Focusing on Faces

Difficulties in social interaction are considered to be one of the behavioral hallmarks of autism spectrum disorders (ASDs). Previous studies have shown these difficulties to be related to differences in how the brains of autistic individuals process sensory information about faces. Now, a group of researchers led by California Institute of Technology (Caltech) neuroscientist Ralph Adolphs has made the first recordings of the firings of single neurons in the brains of autistic individuals, and has found specific neurons in a region called the amygdala that show reduced processing of the eye region of faces. Furthermore, the study found that these same neurons responded more to mouths than did the neurons seen in the control-group individuals.

"We found that single brain cells in the amygdala of people with autism respond differently to faces in a way that explains many prior behavioral observations," says Adolphs, Bren Professor of Psychology and Neuroscience and professor of biology at Caltech and coauthor of a study in the November 20 issue of Neuron that outlines the team’s findings. “We believe this shows that abnormal functioning in the amygdala is a reason that people with autism process faces abnormally.”

The amygdala has long been known to be important for the processing of emotional reactions. To make recordings from this part of the brain, Adolphs and lead author Ueli Rutishauser, assistant professor in the departments of neurosurgery and neurology at Cedars-Sinai Medical Center and visiting associate in biology at Caltech, teamed up with Adam Mamelak, professor of neurosurgery and director of functional neurosurgery at Cedars-Sinai, and neurosurgeon Ian Ross at Huntington Memorial Hospital in Pasadena, California, to recruit patients with epilepsy who had electrodes implanted in their medial temporal lobes—the area of the brain where the amygdala is located—to help identify the origin of their seizures. Epileptic seizures are caused by a burst of abnormal electric activity in the brain, which the electrodes are designed to detect. It turns out that epilepsy and ASD sometimes go together, and so the researchers were able to identify two of the epilepsy patients who also had a diagnosis of ASD.

By using the implanted electrodes to record the firings of individual neurons, the researchers were able to observe activity as participants looked at images of different facial regions, and then correlate the neuronal responses with the pictures. In the control group of epilepsy patients without autism, the neurons responded most strongly to the eye region of the face, whereas in the two ASD patients, the neurons responded most strongly to the mouth region. Moreover, the effect was present in only a specific subset of the neurons. In contrast, a different set of neurons showed the same response in both groups when whole faces were shown.

"It was surprising to find such clear abnormalities at the level of single cells," explains Rutishauser. "We, like many others, had thought that the neurological abnormalities that contribute to autism were spread throughout the brain, and that it would be difficult to find highly specific correlates. Not only did we find highly specific abnormalities in single-cell responses, but only a certain subset of cells responded that way, while another set showed typical responses to faces. This specificity of these cell populations was surprising and is, in a way, very good news, because it suggests the existence of specific mechanisms for autism that we can potentially trace back to their genetic and environmental causes, and that one could imagine manipulating for targeted treatment."

"We can now ask how these cells change their responses with treatments, how they correspond to similar cell populations in animal models of autism, and what genes this particular population of cells expresses," adds Adolphs.

To validate their results, the researchers hope to identify and test additional subjects, which is a challenge because it is very hard to find people with autism who also have epilepsy and who have been implanted with electrodes in the amygdala for single-cell recordings, says Adolphs.

"At the same time, we should think about how to change the responses of these neurons, and see if those modifications correlate with behavioral changes," he says.

Shedding new light on learning disorders

A Michigan State University researcher has discovered the first anatomical evidence that the brains of children with a nonverbal learning disability – long considered a “pseudo” diagnosis – may develop differently than the brains of other children.

The finding, published in Child Neuropsychology, could ultimately help educators and clinicians better distinguish between – and treat – children with a nonverbal learning disability, or NLVD, and those with Asperger’s, or high functioning autism, which is often confused with NLVD.

“Children with nonverbal learning disabilities and Asperger’s can look very similar, but they can have very different reasons for why they behave the way they do,” said Jodene Fine, assistant professor of school psychology in MSU’s College of Education.

