders and Stroke.

A brain structure called the hippocampus is widely thought to turn new information into permanent memories while we sleep. Previous work by the new study’s senior author, NYU School of Medicine professor György Buzsáki, M.D., Ph.D., revealed high-frequency bursts of neural firing called ripples in the hippocampus during sleep and suggested they play a role in memory storage. The current study confirmed the presence of ripples in the hippocampus during sleep and found them in certain parts of association neocortex, an area on the brain’s surface involved in processing complex sensory information.

“When we first observed this, we thought it was incorrect because it had never been observed before,” said Dion Khodagholy, Ph.D., the study’s co-first author and assistant professor at Columbia University in New York.

Using a cutting-edge NeuroGrid system they invented, along with recording electrodes placed deeper into the brain, the researchers examined activity in several parts of rats’ brains during non-rapid eye movement (NREM) sleep, the longest stage of sleep. Their NeuroGrid consists of a collection of tiny electrodes linked together like the threads of a blanket, which is then laid across an area of the brain so that each electrode can continuously monitor the activity of a different set of neurons.

“This particular device allows us to look at multiple areas of the brain at the same time,” said Jennifer Gelinas, M.D., Ph.D., the study’s co-first author and assistant professor at Columbia University.

The team was also surprised to find that the ripples in the association neocortex and hippocampus occurred at the same time, suggesting the two regions were communicating as the rats slept. Because the association neocortex is thought to be a storage location for memories, the researchers theorized that this neural dialogue could help the brain retain information.

To test that idea, they examined brain activity during NREM sleep in rats trained to locate rewards in a maze and in rats that explored the maze in a random fashion. In the latter group of animals, the ripples in the hippocampus and cortex were no more synchronized before exploring the maze than afterwards. In the trained rats, the learning task increased the cross-talk between those areas, and a second training session boosted it even more, further suggesting that such communication is important for the creation and storage of memories.

The group hopes to use the NeuroGrid in people undergoing brain surgery for other reasons to determine if the same ripples occur in the human brain. The researchers also plan to investigate if manipulating that neural firing in animals can boost or suppress memory formation in order to confirm that ripples are important for that process.

“Identifying the specific neural patterns that go along with memory formation provides a way to better understand memory and potentially even address disorders of memory,” said Dr. Gelinas.

Read more.

Female axons are smaller and microtubules more likely to break during head trauma

From Penn State News:

PHILADELPHIA – Women have smaller, more breakable nerve fibers in the brain compared to men that may make them more susceptible to concussions, suggests a new study from Penn Medicine neuroscientists published online today in the journal Experimental Neurology.
press

In a series of laboratory tests using rat and human neuronal cells, the research team, led by Douglas H. Smith, MD, director of the Penn Center for Brain Injury and Repair and the Robert A. Groff Professor of Neurosurgery at the Perelman School of Medicine at the University of Pennsylvania, found that female axons were smaller and had fewer microtubules – “train tracks” that transport molecules up and down the axons – that were more likely to break after applying the same amount of force from a simulated traumatic brain injury.

That breaking is what researchers believe may lead to symptoms associated with concussions, such as dizziness or loss of consciousness. The susceptibility may also help explain why female athletes have an increased risk of concussions and worse outcomes than male athletes, as previous studies have shown.

“The paper shows us that there is a fundamental, anatomical difference between male and female axons,” Smith said. “In the male axon, there are a great number of microtubules, which make the entire structure stronger, whereas in female axons, it’s more of a leaner type of architecture, so it’s not as strong.”

Considered the “electric grid” of the brain, axons are long, slender parts of the neuron that communicate messages from one cell to another. When someone suffers a traumatic blow to the head, the axons are stretched at a very rapid rate. While the axons typically stay intact, their microtubules can break under the strain. The faster they stretch, the stiffer the crosslinking proteins known as tau become. This transfers high stress onto the microtubule that can result in them rupturing, setting off a molecular imbalance.

