Posts tagged neuroscience
Articles and news from the latest research reports.
New Mapping Approach Lets Scientists Zoom In And Out As The Brain Processes Sound
Researchers at Johns Hopkins have mapped the sound-processing part of the mouse brain in a way that keeps both the proverbial forest and the trees in view. Their imaging technique allows zooming in and out on views of brain activity within mice, and it enabled the team to watch brain cells light up as mice “called” to each other. The results, which represent a step toward better understanding how our own brains process language, appear online July 31 the journal Neuron.
In the past, researchers often studied sound processing in various animal brains by poking tiny electrodes into the auditory cortex, the part of the brain that processes sound. They then played tones and observed the response of nearby neurons, laboriously repeating the process over a gridlike pattern to figure out where the active neurons were. The neurons seemed to be laid out in neatly organized bands, each responding to a different tone. More recently, a technique called two-photon microscopy has allowed researchers to focus in on minute slices of the live mouse brain, observing activity in unprecedented detail. This newer approach has suggested that the well-manicured arrangement of bands might be an illusion. But, says David Yue, M.D., Ph.D., a professor of biomedical engineering and neuroscience at the Johns Hopkins University School of Medicine, “You could lose your way within the zoomed-in views afforded by two-photon microscopy and not know exactly where you are in the brain.” Yue led the study along with Eric Young, Ph.D., also a professor of biomedical engineering and a researcher in Johns Hopkins’ Institute for Basic Biomedical Sciences.
To get the bigger picture, John Issa, a graduate student in Yue’s lab, used a mouse genetically engineered to produce a molecule that glows green in the presence of calcium. Since calcium levels rise in neurons when they become active, neurons in the mouse’s auditory cortex glow green when activated by various sounds. Issa used a two-photon microscope to peer into the brains of live mice as they listened to sounds and saw which neurons lit up in response, piecing together a global map of a given mouse’s auditory cortex. “With these mice, we were able to both monitor the activity of individual populations of neurons and zoom out to see how those populations fit into a larger organizational picture,” he says.
With these advances, Issa and the rest of the research team were able see the tidy tone bands identified in earlier electrode studies. In addition, the new imaging platform quickly revealed more sophisticated properties of the auditory cortex, particularly as mice listened to the chirps they use to communicate with each other. “Understanding how sound representation is organized in the brain is ultimately very important for better treating hearing deficits,” Yue says. “We hope that mouse experiments like this can provide a basis for figuring out how our own brains process language and, eventually, how to help people with cochlear implants and similar interventions hear better.”
Yue notes that the same approach could also be used to understand other parts of the brain as they react to outside stimuli, such as the visual cortex and the parts of the brain responsible for processing stimuli from limbs.
Noise-Induced Hearing Loss Alters Brain Responses to Speech
Prolonged exposure to loud noise alters how the brain processes speech, potentially increasing the difficulty in distinguishing speech sounds, according to neuroscientists at The University of Texas at Dallas.
In a paper published this week in Ear and Hearing, researchers demonstrated for the first time how noise-induced hearing loss affects the brain’s recognition of speech sounds.
Noise-induced hearing loss (NIHL) reaches all corners of the population, affecting an estimated 15 percent of Americans between the ages of 20 and 69, according to the National Institute of Deafness and Other Communication Disorders (NIDCD).
Exposure to intensely loud sounds leads to permanent damage of the hair cells, which act as sound receivers in the ear. Once damaged, the hair cells do not grow back, leading to NIHL.
“As we have made machines and electronic devices more powerful, the potential to cause permanent damage has grown tremendously,” said Dr. Michael Kilgard, co-author and Margaret Fonde Jonsson Professor in the School of Behavioral and Brain Sciences. “Even the smaller MP3 players can reach volume levels that are highly damaging to the ear in a matter of minutes.”
Before the study, scientists had not clearly understood the direct effects of NIHL on how the brain responds to speech.
To simulate two types of noise trauma that clinical populations face, UT Dallas scientists exposed rats to moderate or intense levels of noise for an hour. One group heard a high-frequency noise at 115 decibels inducing moderate hearing loss, and a second group heard a low-frequency noise at 124 decibels causing severe hearing loss.
