Neuroscience

Study finds fog-like condition related to chemotherapy’s effect on new brain cells and rhythms.

It’s not unusual for cancer patients being treated with chemotherapy to complain about not being able to think clearly, connect thoughts or concentrate on daily tasks. The complaint – often referred to as chemo-brain – is common. The scientific cause, however, has been difficult to pinpoint.

New research by Rutgers University behavioral neuroscientist Tracey Shors offers new clues for this fog-like condition, medically known as chemotherapy-induced cognitive impairment. In a featured article published in the European Journal of Neuroscience, Shors and her colleagues argue that prolonged chemotherapy decreases the development of new brain cells, a process known as neurogenesis, and disrupts ongoing brain rhythms in the part of the brain responsible for making new memories. Both, she says, are affected by learning and in some cases are necessary for learning to occur.

“One of the things that these brain rhythms do is to connect information across brain regions,” says Shors, Professor II in the Department of Psychology and Center for Collaborative Neuroscience at Rutgers. “We are starting to have a better understanding of how these natural rhythms are used in the process of communication and how they change with experience.”

Working in the Shors laboratory, postdoctoral fellow Miriam S. Nokia from the Department of Psychology at the University of Jyvaskyla in Finland and Rutgers neuroscience graduate student Megan Anderson treated rats with a chemotherapy drug – temozolomide (TMZ) – used on individuals with either malignant brain tumors or skin cancer to stop rapidly dividing cells that have gone out of control and resulted in cancer.

In this study, scientists found that the production of new healthy brain cells treated with the TMZ was reduced in the hippocampus by 34 percent after being caught in the crossfire of the drug’s potency. The cell loss, coupled with the interference in brain rhythms, resulted in the animal being unable to learn difficult tasks.

Shors says the rats had great difficulty learning to associate stimulus events if there was a time gap between the activities but could learn simple task if the stimuli were not separated in time.  Interestingly, she says, the drug did not disrupt the memories that were already present when the treatment began.

For cancer patients undergoing long-term chemotherapy this could mean that although they are able to do simple everyday tasks, they find it difficult to do more complicated activities like processing long strings of numbers, remembering recent conversations, following instructions and setting priorities. Studies indicate that while most cancer patients experience short-term memory loss and disordered thinking, about 15 percent of cancer patients suffer more long-lasting cognitive problems as a result of the chemotherapy treatment.

“Chemotherapy is an especially difficult time as patients are learning how to manage their treatment options while still engaging in and appreciating life. The disruptions in brain rhythms and neurogenesis during treatment may explain some of the cognitive problems that can occur during this time. The good news is that these effects are probably not long-lasting,” says Shors.

A University of Illinois study has established a possible link between high-fat diets and such childhood brain-based conditions as attention deficit hyperactivity disorder (ADHD) and memory-dependent learning disabilities.

“We found that a high-fat diet rapidly affected dopamine metabolism in the brains of juvenile mice, triggering anxious behaviors and learning deficiencies. Interestingly, when methylphenidate (Ritalin) was administered, the learning and memory problems went away,” said Gregory Freund, a professor in the U of I College of Medicine and a member of the university’s Division of Nutritional Sciences.

The research was published in Psychoneuroendocrinology.

Freund said that altered dopamine signaling in the brain is common to both ADHD and the overweight or obese state. “And an increase in the number of dopamine metabolites is associated with anxiety behaviors in children,” he added.

Intrigued by the recent upsurge in both child obesity and adverse childhood psychological conditions, including impulsivity, depression, and ADHD, Freund’s team examined the short-term effects of a high-fat (60% calories from fat) versus a low-fat (10% calories from fat) diet on the behavior of two groups of four-week-old mice. A typical Western diet contains from 35 to 45 percent fat, he said.

“After only one week of the high-fat diet, even before we were able to see any weight gain, the behavior of the mice in the first group began to change,” he said.

Evidence of anxiety included increased burrowing and wheel running as well a reluctance to explore open spaces. The mice also developed learning and memory deficits, including decreased ability to negotiate a maze and impaired object recognition.

Switching mice from a high-fat to a low-fat diet restored memory in one week, he noted.

In mice that continued on the high-fat diet, impaired object recognition remained three weeks after the onset of symptoms. But Freund knows from other studies that brain biochemistry normalizes after 10 weeks as the body appears to compensate for the diet. At that point, brain dopamine has returned to normal, and mice have become obese and developed diabetes.

“Although the mice grow out of these anxious behaviors and learning deficiencies, the study suggests to me that a high-fat diet could trigger anxiety and memory disorders in a child who is genetically or environmentally susceptible to them,” he said.