“You can imagine that if something goes wrong with that transport system, the cargos get dumped out and start to pile up and that will create a huge problem,” Smith said.

This buildup causes abnormal inflows of sodium and calcium ions. Researchers believe that levels of calcium become high enough to trigger a self-destruct process, in which protein-breaking enzymes are unleashed, begin to degrade the axonal structure, and ultimately compromise the nerve fiber. The researchers found that 24 hours after trauma, female axons had significantly more swellings and a greater loss of calcium signaling function than male axons.

“When axons function normally, they let sodium pass through the membrane, and it creates a spark that can be transferred as ‘electricity’ down the axon,” Smith said. “In concussion, you can have immediate loss of that ability to transfer that ‘electricity.’ That’s why the characteristic, behavioral changes occur.”

People who suffer from concussions – about two million sports-related concussions occur in the United State every year – can experience confusion, headaches, dizziness, and temporary loss of consciousness, which typically disappear after a few hours or days. Recent Penn studies have also suggested that concussions can lead to long-term cognitive impairments.

The researchers, which included first author, Jean-Pierre Dollé, PhD, of the Penn Center for Brain Injury and Repair, used transmission electron microscopy to study the structural differences between female and male axons from both rat and human neurons. Next, they evaluated the axons’ response to dynamic stretch injury, to mimic a traumatic axonal injury, using computational and in vitro models.

Past studies have shown that female athletes have a higher rate of concussion and appear to have worse outcomes than their male counterparts participating in the same sport, the researchers noted in the current study. Also, results from a 2017 study, presented at this year’s American Academy of Neurology’s annual meeting, found that women athletes are 50 percent more likely than male athletes to have a sports-related concussion.

The in vitro findings, researchers said, may have implications for concussion, where axonal injury is the most commonly described pathological feature. “It is conceivable that under the same level of mechanical loading during head impact, axons in female brains may be more susceptible to damage than axons in male brains due to fundamental differences in axon ultrastructure,” they wrote.

Further in vivo studies are needed to support these findings, Smith said. One next step would be to compare blood biomarkers. For instance, do concussed females have more axon proteins, which rise in the blood after a concussion, than males? SNTF (alpha II-spectrin N-terminal fragment), and APP (amyloid precursor protein) are two examples of biomarkers of axonal injury, Penn researchers reported in previous studies. Investigating white matter changes in male and female athletes playing the same sport with advanced neuroimaging is another avenue to explore, Smith said.

Read more.

Optogenetics in Monkeys and Other Primates

From The Scientist:

Lighting Up Monkey Brains

Optogenetic and chemogenetic tools illuminate brain and behavior connections in nonhuman primates.

By Jyoti Madhusoodanan | November 1, 2017

TYPECASTING: Immunohistochemical staining shows selective labeling of Purkinje cells (green) and their axons (red) in the granular layer of the cerebellar cortex. (Scale bar = 200 microns) NEURON, 95:51-62, 2017

Since optogenetics burst onto the scene in the early 2000s, brain researchers have embraced the technique to study functions ranging from sleep and hunger to voluntary movements and sensory input. The vast majority of these studies have been conducted in rodents, and much has been learned, but extrapolating to humans from a species so different from us poses a challenge.

Brain research in nonhuman primates precedes optogenetics by decades. Attempts to understand the links between brain function and behavior have relied on techniques such as inserting an electrode into the brain to activate or interrupt neural signals, and creating lesions to disrupt pathways. But these approaches only reveal whether the altered brain regions are involved in the functions being studied, with little detail about the types of cells or networks involved.

Controlling neurons with light (optogenetics) or chemicals (chemogenetics) offers researchers a much more precise way to study brain function. Optogenetics utilizes a microbial protein known as channelrhodopsin (ChR), a light-activated ion channel. When inserted into animal cells under the control of a cell type–specific promoter, the protein is expressed in subsets of neurons, and a beam of light can be used to trigger its activity, spurring those neurons to action. Chemogenetics deploys chemicals rather than light. Cells are engineered to carry DREADD (designer receptors exclusively activated by designer drugs) pro­teins, which are then activated by a drug that doesn’t otherwise affect animal metabolism.