For comparison, the American Speech-Language-Hearing Association lists the maximum output of an MP3 player or the sound of a chain saw at about 110 decibels and the siren on an emergency vehicle at 120 decibels. Regular exposure to sounds greater than 100 decibels for more than a minute at a time may lead to permanent hearing loss, according to the NIDCD.
Researchers observed how the two types of hearing loss affected speech sound processing in the rats by recording the neuronal response in the auditory cortex a month after the noise exposure. The auditory cortex, one of the main areas that processes sounds in the brain, is organized on a scale, like a piano. Neurons at one end of the cortex respond to low-frequency sounds, while other neurons at the opposite end react to higher frequencies.
In the group with severe hearing loss, less than one-third of the tested auditory cortex sites that normally respond to sound reacted to stimulation. In the sites that did respond, there were unusual patterns of activity. The neurons reacted slower, the sounds had to be louder and the neurons responded to frequency ranges narrower than normal. Additionally, the rats could not tell the speech sounds apart in a behavioral task they could successfully complete before the hearing loss.
In the group with moderate hearing loss, the area of the cortex responding to sounds didn’t change, but the neurons’ reaction did. A larger area of the auditory cortex responded to low-frequency sounds. Neurons reacting to high frequencies needed more intense sound stimulation and responded slower than those in normal hearing animals. Despite these changes, the rats were still able to discriminate the speech sounds in a behavioral task.
“Although the ear is critical to hearing, it is just the first step of many processing stages needed to hold a conversation,” Kilgard said. “We are beginning to understand how hearing damage alters the brain and makes it hard to process speech, especially in noisy environments.”
New research links anxiety to epilepsy-like seizures
New research by clinical psychologists from Arizona State University and the United Kingdom has revealed seizures that could be mistaken for epilepsy are linked to feelings of anxiety.
The team of researchers devised a new set of tests to determine whether there was a link between how people interpret and respond to anxiety, and incidences of psychogenic nonepileptic seizures (PNES).
Nicole Roberts, an associate professor in ASU’s New College of Interdisciplinary Arts and Sciences, collaborated with colleagues from the University of Lincoln, University of Nottingham and University of Sheffield in the United Kingdom. The team’s findings were published in the journal Epilepsy and Behavior.
The researchers used a series of questionnaires and computer tests to determine if a patient regularly avoids situations which might bring on anxiety.
These tests correctly predicted whether a patient had epilepsy or PNES – seizures that can be brought on by threatening situations, sensations, emotions, thoughts or memories – in 83 percent of study participants. Such seizures appear on the surface to be similar to epileptic fits, which are caused by abnormal brain activity.
“This research underscores the fact that PNES is a ‘real’ and disabling disorder with a potentially identifiable pathophysiology,” said Roberts, who directs New College’s Emotion, Culture, and Psychophysiology Laboratory, located on ASU’s West campus. “We need to continue to search for answers, not just in epilepsy clinics, but also in the realm of affective science and complex brain-behavior relationships.”
“PNES can be a very disabling condition, and it is important that we understand the triggers so that we provide the correct care and treatment,” said Lian Dimaro, a clinical psychologist based at Nottinghamshire Healthcare NHS Trust, who served as lead researcher for the study.
“This study was one of the first to bring modern psychological tools of investigation to this problem,” Dimaro said. “The findings support the idea that increasing a person’s tolerance of unpleasant emotions and reducing avoidant behavior may help with treatment, suggesting that patients could benefit from a range of therapies, including acceptance and commitment therapy to help reduce the frequency of seizures, although more research is needed in this area.”
Participants completed questionnaires to determine the level to which they suffered from anxiety, their awareness of their experiences and if they would avoid situations which would make them feel anxious.
They then completed a computer task which required rapid responses to true or false statements. This test was designed to gather data on immediate, or implicit, beliefs about anxiety. Participants also answered questions about common physical complaints that may have no medical explanation, also called somatic symptoms. These can include things like gastrointestinal problems, tiredness and back pain.
Results showed that those with PNES reported significantly more somatic symptoms than others in the study, as well as avoidance of situations which might make them anxious. The group with PNES also scored significantly higher on a measure of how aware they were of their anxiety compared with the control group.
The test subjects were 30 adults with PNES, 25 with epilepsy and 31 with no reported history of seizures who served as a nonclinical control group.
The researchers suggest that including tests to determine levels of anxiety and avoidance behavior may enable health professionals to make earlier diagnosis, and develop more effective intervention plans.