Understanding the biological differences in children with learning and behavioral challenges could help lead to more appropriate intervention strategies.

Children with nonverbal learning disability tend to have normal language skills but below average math skills and difficulty solving visual puzzles. Because many of these kids also show difficulty understanding social cues, some experts have argued that NVLD is related to high functioning autism – which this latest study suggests may not be so.

Fine and Kayla Musielak, an MSU doctoral student in school psychology, studied about 150 children ages 8 to 18. Using MRI scans of the participants’ brains, the researchers found that the children diagnosed with NVLD had smaller spleniums than children with other learning disorders such as Asperger’s and ADHD, and children who had no learning disorders.

The splenium is part of the corpus callosum, a thick band of fibers in the brain that connects the left and right hemispheres and facilitates communication between the two sides. Interestingly, this posterior part of the corpus callosum serves the areas of the brain related to visual and spatial functioning.

In a second part of the study, the participants’ brain activity was analyzed after they were shown videos in an MRI that portrayed both positive and negative examples of social interaction. (A typical example of a positive event was a child opening a desired birthday present with friend; a negative event included a child being teased by other children.)

The researchers found that the brains of children with nonverbal learning disability responded differently to the social interactions than the brains of children with high functioning autism, or HFA, suggesting the neural pathways that underlie those behaviors may be different.

“So what we have is evidence of a structural difference in the brains of children with NLVD and HFA, as well as evidence of a functional difference in the way their brains behave when they are presented with stimuli,” Fine said.

While more research is needed to better understand how nonverbal learning disability fits into the family of learning disorders, Fine said her findings present “an interesting piece of the puzzle.”

“I would say at this point we still don’t have enough evidence to say NVLD is a distinct diagnosis, but I do think our research supports the idea that it might be,” she said.

Connections in the brains of young children strengthen during sleep

While young children sleep, connections between the left and the right hemispheres of their brain strengthen, which may help brain functions mature, according to a new study by the University of Colorado Boulder.

The research team—led by Salome Kurth, a postdoctoral researcher, and Monique LeBourgeois, assistant professor in integrative physiology—used electroencephalograms, or EEGs, to measure the brain activity of eight sleeping children multiple times at the ages of 2, 3 and 5 years.

“Interestingly, during a night of sleep, connections weakened within hemispheres but strengthened between hemispheres,” Kurth said.

Scientists have known that the brain changes drastically during early childhood: New connections are formed, others are removed and a fatty layer called “myelin” forms around nerve fibers in the brain. The growth of myelin strengthens the connections by speeding up the transfer of information.

Maturation of nerve fibers leads to improvement in skills such as language, attention and impulse control. But it is still not clear what role sleep plays in the development of such brain connections.

In the new study, appearing online in the journal Brain Sciences, the researchers looked at differences in brain activity during sleep as the children got older and differences in brain activity of each child over a night’s sleep. They found that connections in the brain generally became stronger during sleep as the children aged. They also found that the strength of the connections between the left and right hemispheres increased by as much as 20 percent over a night’s sleep.

“There are strong indications that sleep and brain maturation are closely related, but at this time, it is not known how sleep leads to changes in brain structure,” Kurth said.

Future studies will be aimed at determining how sleep disruption during childhood may affect brain development and behavior.

“I believe inadequate sleep in childhood may affect the maturation of the brain related to the emergence of developmental or mood disorders,” Kurth said.

Researchers Discover Idling Brain Activity in Severely Brain Injured Patients Who “Wake Up” After Using a Sleep Drug

George Melendez has been called a medical miracle. After a near drowning deprived his brain of oxygen, Melendez remained in a fitful, minimally conscious state until his mother, in 2002, decided to give him the sleep aid drug Ambien to quiet his moaning and writhing. The next thing she knew, her son was quietly looking at her and trying to talk. He has been using the drug ever since to maintain awareness, but no one could understand why Ambien led to such an awakening.