Rodents are often genetically engineered to encode ChR, DREADDs, or other controlling elements. But so far, genetically modifying primates has proven more difficult and expensive, limiting researchers to using viral vectors for delivering genes for these proteins to the brain. These vectors are generally derived from adenoviruses, says Jessica Raper of the Yerkes National Primate Research Center. “Just like humans, nonhuman primates can have neutralizing antibodies for these viruses, so any method must prescreen for antibodies specific to the serotype being used,” she explains.

The larger primate brain also requires larger amounts of vector to be injected directly into the brain, sometimes in multiple doses that may damage tissue. Furthermore, delivering light deep into the brain requires inserting an optical fiber, and chemicals designed to activate inserted genetic sequences must be able to cross the blood-brain barrier. (See “Getting Drugs Past the Blood-Brain Barrier”) That means much more trial and error than in mouse studies. “There’s no universal solution for primates as there is with the host of genetically modified rodents,” says William Stauffer of the University of Pittsburgh.

Nonetheless, several recent studies have managed to probe the function of specific brain regions or cell types in rhesus monkeys, marmosets, and other primates using optogenetic and chemogenetic tools. Here, The Scientist profiles some of these recent efforts.

 

Read more.

Chronic tinnitus associated with increased connectivity of precuneus with dorsal attention network

From Illinois News Bureau:

Ringing in ears keeps brain more at attention, less at rest, study finds

  • Neuroscience graduate student Sara Schmidt and speech and hearing science professor Fatima Husain conducted a study that found that tinnitus patients have differences in the region of the brain called the precuneus, which cause the brain to stay more at attention and be less at rest.

    Neuroscience graduate student Sara Schmidt, left, and speech and hearing science professor Fatima Husain conducted a study that found that tinnitus patients have differences in the region of the brain called the precuneus, which cause the brain to stay more at attention and be less at rest.

    Photo by Joyce Seay-Knoblauch

CHAMPAIGN, Ill. — Tinnitus, a chronic ringing or buzzing in the ears, has eluded medical treatment and scientific understanding. A new study by University of Illinois researchers found that chronic tinnitus is associated with changes in certain networks in the brain, and furthermore, those changes cause the brain to stay more at attention and less at rest.

Scientists identify new subtypes of neurons based on methylation patterns

From Salk News Releases:

New kinds of brain cells revealed

Salk and UC San Diego scientists analyzed methylation patterns of neurons to find new subtypes

LA JOLLA—Under a microscope, it can be hard to tell the difference between any two neurons, the brain cells that store and process information. So scientists have turned to molecular methods to try to identify groups of neurons with different functions.

Now, Salk Institute and University of California San Diego scientists have, for the first time, profiled chemical modifications of DNA molecules in individual neurons, giving the most detailed information yet on what makes one brain cell different from its neighbor. This is a critical step in beginning to identify how many types of neurons exist, which has eluded neuroscientists but could lead to a dramatically better understanding about brain development and dysfunction. Each cell’s methylome—the pattern of chemical markers made up of methyl groups that stud its DNA—gave a distinct readout that helped the Salk team sort neurons into subtypes. The work appears in the journal Science on August 10, 2017.

Looking beyond shape: the DNA methylome reveals neuronal identity. Human cortical neuron types are identified by their cytosine methylation signatures. Each type of human neuron has a distinct cytosine methylation profile. Luo et al. used a newly developed single-cell methylome sequencing method to survey both mouse and human cortical neuron diversity (colored dots in distinct clusters), extending the legendary studies of neuronal morphology (background image) by Santiago Ramón y Cajal (1852–1934).Click here for a high-resolution image. Credit: Salk Institute/Jamie Simon

“We think it’s pretty striking that we can tease apart a brain into individual cells, sequence their methylomes, and identify many new cell types along with their gene regulatory elements, the genetic switches that make these neurons distinct from each other,” says co-senior author Joseph Ecker, professor and director of Salk’s Genomic Analysis Laboratory and an investigator of the Howard Hughes Medical Institute.

