A look inside children’s minds

University of Iowa study shows how 3- and 4-year-olds retain what they see around them

When young children gaze intently at something or furrow their brows in concentration, you know their minds are busily at work. But you’re never entirely sure what they’re thinking.

Now you can get an inside look. Psychologists led by the University of Iowa for the first time have peered inside the brain with optical neuroimaging to quantify how much 3- and 4-year-old children are grasping when they survey what’s around them and to learn what areas of the brain are in play. The study looks at “visual working memory,” a core cognitive function in which we stitch together what we see at any given point in time to help focus attention. In a series of object-matching tests, the researchers found that 3-year-olds can hold a maximum of 1.3 objects in visual working memory, while 4-year-olds reach capacity at 1.8 objects. By comparison, adults max out at 3 to 4 objects, according to prior studies.

“This is literally the first look into a 3 and 4-year-old’s brain in action in this particular working memory task,” says John Spencer, psychology professor at the UI and corresponding author of the paper, which appears in the journal NeuroImage.

The research is important, because visual working memory performance has been linked to a variety of childhood disorders, including attention-deficit/hyperactivity disorder (ADHD), autism, developmental coordination disorder as well as affecting children born prematurely. The goal is to use the new brain imaging technique to detect these disorders before they manifest themselves in children’s behavior later on.

“At a young age, children may behave the same,” notes Spencer, who’s also affiliated with the Delta Center and whose department is part of the College of Liberal Arts and Sciences, “but if you can distinguish these problems in the brain, then it’s possible to intervene early and get children on a more standard trajectory.”

Plenty of research has gone into better understanding visual working memory in children and adults. Those prior studies divined neural networks in action using function magnetic resonance imaging (fMRI). That worked great for adults, but not so much with children,­ especially young ones, whose jerky movements threw the machine’s readings off kilter. So, Spencer and his team turned to functional near-infrared spectroscopy (fNIRS), which has been around since the 1960s but has never been used to look at working memory in children as young as three years of age.

“It’s not a scary environment,” says Spencer of the fNIRS. “No tube, no loud noises. You just have to wear a cap.”

Like fMRI, fNIRS records neural activity by measuring the difference in oxygenated blood concentrations anywhere in the brain. You’ve likely seen similar technology when a nurse puts your finger in a clip to check your circulation. In the brain, when a region is activated, neurons fire like mad, gobbling up oxygen provided in the blood. Those neurons need another shipment of oxygen-rich blood to arrive to keep going. The fNIRS measures the contrast between oxygen-rich and oxygen-deprived blood to gauge which area of the brain is going full tilt at a point in time.

The researchers outfitted the youngsters with colorful, comfortable ski hats in which fiber optic wires had been woven. The children played a computer game in which they were shown a card with one to three objects of different shapes for two seconds. After a pause of a second, the children were shown a card with either the same or different shapes. They responded whether they had seen a match.

The tests revealed novel insights. First, neural activity in the right frontal cortex was an important barometer of higher visual working memory capacity in both age groups. This could help clinicians evaluate children’s visual working memory at a younger age than before, and work with those whose capacity falls below the norm, the researchers say.

Secondly, 4-year olds showed a greater use than 3-year olds of the parietal cortex, located in both hemispheres below the crown of the head and which is believed to guide spatial attention.

"This suggests that improvements in performance are accompanied by increases in the neural response," adds Aaron Buss, a UI graduate student in psychology and the first author on the paper. "Further work will be needed to explain exactly how the neural response increases—either through changes in local tuning, or through changes in long range connectivity, or some combination."

Promising Alzheimer’s ‘drug’ halts memory loss

A new class of experimental drug-like small molecules is showing great promise in targeting a brain enzyme to prevent early memory loss in Alzheimer’s disease, according to Northwestern Medicine® research.

Developed in the laboratory of D. Martin Watterson, the molecules halted memory loss and fixed damaged communication among brain cells in a mouse model of Alzheimer’s.

"This is the starting point for the development of a new class of drugs," said Watterson, lead author of a paper on the study and the John G. Searle Professor of Molecular Biology and Biochemistry at Northwestern University Feinberg School of Medicine. "It’s possible someday this class of drugs could be given early on to people to arrest certain aspects of Alzheimer’s."

Changes in the brain start to occur ten to 15 years before serious memory problems become apparent in Alzheimer’s.

"This class of drugs could be beneficial when the nerve cells are just beginning to become impaired," said Linda Van Eldik, a senior author of the paper and director of the University of Kentucky Sanders-Brown Center on Aging.