“Epileptic seizures are caused by abnormal electrical activity in the brain, while most PNES are thought to be a consequence of complex psychological processes that manifest in physical attacks,” said David Dawson, a research clinical psychologist from the University of Lincoln.
“It is believed that people suffering with PNES may have difficulty actively engaging with anxiety – a coping style known as experiential avoidance,” Dawson said. “We wanted to examine whether it was possible to make a clear link between seizure frequency and how people experience and manage anxiety. Our study is another step in understanding PNES, which could ultimately lead to better treatment and, therefore, patient outcomes in the future.”
Roberts, who received her doctorate in clinical psychology from the University of California, Berkeley, focuses her research on the study of emotion and on the cultural and biological forces that shape emotional responses. Examples include investigating how ethnicity and culture influence emotional displays and experiences; how the daily hassles of life, such as job stress and sleep deprivation, impact emotion regulation among individuals and couples; and how the emotion system breaks down in patients with psychopathology (such as PNES and post-traumatic stress disorder) or neurological dysfunction (such as epilepsy).
(Source: asunews.asu.edu)
New Mouse Model May Open Autism Treatment Research Avenues
The hallmark of an excellent researcher is an open mind. That flexibility and openness is what led Nina Schor, M.D., Ph.D., the William H. Eilinger Chair of Pediatrics at the University of Rochester, to follow a hunch about a brain receptor – resulting in a new mouse model that may give researchers a new avenue for testing drugs for autism. Nature Publishing Groups’ Translational Psychiatry published the study online today.
Schor had been studying p75 neurotrophin receptors in her long-standing neuroblastoma research, but she also knew that p75NTR is involved in the reaction to oxidative stress in the brain, which some research posits plays a role in the development of autism. The receptor is also prevalent in the developing brain and drops off as a child reaches 2 to 3 years old, which is when autism symptoms often begin to appear. P75NTR stays present in the typically developing cerebellum, hippocampus and basal forebrain, parts of the brain that are anatomically abnormal in autism.
“Science doesn’t always travel in a straight line,” Schor said. “Sometimes the importance of a scientific study in one field is what it unexpectedly tells us about another field.”
While other researchers are focused on the proteins found to be abnormal in patients with autism, Schor approached her investigation from the opposite direction. She thought about what characteristics a protein would have to have to be involved in processes thought to play a role in autism. “That list of characteristics looked suspiciously like those we had found to be associated with p75NTR.”
Then, Schor and her colleagues prevented mouse brains from making p75NTR in one autism-associated type of cell in the cerebellum. What they found was that not only does the mouse’s cerebellum resemble that of children with autism, but the mouse also behaves much like children with autism. They don’t engage in typical social behaviors of mice and instead, ignore stranger mice and lack curiosity about their surroundings. They also jump twice as much as typical mice, which is like a “stimming,” or self-stimulatory, behavior typical in children with autism.
“Whether or not p75NTR turns out to be abnormal in children with autism,” Schor explained, “these studies still hold the promise of helping us explain the mechanisms behind the component behaviors of children with autism.
Schor plans to continue the research, focusing on more behavioral testing, finding evidence of whether children with autism have a p75NTR deficit in their cerebellum and starting pharmaceutical testing to see whether there is a drug that can replace the role p75NTR plays in that part of the brain.
“It’s a long way from a mouse model to a successful treatment in humans, but this is a good clue,” Schor said.
Kids with Autism, Sensory Processing Disorders Show Brain Wiring Differences
Researchers at UC San Francisco have found that children with sensory processing disorders have decreased structural brain connections in specific sensory regions different than those in autism, further establishing SPD as a clinically important neurodevelopmental disorder.
The research, published in the journal PLOS ONE, is the first study to compare structural connectivity in the brains of children with an autism diagnosis versus those with an SPD diagnosis, and with a group of typically developing boys. This new research follows UCSF’s groundbreaking study published in 2013 that was the first to find that boys affected with SPD have quantifiable regional differences in brain structure when compared to typically developing boys. This work showed a biological basis for the disease but prompted the question of how these differences compared with other neurodevelopmental disorders.
“With more than 1 percent of children in the U.S. diagnosed with an autism spectrum disorder, and reports of 5 to 16 percent of children having sensory processing difficulties, it’s essential we define the neural underpinnings of these conditions, and identify the areas they overlap and where they are very distinct,” said senior author Pratik Mukherjee, MD, PhD, a professor of radiology and biomedical imaging and bioengineering at UCSF.