In the past, to identify what sets different types of neurons apart from each other, researchers have studied levels of RNA molecules inside individual brain cells. But levels of RNA can rapidly change when a cell is exposed to new conditions, or even throughout the day. So the Salk team turned instead to the cells’ methylomes, which are generally stable throughout adulthood.

“Our research shows that we can clearly define neuronal types based on their methylomes,” says Margarita Behrens, a Salk senior staff-scientist and co-senior author of the new paper. “This opens up the possibility of understanding what makes two neurons—that sit in the same brain region and otherwise look similar—behave differently.”

Salk and UC San Diego scientists identified neuron types predicted by epigenomic signatures. The image shows neuron populations expressing marker genes for specific neuron subtypes: Tle4 (red), Sulf1 (green) or both (yellow).Click here for a high-resolution image. Credit: Salk Institute

The team began their work on both mouse and human brains by focusing on the frontal cortex, the area of the brain responsible for complex thinking, personality, social behaviors and decision making, among other things. They isolated 3,377 neurons from the frontal cortex of mice and 2,784 neurons from the frontal cortex of a deceased 25-year-old human.

The researchers then used a new method they recently developed called snmC-seq to sequence the methylomes of each cell. Unlike other cells in the body, neurons have two types of methylation, so the approach mapped both types—called CG methylation (for DNA sequence containing the nucleotides cytosine and guanine) and non-CG methylation.

Neurons from the mouse frontal cortex, they found, clustered into 16 subtypes based on methylation patterns, while neurons from the human frontal cortex were more diverse and formed 21 subtypes. Inhibitory neurons—those that provide stop signals for messages in the brain—showed more conserved methylation patterns between mice and humans compared to excitatory neurons. The study also identified unique human neuron subtypes that had never been defined before. These results open the door to a deeper understanding of what sets human brains apart from those of other animals.

“This study opens a new window into the incredible diversity of brain cells,” says Eran Mukamel of the UC San Diego Department of Cognitive Science, a co-senior author of the work.

Next, the researchers plan to expand their methylome study to look at more parts of the brain, and more brains.

Read more.

Thalamus is critical hub in neural circuits that maintain working memory and in those that prepare for movement

From NINDS Press Release:

Brain “relay” also key to holding thoughts in the mind

Wednesday, May 3, 2017

 

Cartoon of brain circuit that may help holds thoughts in mind

Hold that thought
Scientists showed that neurons connecting the thalamus to the prefrontal cortex helped mouse brains hold thoughts in mind.
Halassa lab, NYU Langone Medical Center

 

Halassa lab, NYU Langone Medical Center

Thalamus eyed as potential treatment target for schizophrenia’s working memory deficits

Long assumed to be a mere “relay,” an often-overlooked egg-like structure in the middle of the brain also turns out to play a pivotal role in tuning-up thinking circuity. A trio of studies in mice funded by the National Institutes of Health revealed that the thalamus sustains the ability to distinguish categories and hold thoughts in mind.

By manipulating activity of thalamus neurons, scientists were able to control an animal’s ability to remember how to find a reward. In the future, the thalamus might even become a target for interventions to reduce cognitive deficits in psychiatric disorders such as schizophrenia, researchers say.

“If the brain works like an orchestra, our results suggest the thalamus may be its conductor,” explained Michael Halassa, M.D., Ph.D., of New York University (NYU) Langone Medical Center, a BRAINS Award grantee of the NIH’s National Institute of Mental Health (NIMH), and also a grantee of the National Institute of Neurological Disorders and Stroke (NINDS). “It helps ensembles play in-sync by boosting their functional connectivity.”