The study is a collaboration between Northwestern’s Feinberg School, Columbia University Medical Center and the University of Kentucky. It will be published June 26 in the journal PLOS ONE.

The novel drug-like molecule, called MW108, reduces the activity of an enzyme that is over-activated during Alzheimer’s and is considered a contributor to brain inflammation and impaired neuron function. Strong communication between neurons in the brain is an essential process for memory formation.

"I’m not aware of any other drug that has this effect on the central nervous system," Watterson said.

"These exciting results provide new hope for developing drugs against an important molecular target in the brain," said Roderick Corriveau, program director at the National Institute of Neurological Disorders and Stroke, which helped support the research. "They also provide a promising strategy for identifying small molecule drugs designed to treat Alzheimer’s disease and other neurological disorders."

Watterson and his collaborators have a new National Institutes of Health (NIH) award to further refine the compound so it is metabolically stable and safe for use in humans and develop it to the point of starting a phase 1 clinical trial.

(Image: Jay Vollmar)

Addiction Relapse Might Be Thwarted By Turning Off Brain Trigger

Researchers at the Ernest Gallo Clinic and Research Center at UC San Francisco have been able to identify and deactivate a brain pathway linked to memories that cause alcohol cravings in rats, a finding that may one day lead to a treatment option for people who suffer from alcohol abuse disorders and other addictions.

In the study, researchers were able to prevent the addicted animals from seeking alcohol and drinking it, the equivalent of relapse.

“One of the main causes of relapse is craving, triggered by the memory by certain cues – like going into a bar, or the smell or taste of alcohol,” said lead author Segev Barak, PhD, at the time a postdoctoral fellow in the lab of co-senior author Dorit Ron, PhD, a Gallo Center investigator and UCSF professor of neurology.

“We learned that when rats were exposed to the smell or taste of alcohol, there was a small window of opportunity to target the area of the brain that reconsolidates the memory of the craving for alcohol and to weaken or even erase the memory, and thus the craving” he said.

The study, also supervised by co-senior author Patricia H. Janak, PhD, a Gallo Center investigator and UCSF professor of neurology, was published online on June 23 in Nature Neuroscience.

Neural Mechanism That Triggers Alcohol Memory

In the first phase of the study, rats had the choice to freely drink water or alcohol over the course of seven weeks, and during this time developed a high preference for alcohol.

In the next phase, they had the opportunity to access alcohol for one hour a day, which they learned to do by pressing a lever. They were then put through a 10-day period of abstinence from alcohol.

Following this period, the animals were exposed for five minutes to just the smell and taste of alcohol, which cued them to remember how much they liked drinking it. The researchers then scanned the animals’ brains, and identified the neural mechanism responsible for the reactivation of the memory of the alcohol – a molecular pathway mediated by an enzyme known as mammalian target of rapamycin complex 1 (mTORC1).

They found that just a small drop of alcohol presented to the rats turned on the mTORC1 pathway specifically in a select region of the amygdala, a structure linked to emotional reactions and withdrawal from alcohol, and cortical regions involved in memory processing.

They further showed that once mTORC1 was activated, the alcohol-memory stabilized (reconsolidated) and the rats relapsed on the following days, meaning in this case, that they started again to push the lever to dispense more alcohol.

“The smell and taste of alcohol were such strong cues that we could target the memory specifically without impacting other memories, such as a craving for sugar,” said Barak, who added that the Ron research group has been doing brain studies for many years and has never seen such a robust and specific activation in the brain.

Drug that Erases the Memory of Alcohol

In the next part of the study, the researchers set out to see if they could prevent the reconsolidation of the memory of alcohol by inhibiting mTORC1, thus preventing relapse. When mTORC1 was inactivated using a drug called rapamycin, administered immediately after the exposure to the cue (smell, taste), there was no relapse to alcohol-seeking the next day.

Strikingly, drinking remained suppressed for up to 14 days, the end point of the study. These results suggest that rapamycin erased the memory of alcohol for a long period, said Ron.

The authors said the study is an important first step, but that more research is needed to determine how mTORC1 contributes to alcohol memory reconsolidation and whether turning off mTORC1 with rapamycin would prevent relapse for more than two weeks.

The authors also said it would be interesting to test if rapamycin, an FDA-approved drug currently used to prevent organ rejection after transplantation, or other mTORC1 inhibitors that are currently being developed in pharmaceutical companies, would prevent relapse in human alcoholics.