Now, a team of scientists led by Weill Cornell Medical College has discovered a signature of brain activity in Melendez and two other similarly “awakened” patients they say explain why he and others regain some consciousness after using Ambien or other drugs or treatments. The pattern of activity, reported Nov. 19 in the journal eLife, was identified by analyzing the common electroencephalography (EEG) test, which tracks brain waves.

"We found a surprisingly consistent picture of electrical activity in all three patients before they receive the drug. Most interesting is that their specific pattern of activity suggests a particular process occurring in the brain cells of the cerebral cortex and also supports the role of a crucial brain circuit," says the study’s senior investigator, Dr. Nicholas Schiff, the Jerold B. Katz Professor of Neurology and Neuroscience and professor of public health at Weill Cornell. "These findings may help predict other patients who might similarly harbor reserve capacity, whether they are able to respond to Ambien or other approaches." Dr. Schiff is also on the faculty of the Feil Family Brain and Mind Research Institute at Weill Cornell and is a neurologist at NewYork-Presbyterian Hospital/Weill Cornell Medical Center.

"We are focused on finding ways to identify patients who have a functional reserve of cognitive capacities that can be rescued and how to achieve this result," Dr. Schiff adds. "These findings give us a very important lead to follow, and we will now rigorously test their implications in other patients."

Although it is not precisely known how many Americans are diagnosed as severely brain injured with disorders of consciousness, by one estimate there are nearly 300,000 patients trapped in a minimally conscious state who may retain some awareness, according to Dr. Schiff.

Riding a Wave of Excitation

The three patients in the study suffered brain damage in different ways. One fell and the other had a brain aneurysm that led to multiple strokes. Melendez was in a car accident that led to his nearly drowning. All three patients — two men and a woman — become aware when Ambien was used, a rare response that has been documented in fewer than 15 brain-injured patients.

The research team, which included scientists from Memorial Sloan-Kettering Cancer Center, Boston University School of Medicine, and the University Hospital of Liège in Belgium, used EEG to measure electrical activity in the patients’ brains before and after they were given the drug.

Although each patient’s brain was damaged in different ways, all showed the same unique features of low frequency waves in their EEG readings. These low frequency oscillations are most prominent over the frontal cortex, a region strongly dependent for its activity on other brain structures, particularly the central thalamus and the striatum, which together support short-term memory, reward, motivation, attention, alertness and sleep, among other functions.

In this setting of an idling brain, the investigators propose that Ambien works like any anesthesia drug, in that it briefly triggers a fast wave of excitation in brain cells before producing sleep — a phenomenon known as paradoxical excitation. Instead of going on to produce sedation and sleep, as it does in healthy people who use the drug, zolpidem further activates the brain after it’s affected the idling cells, allowing the patients to become more awake than at baseline. “What we think is happening in these patients is that the initial excitation produced by Ambien turns on a specific circuit. The drug creates the opportunity for the brain to effectively catch a ride on this initial wave of excitation, and turn itself back on,” Dr. Schiff says.

This proposed “mesocircuit” links the cortical regions of the brain to the central thalamus and striatum. Neurons in the central thalamus are highly connected to other parts of the brain, “so damage in one part of the brain or another will affect the thalamus, which is key to consciousness,” Dr. Schiff says. Neurons in the striatum “will only fire if there is a lot of electrical input coming to them quickly,” he says.

"We believe the switch that Ambien turns on is at the level of the joint connections between these three brain structures," Dr. Schiff says.

The pattern of brain activity seen in the EEG on Ambien was also the same in all the patients in the study. But the circuit turns off again when the effects of the drug diminish. Using the drug regularly at mealtimes, Melendez can speak fluently, and read and write simple phrases. His tremors and spasticity are significantly reduced on Ambien and he can use objects, such as a spoon, and is alert and can communicate. The first patient in the study can reliably move from minimally conscious to “the mid-range of what is called a confusional state — a more alert status, but not full consciousness,” Dr. Schiff says. “Use of Ambien offers a step in the right direction, but certainly not a cure.”

