WHAT: National Institutes of Health (NIH) scientists investigating how prion diseases destroy the brain have observed a new form of the disease in mice that does not cause the sponge-like brain deterioration typically seen in prion diseases. Instead, it resembles a form of human Alzheimer’s disease, cerebral amyloid angiopathy, that damages brain arteries.

The study results, reported by NIH scientists at the National Institute of Allergy and Infectious Diseases (NIAID), are similar to findings from two newly reported human cases of the prion disease Gerstmann-Straussler-Scheinker syndrome (GSS). This finding represents a new mechanism of prion disease brain damage, according to study author Bruce Chesebro, M.D., chief of the Laboratory of Persistent Viral Diseases at NIAID’s Rocky Mountain Laboratories.

Prion diseases, also known as transmissible spongiform encephalopathies, primarily damage the brain. Prion diseases include mad cow disease or bovine spongiform encephalopathy in cattle; scrapie in sheep; sporadic Creutzfeldt-Jakob disease (CJD), variant CJD and GSS in humans; and chronic wasting disease in deer, elk and moose.

The role of a specific cell anchor for prion protein is at the crux of the NIAID study. Normal prion protein uses a specific molecule, glycophosphoinositol (GPI), to fasten to host cells in the brain and other organs. In their study, the NIAID scientists genetically removed the GPI anchor from study mice, preventing the prion protein from fastening to cells and thereby enabling it to diffuse freely in the fluid outside the cells.

The scientists then exposed those mice to infectious scrapie and observed them for up to 500 days to see if they became sick. The researchers documented signs typical of prion disease including weight loss, lack of grooming, gait abnormalities and inactivity. But when they examined the brain tissue, they did not observe the sponge-like holes in and around nerve cells typical of prion disease. Instead, the brains contained large accumulations of prion protein plaques trapped outside blood vessels in a disease process known as cerebral amyloid angiopathy, which damages arteries, veins and capillaries in the brain. In addition, the normal pathway by which fluid drains from the brain appeared to be blocked.

Their study, Dr. Chesebro says, indicates that prion diseases can be divided into two groups: those with plaques that destroy brain blood vessels and those without plaques that lead to the sponge-like damage to nerve cells. Dr. Chesebro says the presence or absence of the prion protein anchor appears to determine which form of disease develops.

The new mouse model used in the study and the two new human GSS cases, which also lack the usual prion protein cell anchor, are the first to show that in prion diseases, the plaque-associated damage to blood vessels can occur without the sponge-like damage to the brain. If scientists can find an inhibitor for the new form of prion disease, they might be able to use the same inhibitor to treat similar types of damage in Alzheimer’s disease, Dr. Chesebro says.

Psychosurgery is making a comeback. Recently published case series have shown encouraging results of so-called deep brain stimulation (DBS) in treatment-resistant obsessive-compulsive disorder, depressive disorders, and Tourette syndrome. In the current issue of Deutsches Ärzteblatt International, authors Jens Kuhn (University of Cologne) and Theo P J Gründer (Max Planck Institute, Cologne) and their co-authors provide an introduction to the method (Dtsch Arztebl Int 2010; 107(7)105-13).

In order to determine the clinical utility of DBS in psychiatric disorders, the authors evaluated therapeutic studies from 1980 to 2009. They found improvement rates of between 35% and 70% in treatment-resistant obsessive-compulsive disorder, depression, and Tourette syndrome. The rate of side effects associated with DBS was usually low and mostly reversible by modulating the stimulation parameters.

This favourable side effect profile is not all that surprising because DBS is a procedure that is well known; it has been in use for 20 years. In Parkinson’s disease and essential tremor, the method has proved to be so effective that it has been licensed as a therapeutic option for many years. To administer DBS, two electrodes are implanted into the patient that deliver continuous, high frequency, short electrical impulses, enabling modulation of the functional neuronal circuits. The electrodes are connected via a cable to an impulse generator, which is usually implanted below the collarbone.

Although DBS seems to offer new perspectives for the treatment of psychiatric disorders, further studies into its efficacy, mechanisms of action, and side effect profile and especially its long term course are needed.

UC Irvine neurobiologists are providing the first visual evidence that learning promotes brain health – and, therefore, that mental stimulation could limit the debilitating effects of aging on memory and the mind.