“One of the main problems in alcohol abuse disorders is relapse, and current treatment options are very limited.” Barak said. “Even after detoxification and a period of rehabilitation, 70 to 80 percent of patients will relapse in the first several years. It is really thrilling that we were able to completely erase the memory of alcohol and prevent relapse in these animals. This could be a revolution in treatment approaches for addiction, in terms of erasing unwanted memories and thereby manipulating the brain triggers that are so problematic for people with addictions.”

Repairing Bad Memories

It was a Saturday night at the New York Psychoanalytic Institute, and the second-floor auditorium held an odd mix of gray-haired, cerebral Upper East Side types and young, scruffy downtown grad students in black denim. Up on the stage, neuroscientist Daniela Schiller, a riveting figure with her long, straight hair and impossibly erect posture, paused briefly from what she was doing to deliver a mini-lecture about memory.

She explained how recent research, including her own, has shown that memories are not unchanging physical traces in the brain. Instead, they are malleable constructs that may be rebuilt every time they are recalled. The research suggests, she said, that doctors (and psychotherapists) might be able to use this knowledge to help patients block the fearful emotions they experience when recalling a traumatic event, converting chronic sources of debilitating anxiety into benign trips down memory lane.

And then Schiller went back to what she had been doing, which was providing a slamming, rhythmic beat on drums and backup vocals for the Amygdaloids, a rock band composed of New York City neuroscientists. During their performance at the institute’s second annual “Heavy Mental Variety Show,” the band blasted out a selection of its greatest hits, including songs about cognition (“Theory of My Mind”), memory (“A Trace”), and psychopathology (“Brainstorm”).

“Just give me a pill,” Schiller crooned at one point, during the chorus of a song called “Memory Pill.” “Wash away my memories …”

The irony is that if research by Schiller and others holds up, you may not even need a pill to strip a memory of its power to frighten or oppress you.

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Time perception altered by mindfulness meditation

New published research from psychologists at the universities of Kent and Witten/Herdecke has shown that mindfulness meditation has the ability to temporarily alter practitioners’ perceptions of time – a finding that has wider implications for the use of mindfulness both as an everyday practice, and in clinical treatments and interventions.

Led by Dr Robin Kramer from Kent’s School of Psychology, the research team hypothesised that, given mindfulness’ emphasis on moment-to-moment awareness, mindfulness meditation would slow down time and produce the feeling that short periods of time lasted longer.

To test this hypothesis, they used a temporal bisection task, which allows researchers to measure where each individual subjectively splits a period of time in half. Participants’ responses to this task were collected twice, once before and then again after a listening task. By separating people into two groups, participants listened for ten minutes to either an audiobook or a meditation exercise designed to focus their attention on the movement of breath in the body. The results showed that the control group (audiobook) didn’t change in their responses after the listening task compared with before. However, meditation led to a relative overestimation of durations i.e. time periods felt longer than they had before.

The reasons for this have been interpreted by Dr Kramer and team as the result of attentional changes, producing either improved attentional resources that allow increased attention to the processing of time, or a shift to internally-oriented attention that would have the same effect.

Dr Kramer said: ‘Our findings represent some of the first to demonstrate how mindfulness meditation can alter the perception of time. Given the increasing popularity of mindfulness in everyday practice, its relationship with time perception may provide an important step in our understanding of this pervasive, ancient practice in our modern world.’

Dr Kramer also explained that the benefits of mindfulness and mindfulness-based therapies in a variety of domains are now being identified. These include decreases in rumination, improvements in cognitive flexibility, working memory capacity and sustained attention, and reductions in reactivity, anxiety and depressive symptoms. Mindfulness-based treatments also appear to provide broad antidepressant and antianxiety effects, as well as decreases in general psychological distress. As such, these interventions have been applied with a variety of patients, including those suffering from fibromyalgia, psoriasis, cancer, binge eating and chronic pain.

Dr Dinkar Sharma, Senior Lecturer in Psychology at Kent, commented: ‘Demonstrating that mindfulness has an effect on time perception is important because it opens up the opportunity that mindfulness could be used to alter psychological disorders that are associated with a range of distortions in the perception of time - such as disorders of memory, emotion and addiction.’

Dr Ulrich Weger, of Witten/Herdecke’s Department of Psychology and Psychotherapy, concluded by stating that ‘the impact of a brief mindfulness exercise on elementary processes such as time perception is remarkable’.

What do memories look like?

Oscar Wilde called memory “the diary that we all carry about with us.” Now a team of scientists has developed a way to see where and how that diary is written.

Led by Don Arnold and Richard Roberts of USC, the team engineered microscopic probes that light up synapses in a living neuron in real time by attaching fluorescent markers onto synaptic proteins — all without affecting the neuron’s ability to function.

