Neuroscience

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.

For many patients with difficult-to-treat neuropathic pain, deep brain stimulation (DBS) can lead to long-term improvement in pain scores and other outcomes, according to a study in the February issue of Neurosurgery, official journal of the Congress of Neurological Surgeons. The journal is published by Lippincott Williams & Wilkins, a part of Wolters Kluwer Health.

About two-thirds of eligible patients who undergo DBS achieve significant and lasting benefits in terms of pain, quality of life, and overall health, according to the report by Sandra G.J. Boccard, PhD, and colleagues of University of Oxford, led by Tipu Aziz FMedSci and Alex Green, MD. Some outcomes show continued improvement after the first year, according to the new report, which is one of the largest studies of DBS for neuropathic pain performed to date.

Most Patients Benefit from DBS for Neuropathic Pain

The authors reviewed their 12-year experience with DBS for neuropathic pain. Neuropathic pain is a common and difficult-to-treat type of pain caused by nerve damage, seen in patients with trauma, diabetes, and other conditions. Phantom limb pain after amputation is an example of neuropathic pain.

In DBS, a small electrode is surgically placed in a precise location in the brain. A mild electrical current is delivered to stimulate that area of the brain, with the goal of interrupting abnormal activity. Deep brain stimulation has become a standard and effective treatment for movement disorders such as Parkinson’s disease. Although DBS has also been used to treat various types of chronic pain, its role in patients with neuropathic pain remains unclear.

Between 1999 and 2011, that authors’ program evaluated 197 patients with chronic neuropathic pain for eligibility for DBS. Of these, 85 patients proceeded to DBS treatment. The remaining patients did not receive DBS—most commonly because they were unable to secure funding from the U.K. National Health Service or decided not to undergo electrode placement surgery.

The patients who underwent DBS were 60 men and 25 women, average age 52 years. Stroke was the most common cause of neuropathic pain, followed by head and face pain, spinal disease, amputation, and injury to nerves from the upper spinal cord (brachial plexus).

In 74 patients, a trial of DBS produced sufficient pain relief to proceed with implantation of an electrical pulse generator. Of 59 patients with sufficient follow-up data, 39 had significant improvement in their overall health status up to four years later. Thus, 66 percent of patients “gained benefit and efficacy” by undergoing DBS.

Benefits Vary by Cause; Some Outcomes Improve with Time

The benefits of DBS varied for patients with different causes of neuropathic pain. Treatment was beneficial for 89 percent for patients with amputation and 70 percent of those with stroke, compared to 50 percent of those with brachial plexus injury.

On average, scores on a 10-point pain scale (with 10 indicating the most severe pain) decreased from about 8 to 4 within the first three months, remaining about the same with longer follow-up. Continued follow-up in a small number of patients suggested further improvement in other outcomes, including quality-of-life scores.

Deep brain stimulation has long been regarded as potentially useful for patients with severe neuropathic pain that is not relieved by other treatments. However, because of the difficulties of performing studies of this highly specialized treatment, there has been relatively little research to confirm its benefits; only about 1,500 patients have been treated worldwide. The new study—accounting for about five percent of all reported patients—used up-to-date DBS technologies, imaging, and surgical techniques.

Dr. Boccard and coauthors acknowledge some important limitations of their study—especially the lack of complete patient follow-up. However, they believe their experience is sufficiently encouraging to warrant additional studies, especially with continued advances in stimulation approaches and technology. The researchers conclude, “Clinical trials retaining patients in long-term follow-up are desirable to confirm findings from prospectively assessed case series.”

A new type of prophylactic treatment for brain injury following prolonged epileptic seizures has been developed by Emory University School of Medicine investigators.

Status epilepticus, a persistent seizure lasting longer than 30 minutes [check this, some people say FIVE], is potentially life-threatening and leads to around 55,000 deaths each year in the United States. It can be caused by stroke, brain tumor or infection as well as inadequate control of epilepsy. Physicians or paramedics now treat status epilepticus by administering an anticonvulsant or general anesthesia, which stops the seizures.

Researchers at Emory have been looking for something different: anti-inflammatory compounds that can be administered after acute status epilepticus has ended to reduce damage to the brain. They have discovered a potential lead compound that can reduce mortality when given to mice after drug-induced seizures.

The results are scheduled for publication Monday in Proceedings of the National Academy of Sciences Early Edition.

"For adults who experience a period of status epilepticus longer than one hour, more than 30 percent die within four weeks of the event, making this a major medical problem," says Ray Dingledine, PhD, chair of the Department of Pharmacology at Emory University School of Medicine. "Medications that would reduce the severe consequences of refractory status epilepticus have been elusive. We believe we have an effective route to minimizing the brain injury caused by uncontrolled status epilepticus."

Dingledine’s laboratory has identified compounds that block the effects of prostaglandin E2, a hormone involved in processes such as fever, childbirth, digestion and blood pressure regulation. Prostaglandin E2 is also involved in the toxic inflammation in the brain arising after status epilepticus.

The first author of the paper is postdoctoral fellow Jianxiong Jiang, PhD, and the medicinal chemist largely responsible for developing the compounds is Thota Ganesh, PhD.

Jiang and colleagues induced status epilepticus in mice with the alkaloid drug pilocarpine, and gave them a compound, TG6-10-1, starting four hours later and again at 21 and 30 hours. TG6-10-1 blocks signals from EP2, one of four receptors for prostaglandin E2.

Among animals that received the EP2 blocker, 90 percent survived after one week, while 60 percent of a control group survived. The scientists also used nest-building behavior and weight loss as gauges of damage to the brain. Four days after status epilepticus, all the animals that received TG6-10-1 displayed normal nest-building, but more than a quarter of living control animals were not able to build nests. In addition, the brains of TG6-10-1-treated mice had reduced levels of inflammatory messenger proteins called cytokines, less brain injury and less breach of the blood-brain-barrier.

Consequences of refractory status epilepticus can include brain damage, difficulty breathing, abnormal heart rhythms and heart failure.

Dingledine says the first clinical test of an EP2 blocking compound would probably be as an add-on treatment for prolonged status epilepticus, several hours after seizures have ended. It could also be tested in similar situations such as subarachnoid hemorrhage, prolonged febrile seizures or medication-resistant epilepsy, he says.

Dingledine and his colleagues have a patent pending for novel technology related to this research. Under Emory policies, they are eligible to receive a portion of any royalties or fees received by Emory from this technology.