Different Ways to Kick-Start the Brain

The resting EEG pattern the researchers saw in the patients indicates they have a “recruitable reserve” of function in these critical brain areas that Ambien can harness to turn the brain on, even if only temporarily. “The idea is that hopefully we can screen other patients with EEG to find out if they also have such a reserve,” Dr. Schiff says.

And while some of these patients may not respond to Ambien — as the drug works at a very specific brain receptor and individuals can vary considerably in having enough of it in the key components of the proposed circuit — other drugs may target the same structures and potentially produce similar effects, he says. For example, two drugs (amantadine and L-Dopa) that provide extra dopamine, a brain chemical that fuels the part of the brain damaged in the study’s patients, have been shown to have similar effects on restoring function in patients with severe brain injuries, as has electrical brain stimulation of the central thalamus.

"Now that we have uncovered important insight into fundamental mechanisms underlying the dramatic and rare response of some severely brain-injured patients to Ambien, we hope to systematically explore ways to achieve such kick-starts in other patients — that is our goal," Dr. Schiff says.

(Image credit)

People with highly superior powers of recall also vulnerable to false memories

People who can accurately remember details of their daily lives going back decades are as susceptible as everyone else to forming fake memories, UC Irvine psychologists and neurobiologists have found.

In a series of tests to determine how false information can manipulate memory formation, the researchers discovered that subjects with highly superior autobiographical memory logged scores similar to those of a control group of subjects with average memory.

“Finding susceptibility to false memories even in people with very strong memory could be important for dissemination to people who are not memory experts. For example, it could help communicate how widespread our basic susceptibility to memory distortions is,” said Lawrence Patihis, a graduate student in psychology & social behavior at UC Irvine. “This dissemination could help prevent false memories in the legal and clinical psychology fields, where contamination of memory has had particularly important consequences in the past.”

Patihis works in the research group of world-renowned psychologist Elizabeth Loftus, who pioneered the study of false memories and their implications.

Persons with highly superior autobiographical memory (HSAM, also known as hyperthymesia) – which was first identified in 2006 by scientists at UC Irvine’s Center for the Neurobiology of Learning & Memory – have the astounding ability to remember even trivial details from their distant past. This includes recalling daily activities of their life since mid-childhood with almost 100 percent accuracy.

The lead researcher on the study, Patihis believes it’s the first effort to test malleable reconstructive memory in HSAM individuals.

Working with neurobiology & behavior graduate student Aurora LePort, Patihis asked 20 people with superior memory and 38 people with average memory to do word association exercises, recall details of photographs depicting a crime, and discuss their recollections of video footage of the United Flight 93 crash on 9/11. (Such footage does not exist.) These tasks incorporated misinformation in an attempt to manipulate what the subjects thought they had remembered.

“While they really do have super-autobiographical memory, it can be as malleable as anybody else’s, depending on whether misinformation was introduced and how it was processed,” Patihis said. “It’s a fascinating paradox. In the absence of misinformation, they have what appears to be almost perfect, detailed autobiographical memory, but they are vulnerable to distortions, as anyone else is.”

He noted that there are still many mysteries about people with highly superior autobiographical memory that need further investigation. LePort, for instance, is studying forgetting curves (which involve how many autobiographical details people can remember from one day ago, one week ago, one month ago, etc., and how the number of details decreases over time) in both HSAM and control participants and will employ functional MRI to better understand the phenomenon.

“What I love about the study is how it communicates something that memory distortion researchers have suspected for some time: that perhaps no one is immune to memory distortion,” Patihis said. “It will probably make some nonexperts realize, finally, that if even memory prodigies are susceptible, then they probably are too. This teachable moment is almost as important as the scientific merit of the study. It could help educate people – including those who deal with memory evidence, such as clinical psychologists and legal professionals – about false memories.”

The study appears this week in the early online version of Proceedings of the National Academy of Sciences.