The fluorescent markers allow scientists to see live excitatory and inhibitory synapses for the first time and, importantly, how they change as new memories are formed.

The synapses appear as bright spots along dendrites (the branches of a neuron that transmit electrochemical signals). As the brain processes new information, those bright spots change, visually indicating how synaptic structures in the brain have been altered by the new data.

“When you make a memory or learn something, there’s a physical change in the brain. It turns out that the thing that gets changed is the distribution of synaptic connections,” said Arnold, associate professor of molecular and computational biology at the USC Dornsife College of Letters, Arts and Sciences, and co-corresponding author of an article about the research that appears in Neuron on June 19.

The probes behave like antibodies, but they bind more tightly and are optimized to work inside the cell — something that ordinary antibodies can’t do. To make these probes, the team used a technique known as “mRNA display,” which was developed by Roberts and Nobel laureate Jack Szostak.

“Using mRNA display, we can search through more than a trillion different potential proteins simultaneously to find the one protein that binds the target the best,” said Roberts, co-corresponding author of the article and professor of chemistry and chemical engineering with joint appointments at USC Dornsife and the USC Viterbi School of Engineering.

Arnold and Roberts’ probes (called “FingRs”) are attached to green fluorescent protein (GFP), a protein isolated from jellyfish that fluoresces bright green when exposed to blue light. Because FingRs are proteins, the genes encoding them can be put into brain cells in living animals, causing the cells themselves to manufacture the probes.

The design of FingRs also includes a regulation system that cuts off the amount of FingR-GFP that is generated after 100 percent of the target protein is labeled, effectively eliminating background fluorescence — generating a sharper, clearer picture.

These probes can be put in the brains of living mice and then imaged through cranial windows using two-photon microscopy.

The new research could offer crucial insight for scientists responding to President Barack Obama’s Brain Research Through Advancing Innovative Neurotechnologies (BRAIN) Initiative, which was announced in April.

Modeled after the Human Genome Project, the objective of the $100 million initiative is to fast-track research that maps out exactly how the brain works and “better understand how we think, learn and remember,” according to the BRAIN Initiative website.

The discerning fruit fly: Linking brain-cell activity and behavior in smell recognition

Behind the common expression “you can’t compare apples to oranges” lies a fundamental question of neuroscience: How does the brain recognize that apples and oranges are different? A group of neuroscientists at Cold Spring Harbor Laboratory (CSHL) has published new research that provides some answers.

In the fruit fly, the ability to distinguish smells lies in a region of the brain called the mushroom body (MB). Prior research has demonstrated that the MB is associated with learning and memory, especially in relation to the sense of smell, also known as olfaction.

CSHL Associate Professor Glenn Turner and colleagues have now mapped the activity of brain cells in the MB, in flies conditioned to have Pavlovian behavioral responses to different odors. Their results, outlined in a paper published today by the Journal of Neuroscience, suggest that the activity of a remarkably small number of neurons — as few as 25 — is required to be able to distinguish between different odors.

They also found that a similarly small number of nerve cells are involved in grouping alike odors. This means, for instance, that “if you’ve learned that oranges are good, the smell of a tangerine will also get you thinking about food,” says Robert Campbell, a postdoctoral researcher in the Turner lab and lead author on the new study.

These intriguing new findings are part of a broad effort in contemporary neuroscience to determine how the brain, easily the most complex organ in any animal, manages to make a mass of raw sensory data intelligible to the individual — whether a person or a fly — in order to serve as a basis for making vital decisions.

Looking closely at Kenyon cells

The neurons in the fly MB are known as Kenyon cells, named after their discoverer, the neuroscientist Frederick Kenyon, who was the first person to stain and visualize individual neurons in the insect brain. Kenyon cells receive sensory inputs from organs that perceive smell, taste, sight and sound. This confluence of sensory input in the MB is important for memory formation, which comes about through a linking of different types of information.

Kenyon cells make up only about 4% of the entire fly brain and are extremely sensitive to inputs triggered by odors, in which only two connections between neurons, called synapses, separate them from the receptor cells at the “front end” of the olfactory system.

But in contrast to other regions of the brain, such as the vertebrate hippocampus, the sensory responses in the MB are few in number and relatively weak. It is the sparseness of the signals in the Kenyon cell neurons that makes studying memory formation in flies so promising to Turner and his team. “We set out to learn if these signals were really informative to the animal’s learning and memory with regard to smell,” Turner says.