Using a novel visualization technique they devised to study memory, a research team led by Lulu Chen and Christine Gall found that everyday forms of learning animate neuron receptors that help keep brain cells functioning at optimum levels.

These receptors are activated by a protein called brain-derived neurotrophic factor, which facilitates the growth and differentiation of the connections, or synapses, responsible for communication among neurons. BDNF is key in the formation of memories.

“The findings confirm a critical relationship between learning and brain growth and point to ways we can amplify that relationship through possible future treatments,” says Chen, a graduate researcher in anatomy & neurobiology.

Study results appear in the early online edition of the Proceedings of the National Academy of Sciences for the week of March 1.

In addition to discovering that brain activity sets off BDNF signaling at the sites where neurons develop synapses, researchers determined that this process is linked to learning-related brain rhythms, called theta rhythms, vital to the encoding of new memories.

Theta rhythms occurring in the hippocampus involve numerous neurons firing synchronously at a rate of three to eight times per second. These rhythms have been associated with long-term potentiation, a cellular mechanism underlying learning and memory.

In rodent studies, the team found that both unsupervised learning and artificial application of theta rhythms triggered BDNF signaling at synapse creation sites.

“This relationship has implications for maintaining good brain health,” says Gall, a professor of anatomy & neurobiology. “There is evidence that theta rhythms weaken as we age, and our discoveries suggest that this can result in memory impairment. On the other hand, they suggest that staying mentally active as we age can keep neuronal BDNF signaling at a constant rate, which may limit memory and cognitive decline.”

Scientists are beginning to find out why people with Parkinson’s disease often feel socially awkward. Parkinson’s patients find it harder to recognize expressions of emotion in other people’s faces and voices, report two studies published by the American Psychological Association.

One of the studies raises questions about how deep brain stimulation, the best available treatment for patients who no longer respond to medication, more strongly affects the recognition of fear and sadness.

A neurodegenerative disorder, Parkinson’s causes tremors, stiffness and balance problems, as well as fairly frequent depression and dementia.

In the March issue of Neuropsychology, Heather Gray, PhD, and Linda Tickle-Degnen, PhD, report that people with Parkinson’s disease, compared with matched controls, often have difficulty discerning how others are feeling.

Their meta-analysis of 34 different studies using data from 1,295 participants shows a robust link between Parkinson’s and specific deficits in recognizing emotions, especially negative emotions, across different types of stimuli and tasks.

The meta-analysis, conducted at Harvard Medical School and Tufts University, found that patients typically had some degree of problem identifying emotion from faces and voices.

Further clarification is provided in a second study that showed that deep-brain stimulation, compared with medication, caused a consistently large deficit in the recognition of fear and sadness two key facial expressions that, when understood, aid survival. That study is published in the January issue of Neuropsychology.

Researchers led by Julie Péron, PhD, at the Centre Hospitalier Universitaire de Rennes in France, compared the ability of people with Parkinson’s in three different groups to recognize facial emotions: 24 advanced patients implanted with deep-brain stimulators after they didn’t respond or were sensitive to oral levodopa (the usual drug for the disease); 20 advanced patients given apomorphine hydrochloride by injection or infusion pump while they waited an implant; and 30 healthy controls.

Researchers tested all participants using standard photographs of facial expression before and three months after they were treated. Before implantation of the stimulators, all participants read facial expressions equally well.

Patients in the surgical group were implanted with stimulators, electrical devices that prod the brain’s subthalamic nucleus, a small, lens-shaped structure, to normalize the nerve signals that control movement. This nucleus is part of the basal ganglia system, which is thought to integrate movement, cognition and emotion.

Three months after treatment, only the patients with stimulators not the drug-treated patients or the healthy controls were significantly worse at recognizing fear and sadness. Patients with stimulators confused those expressions with others, such as surprise, or even no emotion. Medicated patients and healthy controls were either accurate about fear and sadness or occasionally mistook them for other negative emotions, such as disgust.

“Having Parkinson’s predisposes an individual to errors in emotion recognition,” said Gray. “The research in France, along with previous studies, indicates that deep-brain stimulation produces an even more severe deficit.”

Why would treating a movement disorder affect the perception of emotions? Implants affect a part of the brain that reaches across functions, so the authors suggested that the same electrical stimulation that calms over-excited motor activity may also somehow inhibit emotional processing.