Three independent teams of investigators led by Halassa, Joshua Gordon, M.D., Ph.D., formerly of Columbia University, New York City, now NIMH director, in collaboration with Christoph Kellendonk, Ph.D. of Columbia,  and Karel Svoboda, PhD, at Howard Hughes Medical Institute Janelia Research Campus, Ashburn, Virginia, in collaboration with Charles Gerfen, Ph.D., of the NIMH Intramural Research Program, report on the newfound role for the thalamus online May 3, 2017 in the journals Nature and Nature Neuroscience.

The prevailing notion of the thalamus as a relay was based on its connections with parts of the brain that process inputs from the senses. But the thalamus has many connections with other parts of the brain that have yet to be explored, say the researchers.

Two of the groups investigated a circuit that connects the mid/upper (mediodorsal) thalamus with the prefrontal cortex (PFC), the brain’s thinking and decision making center. Brain imaging studies have detected decreased connectivity in this circuit in patients with schizophrenia, who often experience working memory problems.

Halassa and colleagues found that neurons in the thalamus and PFC appear to talk back and forth with each other. They monitored neural activity in mice performing a task that required them to hold in mind information about categories, so that they could act on cues indicating which of two doors hid a milk reward.

Optogenetically suppressing neuronal activity in the thalamus blocked the mice’s ability to choose the correct door, while optogenetically stimulating thalamus neural activity improved the animals’ performance on the working memory task. This confirmed a previously known role for the structure, extending it to the specialized tasks Halassa and colleagues used and demonstrating for the first time a specific role in the maintenance of information in working memory.

What kind of information was the thalamus helping to maintain? The researchers found sets of neurons in the PFC that held in memory the specific category of information required in order to choose the correct door. They determined that the thalamus did not (at least in this case) relay such specific category information, but instead broadly provided amplification that was crucial in sustaining memory of the category in the PFC. It accomplished this by boosting the synchronous activity, or functional connectivity, of these sets of PFC neurons.

“Our study may have uncovered the key circuit elements underlying how the brain represents categories,” suggested Halassa.

Gordon and colleagues saw similar results when they tested how the same circuit controlled a mouse’s ability to find milk in a maze. The animals had to remember whether they had turned left or right to get their reward prior to a brief delay – and do the opposite. Also using optogenetics, the study teased apart differing roles for subgroups of PFC neurons and interactions with the brain’s memory hub, the hippocampus.

Thalamus inputs to the PFC sustained the maintenance of working memory by stabilizing activity there during the delay. “Top-down” signals from the PFC back to the thalamus supported memory retrieval and taking action. Consistent with previous findings, inputs from the hippocampus were required to encode in PFC neurons the location of the reward – analogous to the correct door in the Halassa experiment.

“Strikingly, we found two separate populations of neurons in the PFC. One encoded for spatial location and required hippocampal input; the other was active during memory maintenance and required thalamic input,” noted Gordon. “Our findings should have translational relevance, particularly to schizophrenia. Further study of how this circuit might go awry and cause working memory deficits holds promise for improved diagnosis and more targeted therapeutic approaches.”

In their study, the Janelia team and Gerfen similarly showed that the thalamus plays a crucial role in sustaining short-term memory, by cooperating with the cortex through bi-directional interactions. Mice needed to remember where to move after a delay of seconds, to gather a reward. In this case, the thalamus was found to be in conversation with a part of the motor cortex during planning of those movements. Neuronal electrical monitoring revealed activity in both structures, indicating that they together sustain information held in the cortex that predicted in which direction the animal would subsequently move. Optogenetic probing revealed that the conversation was bidirectional, with cortex activity dependent on thalamus and vice versa.

“Our results show that cortex circuits alone can’t sustain the neural activity required to prepare for movement,” explained Gerfen. “It also requires reciprocal participation across multiple brain areas, including the thalamus as a critical hub in the circuit.”

Read more.