In particular, Turner’s group wanted to see if they could link these signals with actual behavior in flies. The team used an imaging technique that allowed them to view the responses of over 100 Kenyon cells at a time and, importantly, quantify their results. They found that even the very sparse responses in these cells that are triggered by odors provide a large amount of information about odor identity. Turner suspects the very selectiveness of the response helps in the accurate formation and recall of memories.

When the researchers used two odors blended together in a series of increasingly similar concentrations, they found that two very similar smells could be distinguished as a result of the activity of as few as 25 Kenyon cells. This correlated well with the behavior of the flies: when brain activity suggested the flies had difficulty discerning the odors, their behavior also showed they could not choose between them.

The activity of these cells also accounts for flies’ ability to discern novel odors and group them together. This was determined in a “generalization” test, in which the degree to which flies learned a generalized aversion to unfamiliar test odors could be predicted based upon the relatively similar activity patterns of Kenyon cells that the odors induced.

“Being able to do this type of ‘mind-reading’ means we really understand what signals these activity patterns are sending,” says Turner. Ultimately, he and colleagues hope to be able to relate their findings in the fly brain with the operation of the brain in mammals.

Memory-Boosting Chemical Is Identified in Mice

Memory improved in mice injected with a small, drug-like molecule discovered by UCSF San Francisco researchers studying how cells respond to biological stress.

The same biochemical pathway the molecule acts on might one day be targeted in humans to improve memory, according to the senior author of the study, Peter Walter, PhD, UCSF professor of biochemistry and biophysics and a Howard Hughes Investigator.

The discovery of the molecule and the results of the subsequent memory tests in mice were published in eLife, an online scientific open-access journal, on May 28, 2013.

In one memory test included in the study, normal mice were able to relocate a submerged platform about three times faster after receiving injections of the potent chemical than mice that received sham injections.

The mice that received the chemical also better remembered cues associated with unpleasant stimuli – the sort of fear conditioning that could help a mouse avoid being preyed upon.

Notably, the findings suggest that despite what would seem to be the importance of having the best biochemical mechanisms to maximize the power of memory, evolution does not seem to have provided them, Walter said.

“It appears that the process of evolution has not optimized memory consolidation; otherwise I don’t think we could have improved upon it the way we did in our study with normal, healthy mice,” Walter said.

The memory-boosting chemical was singled out from among 100,000 chemicals screened at the Small Molecule Discovery Center at UCSF for their potential to perturb a protective biochemical pathway within cells that is activated when cells are unable to keep up with the need to fold proteins into their working forms.

However, UCSF postdoctoral fellow Carmela Sidrauski, PhD, discovered that the chemical acts within the cell beyond the biochemical pathway that activates this unfolded protein response, to more broadly impact what’s known as the integrated stress response. In this response, several biochemical pathways converge on a single molecular lynchpin, a protein called eIF2 alpha.

Scientists have known that in organisms ranging in complexity from yeast to humans different kinds of cellular stress — a backlog of unfolded proteins, DNA-damaging UV light, a shortage of the amino acid building blocks needed to make protein, viral infection, iron deficiency — trigger different enzymes to act downstream to switch off eIF2 alpha.

“Among other things, the inactivation of eIF2 alpha is a brake on memory consolidation,” Walter said, perhaps an evolutionary consequence of a cell or organism becoming better able to adapt in other ways.

Turning off eIF2 alpha dials down production of most proteins, some of which may be needed for memory formation, Walter said. But eIF2 alpha inactivation also ramps up production of a few key proteins that help cells cope with stress.

Study co-author Nahum Sonenberg, PhD, of McGill University previously linked memory and eIF2 alpha in genetic studies of mice, and his lab group also conducted the memory tests for the current study.

The chemical identified by the UCSF researchers is called ISRIB, which stands for integrated stress response inhibitor. ISRIB counters the effects of eIF2 alpha inactivation inside cells, the researchers found.

“ISRIB shows good pharmacokinetic properties [how a drug is absorbed, distributed and eliminated], readily crosses the blood-brain barrier, and exhibits no overt toxicity in mice, which makes it very useful for studies in mice,” Walter said. These properties also indicate that ISRIB might serve as a good starting point for human drug development, according to Walter.

Walter said he is looking for scientists to collaborate with in new studies of cognition and memory in mouse models of neurodegenerative diseases and aging, using ISRIB or related molecules.

In addition, chemicals such as ISRIB could play a role in fighting cancers, which take advantage of stress responses to fuel their own growth, Walter said. Walter already is exploring ways to manipulate the unfolded protein response to inhibit tumor growth, based on his earlier discoveries.

At a more basic level, Walter said, he and other scientists can now use ISRIB to learn more about the role of the unfolded protein response and the integrated stress response in disease and normal physiology.