SPD Gains Recognition as Distinct Condition
SPD can be hard to pinpoint, as more than 90 percent of children with autism also are reported to have atypical sensory behaviors, and SPD has not been listed in the Diagnostic and Statistical Manual used by psychiatrists and psychologists.
“One of the most striking new findings is that the children with SPD show even greater brain disconnection than the kids with a full autism diagnosis in some sensory-based tracts,” said Elysa Marco, MD, cognitive and behavioral child neurologist at UCSF Benioff Children’s Hospital San Francisco and the study’s corresponding author. “However, the children with autism, but not those with SPD, showed impairment in brain connections essential to the processing of facial emotion and memory.”
Children with SPD struggle with how to process stimulation, which can cause a wide range of symptoms including hypersensitivity to sound, sight and touch, poor fine motor skills and easy distractibility. Some SPD children cannot tolerate the sound of a vacuum, while others can’t hold a pencil or struggle with emotional regulation. Furthermore, a sound that is an irritant one day can be tolerated the next. The disease can be baffling for parents and has been a source of much controversy for clinicians who debate whether it constitutes its own disorder, according to the researchers.
“These kids, however, often don’t get supportive services at school or in the community because SPD is not yet a recognized condition,” said Marco. “We are starting to catch up with what parents already knew; sensory challenges are real and can be measured both in the lab and the real world. Our next challenge is to find the reason why children have SPD and move these findings from the lab to the clinic.”
Examining White Matter Tracts in the Brain
In the study, researchers used an advanced form of MRI called diffusion tensor imaging (DTI), which measures the microscopic movement of water molecules within the brain in order to give information about the brain’s white matter tracts. The brain’s white matter forms the “wiring” that links different areas of the brain and is therefore essential for perceiving, thinking and action. DTI shows the direction of the white matter fibers and the integrity of the white matter, thereby mapping the structural connections between brain regions.
The study examined the structural connectivity of specific white matter tracts in16 boys with SPD and 15 boys with autism between the ages of 8 and 12 and compared them with 23 typically developing boys of the same age range.
The researchers found that both the SPD and autism groups showed decreased connectivity in multiple parieto-occipital tracts, the areas that handle basic sensory information in the back area of the brain. However, only the autism cohort showed impairment in the inferior fronto-occipital fasciculi (IFOF), inferior longitudinal fasciculi (ILF), fusiform-amygdala and the fusiform-hippocampus tracts – critical tracts for social-emotional processing.
“One of the classic features of autism is decreased eye-to-eye gaze, and the decreased ability to read facial emotions,” said Marco. “The impairment in this specific brain connectivity, not only differentiates the autism group from the SPD group but reflects the difficulties patients with autism have in the real world. In our work, the more these regions are disconnected, the more challenge they are having with social skills.”
Kids with isolated SPD showed less connectivity in the basic perception and integration tracts of the brain that serve as connections for the auditory, visual and somatosensory (tactile) systems involved in sensory processing.
“If we can start by measuring a child’s brain connectivity and seeing how it is playing out in a child’s functional ability, we can then use that measure as a metric for success in our interventions and see if the connectivities are changing based on our clinical interventions,” said Marco. “Larger studies to replicate this early work are clearly needed but we are encouraged that DTI can be a powerful clinical and research tool for understanding the basis for sensory neurodevelopmental differences.”
Striatal dopamine transporter binding correlates with body composition and visual attention bias for food cues in healthy young men
Research to be presented at the Annual Meeting of the Society for the Study of Ingestive Behavior (SSIB), the foremost society for research into all aspects of eating and drinking behavior, describes a way that brain chemistry may make some people notice food more easily, which can tempt overeating even in people who are not overweight. Dopamine activity in the striatum, an area of the brain sensitive to food reward, was linked to how quickly men noticed a food picture hidden among neutral pictures. In turn, the men who quickly noticed food pictures also ate more.
From rodent research it is clear that dopamine action in the striatum motivates eating, and this goes awry in obesity. “We do know that in human obesity the striatal dopamine system is affected, but interesting enough we know little about the striatal dopamine system of young, healthy individuals and how it relates to the motivation to eat” says Susanne la Fleur from the Academic Medical Center in Amsterdam, who directed the study linking dopamine, attention to food, and eating.