Because the animals adapt to the high-fat fare, the scientists also hypothesized that abruptly removing fat from the diet might negatively affect anxiety, learning, and memory.

The researchers had expected that the high-fat diet would stimulate inflammation, which is associated with obesity, but they saw no evidence of an inflammatory response in the brain after one or three weeks on the high-fat regimen.

Instead, they saw evidence that a high-fat diet initiates chemical responses that are similar to the ones seen in addiction, with dopamine, the chemical important to the addict’s pleasurable experiences, increasing in the brain.

Supposedly ‘primitive’ reflexes may involve more sophisticated brain function than previously thought, according to researchers at Imperial College London.

The vestibular-ocular reflex (or VOR), common to most vertebrates, is what allows us to keep our eyes focused on a fixed point even while our heads are moving. Up until now, scientists had assumed this reflex was controlled by the lower brainstem, which regulates eating, sleeping and other low-level tasks.

Researchers at Imperial’s Division of Brain Sciences conducted tests to examine this reflex in left- and right-handed subjects, revealing that handedness plays a key role in the way it operates. This suggests that higher-level functions in the cortex, which govern handedness, are involved in the control of primitive reflexes such as the VOR.

The research, published in the Journal of Neuroscience, involved seating volunteers in a motorised chair which was then spun around at a speed of one revolution every four seconds. This allowed the experimenters to study the VOR by measuring the time it took for the eyes to adjust to the spinning motion. The subjects were then presented with what are known as bistable visual phenomena, optical illusions which appear to flip between two images. Famous examples include the duck which resembles a rabbit, and the cube outline which appears to come out of and go into the page simultaneously.

Scientists already know that this bistable perception is controlled by a part of the cortex which governs more complex, decision-based tasks. Because of this, researcher Qadeer Arshad and his colleagues did not expect to find any link between the two processes.

They were surprised to find that processing bistable phenomena disrupted people’s ability to stabilise their gaze, following rightward rotation in right handers and leftward rotation in left handers. Arshad said “This is the first time that anything of this kind has been shown. Up until now, the vestibular-ocular reflex was considered a low-level reflex, not even approaching higher-order brain function. Now it seems that this primitive reflex was specialised into the cortex, the part of the brain which governs our sense of direction.”

This study could help scientists understand why some people become dizzy through experiencing purely visual stimuli, such as flickering lights or busy supermarket aisles. Professor Adolfo Bronstein, a co-author on the paper, said “Most causes of dizziness start with an inner ear - or vestibular - disorder but this initial phase tends to settle quite rapidly.  In some patients, however, dizziness becomes a problematic long term problem and their dizziness becomes visually induced. The experimental set-up we used would be ideally suited to help us understand how visual stimuli could lead to long-term dizziness. In fact, we have already carried out research at Imperial around using complex visual stimuli to treat patients with long-term dizziness”

A significant number of blind humans, not unlike bats and dolphins, can localize silent objects in their environment simply by making clicking sounds with their mouth and listening to the returning echoes. Some of these individuals have honed this skill to such a degree that they are not only able to localize an object, they are able to recognize the object’s size and shape – and even identify the material it is made from.

Researchers at Western University’s Brain and Mind Institute (BMI) used functional magnetic resonance imaging (fMRI) to study the brain of renowned blind echolocator Daniel Kish as he listened to recordings of his own mouth clicks and the echoes reflected back from different objects.

The results of this study, which was carried out in collaboration with colleagues based in Durham University in the U.K., the Rotman Research Institute at the Baycrest Hospital in Toronto, and World Access for the Blind, a not-for-profit organization based in California, appeared this week in the journal Neuropsychologia. In keeping with the previous research from this group, the researchers found that areas in Kish’s brain that were activated by the echoes corresponded to visual areas in the sighted brain.

But what has senior author and BMI Director Mel Goodale most excited about the new findings is that the particular areas in Kish’s brain that extract echo-based information about object shape are located in exactly the same brain regions that are activated by visual shape cues in the sighted brain.

"This work is shedding new light on just how plastic the human brain really is," says Goodale.

Lead author Stephen Arnott of Baycrest’s Rotman Research Institute explains, “This study implies that the processing of echoes for object shape in the blind brain can take advantage of the brain’s predisposition to process particular object features, such as shape, in particular brain regions – even though the sensory system conveying that information is very different.”

Kish lost both his eyes to cancer when he was only one-year old and taught himself to echolocate when he was a toddler. Interestingly, two other blind individuals who learned to echolocate much later in life do not show nearly the same level of brain activation in these ‘visual’ object areas as Kish.

Learning, memory and habits are encoded in the strength of connections between neurons in the brain, the synapses. These connections aren’t meant to be fixed, they’re changeable, or plastic.