Although the impact of Parkinson’s and deep-brain stimulation varies by patient, it’s important to understand. “The first step is to educate patients and their close associates about the potential for emotion recognition difficulties, so they can learn to manage some of the social consequences, such as misunderstanding and frustration,” said Gray and Tickle-Degnen. The next step might be training in emotion recognition, which they said has shown promise.

The next advance in treating major depression may relate to a group of brain chemicals that are involved in virtually all our brain activity, according to a study published in Biological Psychiatry. The study is co-authored by Drs. Andrea J. Levinson and Zafiris J. Daskalakis of the Centre for Addiction and Mental Health (CAMH).

This study shows that compared to healthy individuals, people who have major depressive disorder have altered functions of the neurotransmitter GABA (gamma-aminobutyric acid). In the study, individuals with the most treatment-resistant forms of illness demonstrated the greatest reductions of GABA levels in the brain.

This points to the possibility that medications which correct a GABA imbalance could advance the treatment of major depressive disorder. Approximately 4% of Canadians experience major depressive disorder each year.

Several current medications for mood disorders correct imbalances in neurotransmitters such as serotonin and dopamine. However, many patients do not benefit from these medications. “Our findings build on the idea that some current medications do not help many patients because those drugs don’t affect the GABA-related brain chemistry,” says study author Dr. Andrea Levinson.

Applying the brakes

The GABA neurotransmitter and its receptors are involved in many different brain functions. Imbalances in GABA also are relevant to bipolar disorder, schizophrenia, and anxiety disorder.

The GABA neurotransmitter and its receptors are critical to how humans think and act, Dr. Levinson adds. “We apply so many conscious and unconscious perceptions and judgments to our actions at every second, without even realizing that we are doing so,” she says. “GABA is part of the brain system that allows us to fine-tune our moods, thoughts, and actions with an incredible level of detail.”

“It’s a little like driving a car. You need the accelerator, but at every stage you need the brakes to work. Some of our neurotransmitters apply the spark and the gas to the engine, and GABA supplies the brakes,” she says. “GABA provides the necessary inhibitory effect that we need in order to block out excessive brain activity that in depression may lead to excessive negative thinking.”

In addition, this study points to the reason why electroconvulsive therapy is still the most efficacious therapy for major depressive disorder, Dr. Levinson adds. “Electroconvulsive therapy may act on GABA brain chemicals in a way that can reset the balance,” she says.

Largest study to date

This study of 85 people is the largest such research effort on GABA and major depressive disorder to date. It compared four groups: 25 individuals with treatment-resistant depression, 16 with major depression who were unmedicated, 19 individuals with major depression who were successfully treated with medication and had normal mood, and a control group of 25 healthy individuals.

In all groups, a thumb twitch response to transcranial magnetic (brain) stimulation (TMS) was used to measure how GABA acts physiologically in the brain. GABA receptors were found to be dysfunctional in the three groups with major depressive disorder when compared to healthy subjects. In people who were the least responsive (treatment-resistant) to medications, the physiological effect of GABA in the brain was at its lowest.

Personalized medicine

“We are advancing the goal of a truly personalized medicine,” says study co-author Dr. Daskalakis. “It is intriguing to think that we may soon be able to apply simple brain stimulation to identify which treatments are most likely to help the individual person, eliminating the guesswork. That is, through these findings we may be able to one day determine who is and who is not going to respond to traditional pharmacological approaches to depression.”

Think back to your last fight with someone you love. How did you feel afterwards? How did you behave? Conflict with a loved one often leaves a person feeling terrible and then behaving badly. So much so that these scenarios have become soap opera clichés. After an argument, one partner may brood, slam the door, and then drive to a local bar to drown their sorrows in alcohol. These dramas rarely have happy endings. Given these stereotypes, how do people control their emotional reactions and prevent emotional storms and their attendant use of intoxicating substances?

A new study published in Biological Psychiatry, by Elsevier, suggests that the lateral prefrontal cortex (LPFC) is a brain region that may help people to control their emotional reactions to negative facial expressions from their romantic partners.

Christine Hooker and her colleagues recruited healthy, adult participants in committed relationships. The research subjects viewed positive, negative, and neutral facial expressions of their partners during a brain scan. In an online daily diary, participants reported conflict occurrence, level of negative mood, rumination, and substance use.