Ordinarily the burst of dopamine during a rewarding activity is eventually stopped when it is re-absorbed into the cells it came from. That re-uptake process requires a brain chemical called “dopamine transporter” (DAT). Lower DAT means dopamine is reabsorbed more slowly, causing it to keep acting on the brain. The researchers scanned brains of healthy, non-obese young men to determine available DAT. The men completed a computerized visual attention task to see how quickly they could detect food pictures among neutral pictures. Subjects were also asked to report food intake during 7 days.
The researchers found that the men with lower DAT, which means higher dopamine activity, showed a stronger visual attention bias towards food, detecting food pictures more quickly. “We could speculate that in healthy humans dopamine does motivate eating, however although we did observe a correlation between striatal dopamine transporter binding and the visual attention bias for food; and between visual attention bias for food and actual food intake, we did not observe a correlation between striatal dopamine transporter binding and actual food intake. Thus, a factor in addition to dopamine must be involved in going from being motivated to actual eating”, la Fleur concluded.
(Source: eurekalert.org)
Brain Response to Appetizing Food Cues Varies Among Obese People
People who have the most common genetic mutation linked to obesity respond differently to pictures of appetizing foods than overweight or obese people who do not have the genetic mutation, according to a new study published in the Endocrine Society’s Journal of Clinical Endocrinology & Metabolism (JCEM).
More than one-third of adults are obese. Obesity typically results from a combination of eating too much, getting too little physical activity and genetics. In particular, consumption of appetizing foods that are high in calories can lead to weight gain. Highly palatable foods such as chocolate trigger signals in the brain that give a feeling of pleasure and reward. These cravings can contribute to overeating. Reward signals are processed in specific areas of the brain, where sets of neurons release chemicals such as dopamine. However, very little is known about whether the reward centers of the brain work differently in some people who are overweight or obese.
The most common genetic cause of obesity involves mutations in the melanocortin 4 receptor (MC4R), which occur in about 1 percent of obese people and contribute to weight gain from an early age. The researchers compared three groups of people: eight people who were obese due to a problem in the MC4R gene, 10 people who were overweight or obese without the gene mutation and eight people who were normal weight. They performed functional Magnetic Resonance Imaging (fMRI) scans to look at how the reward centers in the brain were activated by pictures of appetizing food such as chocolate cake compared to bland food such as rice or broccoli and non-food items such as staplers.
“In our study, we found that people with the MC4R mutation responded in the same way as normal weight people, while the overweight people without the gene problem had a lower response,” said lead researcher Agatha van der Klaauw, MD, PhD, of the Wellcome Trust-MRC Institute of Metabolic Science at Addenbrooke’s Hospital in Cambridge, U.K. “In fact, the brain’s reward centers light up when people with the mutation and normal weight people viewed pictures of appetizing foods. But overweight people without the mutation did not have the same level of response.”
The scans revealed that obese people with the MC4R mutation had similar activity in the reward centers of the brain when shown a picture of a dessert like cake or chocolate as normal weight people. The researchers found that, in contrast, the reward centers were underactive in overweight and obese volunteers who did not have the gene mutation. This finding is intriguing as it shows a completely different response in two groups of people of the same age and weight.
“For the first time, we are seeing that the MC4R pathway is involved in the brain’s response to food cues and its underactivity in some overweight people,” van der Klaauw said. “Understanding this pathway may help in developing interventions to limit the overconsumption of highly palatable foods that can lead to weight gain.”
To address the obesity epidemic, the Cambridge team is continuing to study the pathways in the brain that coordinate the need to eat and the reward and pleasure of eating
(Source: endocrine.org)
Problem drinking in midlife doubles chance of memory problems in later life
A study published in the American Journal of Geriatric Psychiatry indicates that middle-aged adults with a history of problem drinking are more than twice as likely to suffer from severe memory impairment in later life.
The study highlights the hitherto largely unknown link between harmful patterns of alcohol consumption and problems with memory later in life – problems which may place people at a high risk of developing dementia.
The study was carried out by researchers from the University of Exeter Medical School with support from the NIHR Collaboration for Leadership in Applied Health Research and Care South West Peninsula (NIHR PenCLAHRC).