Duke University neurologist and neuroscientist Nicole Calakos studies what happens when those connections aren’t as adaptable as they should be in the basal ganglia, the brain’s “command center” for turning information into actions.

"The basal ganglia is the part of the brain that drives the car when you’re not thinking too hard about it," Calakos said. It’s also the part of the brain where neuroscientists are looking for the roots of obsessive-compulsive disorder, Huntington’s, Parkinson’s, and aspects of autism spectrum disorders.

In her most recent work, which she’ll discuss Saturday morning, Feb. 16 at the American Association for the Advancement of Science annual meeting in Boston, Calakos is mapping the defects in circuitry of the basal ganglia that underlie compulsive behavior. She is studying mice that have a synaptic defect that manifests itself as something like obsessive-compulsive behavior.

Calakos’ former colleague Guoping Feng developed the mice at Duke before moving to the McGovern Institute for Brain Research at MIT, where he now works. Feng was exploring the construction of synapses by knocking out genes one at a time. One set of mice ended up with facial lesions from endlessly grooming themselves until their faces were rubbed raw. When examining synaptic activity in the basal ganglia of these mice, Calakos’ group discovered that metabotropic glutamate receptors, or mGluRs, were overactive and this in turn, left their synapses less able to change. Scientists think overactivity of these receptors can cause many aspects of the autistic spectrum disorder Fragile X mental retardation.

"It’s an example of synaptic plasticity going awry," Calakos said. "They’re stuck with less adaptable synapses." Calakos is now using the mice to determine whether drugs that inhibit mGluRs can be used to improve their behavior and testing whether the circuit defects are a generalizable explanation for similar behaviors in other mouse models. This work may then lead to new understandings for compulsive behaviors and new treatment opportunities.

Cynthia Thompson, a world-renowned researcher on stroke and brain damage, will discuss her groundbreaking research on aphasia and the neurolinguistic systems it affects Feb. 16 at the annual meeting of the American Association for the Advancement of Science (AAAS). An estimated one million Americans suffer from aphasia, affecting their ability to understand and/or produce spoken and/or written language.

For three decades, Thompson has played a crucial role in demonstrating the brain’s plasticity, or ability to change. “Not long ago, the conventional wisdom was that people only could recover language within three months to a year after the onset of stroke,” she says. “Today we know that, with appropriate training, patients can make gains as much as 10 years or more after a stroke.”

Thompson has probably contributed more findings on the effects of brain damage on language processing and the ways the brain and language recover from stroke than any other single researcher. Her particular interest is agrammatic aphasia, which impairs abstract knowledge of grammatical sentence structure and makes sentence production and understanding difficult.

Among the first researchers to use functional magnetic resonance imaging to study recovery from stroke, Thompson found that behavior treatment that focused on improving impaired language processing affects not only the ability to understand and produce language but also brain activity.

She found shifts in neural activity in both cerebral hemispheres associated with recovery, with the greatest recovery seen in undamaged brain regions within the language network engaged by healthy people, albeit regions recruited for various language activities.

"It’s a matter of ‘use it or lose it,’" Thompson says. "The brain has the capacity to learn and relearn throughout life, and it is directly affected by the activities we engage in. Language training that focuses on principles of normal language processing stimulates the recovery of neural networks that support language."

Thompson will discuss research she will conduct as principal investigator of a $12 million National Institutes of Health Clinical Research Center award to study biomarkers of recovery in aphasia.

Working with investigators from a number of universities, Thompson will explore the role blood flow plays in language recovery in chronic stroke patients. In addition, she will conduct cutting-edge, exploratory research using eye tracking to understand how people compute language as they hear it in real time. Eye-tracking techniques have been found to discern subtle problems underlying language deficits in acquired aphasia.

In a landmark 2010 study, she and colleagues discovered two critical variables related to understanding brain damage recovery. They found that stroke not only results in cell death in certain regions of the brain but that it also decreases blood flow (perfusion) to living cells that are adjacent (and sometimes even distant) to the lesion.

Until that study, hypoperfusion (diminished blood flow) was thought only to be associated with acute stroke. Her team also found that greater hypoperfusion led to poorer recovery.

Mice with many of the pathologies of Alzheimer’s Disease showed fewer signs of the disease when given a protein-restricted diet supplemented with specific amino acids every other week for four months.

Mice at advanced stages of the disease were put on the new diet. They showed improved cognitive abilities over their non-dieting peers when their memory was tested using mazes. In addition, fewer of their neurons contained abnormal levels of a damaged protein, called “tau,” which accumulates in the brains of Alzheimer’s patients.