They found that LPFC activity in response to the laboratory-based affective challenge predicted self-regulation after an interpersonal conflict in daily life. When there was no interpersonal conflict, LPFC activity was not related to mood or behavior the next day. However, when an interpersonal conflict did occur, LPFC activity predicted mood and behavior the next day, such that lower activity was related to higher levels of negative mood, rumination, and substance use.

The study findings suggest that low LPFC function may be a risk-factor for mood and behavioral problems after a stressful interpersonal event.

The constructive management of negative emotional states that emerge inevitably within romantic relationships can be a critical facet of coping with the world. These relationships frequently serve as emotional havens from the stresses of the working world. Yet these relationships also may augment rather than reduce life stress. When that happens, problematic behaviors such as over-eating and substance abuse may increase.

Dr. John Krystal, Editor of Biological Psychiatry, commented on the importance of these findings: “When activated in the context of intense emotion, it appears that the LPFC helps us to manage the intensity of negative emotions that emerge in social relationships. When this brain region does not efficiently activate or when the intensity of the conflict is very high, people need to learn behavioral strategies to cope with the emotional response. For some people this strategy can be as simple as counting to 10 before doing something that they might regret later.”

This study raises an important question. How can clinicians enhance the function of the LPFC when its function is compromised? Cognitive and behavioral strategies may be important treatment components.

As Dr. Hooker explained, their findings “suggest that imaging can provide potentially useful information about who may be vulnerable to mood and behavioral problems after a stressful event. We hope that future research will build on this idea and explore ways that imaging can be used to inform people about their emotional vulnerabilities.”

Researchers have successfully reconstructed 3-D hand motions from brain signals recorded in a non-invasive way, according to a study in the March 3 issue of The Journal of Neuroscience. This finding uses a technique that may open new doors for portable brain-computer interface systems. Such a non-invasive system could potentially operate a robotic arm or motorized wheelchair – a huge advance for people with disabilities or paralysis.

Until now, to reconstruct hand motions, researchers have used non-portable and invasive methods that place sensors inside the brain. In this study, a team of neuroscientists led by José Contreras-Vidal, PhD, of the University of Maryland, College Park, placed an array of sensors on the scalps of five participants to record their brains’ electrical activity, using a process called electroencephalography, or EEG. Volunteers were asked to reach from a center button and touch eight other buttons in random order 10 times, while the authors recorded their brain signals and hand motions. Afterward, the researchers attempted to decode the signals and reconstruct the 3-D hand movements.

“Our results showed that electrical brain activity acquired from the scalp surface carries enough information to reconstruct continuous, unconstrained hand movements,” Contreras-Vidal said.

The researchers found that one sensor in particular (of the 34 used) provided the most accurate information. The sensor was located over a part of the brain called the primary sensorimotor cortex, a region associated with voluntary movement. Useful signals were also recorded from another region called the inferior parietal lobule, which is known to help guide limb movement. The authors used these findings to confirm the validity of their methods.

This study has implications for future brain-computer interface technologies and for those already in existence. “It may eventually be possible for people with severe neuromuscular disorders, such as amyotrophic lateral sclerosis (ALS), stroke, or spinal cord injury, to regain control of complex tasks without needing to have electrodes implanted in their brains,” said Jonathan Wolpaw, MD, of the New York State Department of Health’s Wadsworth Center in Albany, who was unaffiliated with the study. “The paper enhances the potential value of EEG for laboratory studies and clinical monitoring of brain function.”

The findings could also help improve existing EEG-based systems designed to allow movement-impaired people to control a computer cursor with just their thoughts. These systems now require that users undergo extensive training sessions. Contreras-Vidal said the length of this training could be reduced and more effortless control achieved using the methods in this study.

New research shows women who don’t receive a clot-busting drug after a stroke fare worse than men who are not treated. The study is published in the March 2, 2010, print issue of Neurology®, the medical journal of the American Academy of Neurology.

“Women need to be treated for stroke as soon as possible,” said study author Michael D. Hill, MD, MSc, FRCPC, with the University of Calgary in Alberta, Canada. “We found that women who weren’t treated had a worse quality of life after stroke than men. However, the good news is that women who were treated responded just as well as men to the treatment.”

For the study, scientists examined information from a stroke database on 2,113 people who had experienced a stroke. Of those, 232 were treated with the clot-busting drug known as tissue plasminogen activator (tPA) and 44 percent were women. Men and women were separately placed in groups based on whether they received tPA within three hours after their stroke. After six months, the people were interviewed by phone about their ability to function and quality of life.