The research team studied the association between a history of alcohol use disorders (AUDs) and the onset of severe cognitive and memory impairment in 6542 middle-aged adults born between 1931 and 1941. These individuals participated in the Health and Retirement Study in the US.
Participants were first assessed in 1992 and follow-up assessments took place every other year from 1996 to 2010.
A history of AUDs was identified using the CAGE* questionnaire (short for Cut down, Annoyed, Guilty, Eye-opener). Where participants registered a history of AUDs their chances of developing severe memory impairment more than doubled.
The study was led by Dr Iain Lang. He commented: “We already know there is an association between dementia risk and levels of current alcohol consumption – that understanding is based on asking older people how much they drink and then observing whether they develop problems. But this is only one part of the puzzle and we know little about the consequences of alcohol consumption earlier in life. What we did here is investigate the relatively unknown association between having a drinking problem at any point in life and experiencing problems with memory later in life.”
He added: “This finding – that middle-aged people with a history of problem drinking more than double their chances of memory impairment when they are older – suggests three things: that this is a public health issue that needs to be addressed; that more research is required to investigate the potential harms associated with alcohol consumption throughout life; and that the CAGE questionnaire may offer doctors a practical way to identify those at risk of memory/cognitive impairment and who may benefit from help to tackle their relationship with alcohol.”
Dr Doug Brown, Director of Research and Development at Alzheimer’s Society said: “When we talk about drinking too much, the media often focuses on young people ending up in A&E after a night out. However, there’s also a hidden cost of alcohol abuse given the mounting evidence that alcohol abuse can also impact on cognition later in life. This small study shows that people who admitted to alcohol abuse at some point in their lives were twice as likely to have severe memory problems, and as the research relied on self-reporting that number may be even higher.
"This isn’t to say that people need to abstain from alcohol altogether. As well as eating a healthy diet, not smoking and maintaining a healthy weight, the odd glass of red wine could even help reduce your risk of developing dementia."
* The CAGE asks four questions (and the acronym comes from words in each question: Cut down, Annoyed, Guilty, Eye-opener):
- Have you ever felt you should cut down on your drinking?
- Have people annoyed you by criticising your drinking?
- Have you ever felt bad or guilty about your drinking?
- Have you ever had a drink first thing in the morning to steady your nerves or get rid of a hangover (eye-opener)?
(Source: exeter.ac.uk)
Watching neurons fire from a front-row seat
They are with us every moment of every day, controlling every action we make, from the breath we breathe to the words we speak, and yet there is still a lot we don’t know about the cells that make up our nervous systems. When things go awry and nerve cells don’t communicate as they should, the consequences can be devastating. Speech can be slurred, muscles stop working on command and memories can be lost forever.
Better understanding of how neurons and brains work could lead to new prevention, diagnostic and treatment techniques, but the brain is complex and difficult to study. If you were to hold your brain, you would likely marvel at how much it feels and moves like Jell-O. This tissue is composed of neurons and other supporting cells with tiny cell bodies, which generate electrical signals that determine how the brain and the nervous system function.
Those signals can be recorded and measured if a suitably small electrode is in the vicinity, but that presents challenges. Brain tissue is always moving in response to the body’s movement and breathing patterns. In addition, the nerve tissue is incredibly sensitive. If disrupted by a foreign body, the cells trigger an immune response to encapsulate the intruder and barricade it from the electrical signal it’s trying to capture and understand.
Working to develop intelligent neural interfaces
That challenge led Jit Muthuswamy, an associate professor of biomedical engineering at Arizona State University, Tempe (ASU), to pursue a robotic electrode system that would seek and maintain contact with neurons of interest autonomously in a subject going through normal behavioral routines. That led him to Sandia National Laboratories.
“We are working to develop chronic, reliable, intelligent neural interfaces that will communicate with single neurons in a variety of applications, some of which are emerging and others that are closer to market,” Muthuswamy said. “Applications like brain prostheses are critically dependent on us being able to interface and communicate with single neurons reliably over the course of a patient’s life. Such reliable neural interfaces are also critical to help us understand the dynamic changes in the wiring diagram of the brain.”
Key to the success of that robotic approach are the microscale actuators needed to reposition the electrodes. This led Muthuswamy in 2000 to seek out Sandia engineer Murat Okandan and the unique microsystems engineering capabilities available at Sandia’s Microsystems and Engineering Sciences Applications facility.