Dietary protein is the major dietary regulator of a growth hormone known as IGF-1, which has been associated with aging and diseases in mice and several diseases in older adults.

Upcoming studies by USC Professor Valter Longo, the study’s corresponding author, will attempt to determine whether humans respond similarly – while simultaneously examining the effects of dietary restrictions on cancer, diabetes and cardiac disease.

"We had previously shown that humans deficient in Growth Hormone receptor and IGF-I displayed reduced incidence of cancer and diabetes. Although the new study is in mice, it raises the possibility that low protein intake and low IGF-I may also protect from age-dependent neurodegeneration," said Longo, who directs the Longevity Institute of the USC Davis School of Gerontology and has a joint appointment the USC Dornsife College of Letters, Arts and Sciences.

Longo worked with Pinchas Cohen, dean of the USC Davis School, as well as USC graduate students Edoardo Parrella, Tom Maxim, Lu Zhang, Junxiang Wan and Min Wei; Francesca Maialetti of the Istituto Superiore di Sanità in Rome; and Luigi Fontana of Washington University in St. Louis.

"Alzheimer’s Disease and other forms of neurodegeneration are a major burden on society, and it is a rising priority for this nation to develop new approaches for preventing and treating these conditions, since the frequencies of these disorders will be rising as the population ages over the next several decades," said Cohen, who became dean of the School of Gerontology in summer 2012. "New strategies to address this, particularly non-invasive, non-pharmacological approaches such as tested in Dr. Longo’s study are particularly exciting."

The results of their study were published online by Aging Cell last month.

The team found that a protein-restricted diet reduced levels of IGF-1 circulating through the body by 30 to 70 percent, and caused an eight-fold increase in a protein that blocks IGF-1’s effects by binding to it.

IGF-1 helps the body grow during youth but is also associated with several diseases later in life in both mice and humans. Exploring dietary solutions to those diseases as opposed to generating pharmaceuticals to manipulate IGF-1 directly allows Longo’s team to make strides that could help sufferers today or in the next few years.

"We always try to do things for people who have the problem now," Longo said. "Developing a drug can take 15 years of trials and a billion dollars.

"Although only clinical trials can determine whether the protein-restricted diet is effective and safe in humans with cognitive impairment, a doctor could read this study today and, if his or her patient did not have any other viable options, could consider introducing the protein restriction cycles in the treatment – understanding that effective interventions in mice may not translate into effective human therapies," he said.

Many elderly individuals may have already be frail, have lost weight or may not be healthy enough to eat a protein-restricted diet every other week. Longo strongly insisted that any dieting be monitored by a doctor or registered dietician to make sure that patients do not become amino acid deficient, lose additional weight or develop other side effects.

New research sheds light on how the brain encodes objects with multiple features, a fundamental task for the perceptual system. The study, published in Psychological Science, a journal of the Association for Psychological Science, suggests that we have limited ability to perceive mixed color-shape associations among objects that exist in several locations.

Research suggests that neurons that encode a certain feature — shape or color, for example — fire in synchrony with neurons that encode other features of the same object. Psychological scientists Liat Goldfarb of the University of Haifa and Anne Treisman of Princeton University hypothesized that if this neural-synchrony explanation were true, then synchrony would be impossible in situations in which the same features are paired differently in different objects.

Say, for example, a person sees a string of letters, “XOOX,” and the letters are printed in alternating colors, red and green. Both letter shape and letter color need to be encoded, but the associations between letter shape and letter color are mixed (i.e., the first X is red, while the second X is green), which should make neural synchrony impossible.

“The perceptual system can either know how many Xs there are or how many reds there are, but it cannot know both at the same time,” Goldfarb and Treisman explain.

The researchers investigated their hypothesis in two experiments, in which they presented participants with strings of green and red Xs and Os and asked them to compare the number of Xs with the number of red letters (i.e., more Xs, more reds, or the same).

Participants’ responses to unique color-shape associations were significantly faster and more accurate than were their responses to displays with mixed color-shape associations.

The results show that relevant color and shape dimensions could be synchronized when the pairings between color and shape were unique, but not when the pairings were mixed.

These findings demonstrate a new behavioral principle that governs object representation. When shapes are repeated in several locations and have mixed color-shape associations, they are hard to perceive.

This research expands on Anne Treisman’s groundbreaking research on feature integration in visual perception, which shows that humans can encode characteristics such as color, form, and orientation, even in the absence of spatial attention.

Treisman is one of 12 scientists who received the National Medal of Science at the White House on February 1, 2013. The National Medal of Science, along with the National Medal of Technology and Innovation, is the highest honor that the US government grants to scientists, engineers, and inventors.