The study found that women who did not receive the clot-busting drug were 12 percent less likely than men to have a good outcome six months later, or 58 percent of the women compared to 70 percent of men. However, women who were treated with these medications fared about the same as men who took the clot-buster drug.

“There could be many reasons why women who weren’t treated with the clot-busting drug fared worse than men, including biological reasons,” said Hill. “One social reason may be that more than 30 percent of women were widowed compared to seven percent of men at the time of stroke, and therefore did not have a spouse who could act as a caregiver. Also, post-stroke depression is more common in women than in men, which slows down recovery.”

New findings by researchers at UNC Lineberger Comprehensive Cancer Center suggest that the most common form of malignant brain cancer in adults, glioblastoma multiforme (GBM), is probably not a single disease but a set of diseases, each with a distinct underlying molecular disease process. The study, published by Cell Press in the January issue of the journal Cancer Cell, provides a solid framework for investigation of future targeted therapies that may improve the near uniformly fatal prognosis of this devastating cancer.

“Previous work has established that gene expression profiling can be used to identify distinct subgroups of GBM,” says senior study author, Dr. D. Neil Hayes from the Division of Hematology/Oncology at the University of North Carolina at Chapel Hill. “However, the exact number and clinical significance of these was unclear.” Dr. Hayes and colleagues at UNC Lineberger expanded on previous GBM classification studies and used expression profiling techniques to comprehensively analyze hundreds of GBM patient samples. The group was able to reliably identify four distinct molecular subtypes of GBM tumors.

The researchers then went on to perform a unique integrative analyses across multiple platforms to look for defining characteristics associated with each subtype. Their findings were quite striking, implying that there are distinct types of GBM and that each one is associated with a specific molecular process. “We discovered a bundle of events that unequivocally occur almost exclusively within a subtype,” explains Dr. Hayes.

The researchers also report that the nature of these events indicate that the underlying disease process for each subtype may involve distinct cells of origin at a specific stage of differentiation. This is finding has potential clinical significance as determining the cells of origin of GBM is critical for establishing effective treatment regimens. Clearly, given this new information, it makes sense that some drug classes would be expected to work for some tumor subtypes and not other. In support of this conclusion, Dr. Hayes’s group found that response to aggressive chemotherapy and radiation differed by subtype.

Taken together, the findings represent an important step towards more rational therapies for GBM. “It appears that the simple classification into these four subtypes carries a rich set of associations for which there is no existing diagnostic test,” says Dr. Hayes “This comprehensive genomic and genetic-based classification of GBM should lay the groundwork from an improved molecular understanding of GBM pathway signaling that could ultimately result in personalized therapies for groups of patients with GBM.”

A recent study, published in the January issue of Mayo Clinic Proceedings , demonstrates that in elderly patients undergoing hip fracture repair under spinal anesthesia with propofol sedation, the prevalence of delirium can be decreased by 50 percent with light sedation, compared to deep sedation.

“These data show that, for every 3.5 to 4.7 patients treated in this manner, one incident of delirium will be prevented,” says Frederick Sieber, M.D., primary investigator of the study from the Department of Anesthesiology and Critical Care Medicine, Johns Hopkins Medicine in Baltimore. “Therefore, interventions capable of reducing the occurrence of postoperative delirium would be important from a public health perspective.”

Several demographic and perioperative variables are associated with postoperative delirium in elderly patients after hip fracture repair. The most important is preoperative dementia. Other risk factors for postoperative delirium include age, systemic disease and functionality. Inhalational and intravenous anesthetics, opioids, benzodiazepines and anticholinergic drugs are all known or suspected risk factors for postoperative delirium.

Although postoperative delirium usually resolves within 48 hours of onset, delirium can persist and is associated with poor functional recovery, increased length of stay in hospitals, higher costs, and greater likelihood of placement in an assisted-living facility after surgery.

In addition to decreasing the prevalence of delirium, lighter sedation in this group of elderly surgical patients was associated with a reduction in delirium that averaged almost one day for each patient in the light sedation group. The effects of lighter sedation were observed in patients with or without preoperative cognitive dysfunction.

Limiting depth of sedation during spinal anesthesia is a simple, safe and cost-effective intervention for preventing postoperative delirium in elderly patients that could be widely and readily adopted, say Dr. Sieber.