“The process flow we use to make these isn’t available anywhere else in the world, so the level of complexity and mechanical design space we had to design and fabricate these was immensely larger than what other researchers might have,” Okandan said. He has been working with Muthuswamy’s research team since that initial contact to find a suitable method to track individual neurons as they fire.
Earlier probes were made of a sharpened metal wire inserted in the tissue. The closer the probe is to the neuron, the stronger the signal, so experimenters ideally try to get as close as possible without disrupting surrounding tissue. The problem is that even a thin wire is too big; such a probe can take measurements around the neuron, but is far too cumbersome to be reliable over time.
Equally important is capturing the signals from an awake animal. Given their size and rigidity, current probes aren’t suited to gather recordings as the animal responds to its environment. Those units aren’t self-contained, so they keep the animals from moving around freely.
Microscale key to capturing signals from awake, moving animals
Microscale actuators and microelectrodes are critical to addressing both of those issues so probes can interact with individual nerve cells while doing minimal damage to surrounding tissue. The microscale actuators and associated packaging system developed at ASU and Sandia let a probe move autonomously in and out of the areas surrounding the cell, collecting measurements while compensating for any movement in the neuron or brain tissue.
About the size of a thumbnail, the self-contained unit has three microelectrodes and associated micro actuators. When a current runs through the thermal actuator, it expands and pushes the microelectrodes outward over the edge of the unit, which is flat to fit against the tissue. Because the actuator is so small, it can be heated to several hundred degrees Celsius and cooled again 1,000 times per second. It takes 540 cycles to fully extend the probe, but that can be done quickly – in a second or less.
The probes were implanted in the somatosensory cortex of rodents and rigorously tested in numerous experiments, both in acute and long-term conditions, Muthuswamy said. Animal procedures were carried out with the approval of ASU’s Institute of Animal Care and Use Committee, and experiments were done in accordance with National Institute of Health guidelines.
Muthuswamy said the neural probes demonstrated significant improvement in the quality and reliability of the signals when the probes were moved with precision using the Sandia microactuators in response to loss of neural signals. Further, he said, adding autonomous closed-loop controls to compensate for microscale perturbations in brain tissue significantly improved the stability of neural recordings from the brain.
Scale of this system is unique
Thermal actuators have been used for years at Sandia and elsewhere, but the scale of this system is unique. “The idea that we could build this system to achieve multiple millimeters of total displacement out of a micron-scaled device was a significant milestone,” said Sandia engineer Michael Baker, who designed the actuator. “We used electrostatic actuators in the past, but the thermal actuator provides much higher force, which is needed to move the probe in tissue.”
The microelectrodes are made of highly conductive polysilicon, which the team discovered has a number of advantages. It is almost metal-like in its conductivity, but durable enough for millions of cycles. It provides a signal-to-noise ratio much greater than previous wire probes and provides high-quality measurement signals.
Muthuswamy and Okandan currently are seeking to produce richer data with resolution in the submicron range to be able to go inside cells and take measurements there. They also are working on stacking the existing neural probe chips and decreasing the spaces between probes. Muthuswamy’s Neural Microsystems lab at ASU has developed a unique stacking approach for creating three-dimensional arrays of actuated microelectrodes.
“By building a three-dimensional array, we would have access to significantly more information, rather than just a slice,” Okandan said. “We’re very encouraged by the progress we have made, and are looking forward to building on that progress.”
Study Suggests Disruptive Effects of Anesthesia on Brain Cell Connections Are Temporary
A study of juvenile rat brain cells suggests that the effects of a commonly used anesthetic drug on the connections between brain cells are temporary.
The study, published in this week’s issue of the journal PLOS ONE, was conducted by biologists at the University of California, San Diego and Weill Cornell Medical College in New York in response to concerns, arising from multiple studies on humans over the past decade, that exposing children to general anesthetics may increase their susceptibility to long-term cognitive and behavioral deficits, such as learning disabilities.
An estimated six million children, including 1.5 million infants, undergo surgery in the United States requiring general anesthesia each year and a least two large-scale clinical studies are now underway to determine the potential risks to children and adults.
“Since these procedures are unavoidable in most cases, it’s important to understand the mechanisms associated with the potentially toxic effects of anesthetics on the developing brain, and on the adult brain as well,” said Shelley Halpain, a professor of biology at UC San Diego and the Sanford Consortium for Regenerative Medicine, who co-headed the investigation. “Because the clinical studies haven’t been completed, preclinical studies, such as ours, are needed to define the effects of various anesthetics on brain structure and function.”
“There is concern now about cognitive dysfunction from surgery and anesthesia—how much these effects are either permanent or slowly reversible is very controversial,” said Hugh Hemmings, Jr., chair of anesthesiology at Weill Cornell and the study’s other senior author. “It has been suggested recently that some of the effects of anesthesia may be more lasting than previously thought. It is not clear whether the residual effects after an operation are due to the surgery itself, or the hospitalization and attendant trauma, medications and stress—or a combination of these issues.”
However, he added, “There is evidence that some of the delayed or persistent cognitive effects after surgery are not primarily due to anesthesia itself, but more importantly to brain inflammation resulting from the surgery. But this is not yet clear.”
The team of biologists examined one of the most commonly used general anesthetics, a derivative of ether called “isoflurane” used to maintain anesthesia during surgery.
“Previous studies in cultured neurons and in the intact brains of rodents provided evidence suggesting that exposure to anesthetics might render neurons more susceptible to cell death through a process called ‘apoptosis’,” said Halpain. “While overt cell death could certainly be one way to explain any long-lasting neurocognitive consequences of general anesthesia, we hypothesized that there could be other cellular mechanisms that disrupt neural circuits without inducing cell death per se.”
One such mechanism, she added, is known as “synaptotoxicity.” In this mechanism of neural-circuit disruption, the “synapses,” or junctions between neurons, become weakened or shrink away due to some factor that injures the neurons locally along their axons (the long processes of neurons that transmit signals) and dendrites (the threadlike extensions of neurons that receive nerve signals) without inducing the neurons themselves to die.
In the experiments at UC San Diego headed by Jimcy Platholi, a postdoctoral researcher in Halpain’s lab who is now at Weill Cornell, the scientists used neurons from embryonic rats taken from the hippocampus, a part of the mammalian forebrain essential for encoding newly acquired memories and ensuring that short-term memories are converted into long-term memories. The researchers cultured these brain cells in a laboratory dish for three weeks, allowing the neurons time to mature and to develop a dense network of synaptic connections and “dendritic spines”—specialized structures that protrude from the dendrites and are essential mediators of activity throughout neural networks.
“Evidence from animal studies indicates that new dendritic spines emerge and existing spines expand in size during learning and memory,” explained Halpain. “Therefore, the overall numbers and size of dendritic spines can profoundly impact the strength of neural networks. Since neural network activity underlies all brain function, changes in dendritic spine number and shape can influence cognition and behavior.”
Using neurons in culture, rather than intact animal brains, allowed the biologists to take images of the synapses at high spatial resolution using techniques called fluorescence light microscopy and confocal imaging. They also used time-lapse microscopy to observe structural changes in individual dendritic spines during exposure to isoflurane. Karl Herold, a research associate in the Hemmings laboratory and a co-author of the study, performed some of the image analysis.
“Imaging of human brain synapses at this level of detail is impossible with today’s technology and it remains very challenging even in laboratory rodents,” said Halpain. “It was important that we performed our study using rodent neurons in a culture dish, so that we could really drill down into the subcellular and molecular details of how anesthetics work.”
The researchers wondered whether brief exposure to isoflurane would alter the numbers and size of dendritic spines, so they applied the anesthetic to the cultured rat cells at concentrations and durations (up to 60 minutes) that are frequently used during surgery.
“We observed detectable decreases in dendritic spine numbers and shape within as little as 10 minutes,” said Halpain. “However this spine loss and shrinkage was reversible after the anesthetic was washed out of the culture.”
“Our study was reassuring in the sense that the effects are not irreversible and this fits in with known clinical effects,” said Hemmings. “For the most part, we find that the effects are reversible.”
“We clearly see an effect—a very marked effect on the dendritic spines—from use of this drug that was reversible, suggesting that it is not a toxic effect, but something more relevant to the pharmacological actions of the drug,” he added. “Connecting what we found to the cognitive effects of isoflurane will require much more detailed analysis.”
The team plans to follow up its study with future experiments to probe the molecular mechanisms and long-lasting consequences of isoflurane’s effects on neuron synapses and examine other commonly-used anesthetics for surgery.