Archive for August 2008
Researchers at the University of Amsterdam (UvA) have demonstrated how much the brain can learn simply through active exposure to many different kinds of music. “More and more labs are showing that people have the sensitivity for skills that we thought were only expert skills,” Henkjan Honing (UvA) explains.
“It turns out that mere exposure makes an enormous contribution to how musical competence develops.”* The results were recently presented at the Music & Language conference, organized by Tufts University in Boston, and will be published in an upcoming issue of the Journal of Experimental Psychology: Human Performance and Perception.
The common view among music scientists is that musical abilities are shaped mostly by intense musical training, and that they remain rather rough in untrained listeners, the so-called Expertise hypothesis.
However, the UvA-study shows that listeners without formal musical training, but with sufficient exposure to a certain musical idiom (the Exposure hypothesis), perform similarly in a musical task when compared to formally trained listeners.
Furthermore, the results show that listeners generally do better in their preferred musical genre. As such the study provides evidence for the idea that some musical capabilities are acquired through mere exposure to music. Just listen and learn!
In addition, the study is one of the first that takes advance of the possibilities of online listening experiments comparing musicians and non-musicians of all ages.
*Eichler, J. (2008, July 13), ‘Can’t get it out of my head’, Boston Globe, p. N6.
Journal of Experimental Psychology: Human Perception and Performance. (in press)
Exposure influences expressive timing judgments in music.
Honing, H. & Ladinig, O.
Abstract (from the lead author’s hp)
This study is concerned with the question whether, and if so to what extent, listeners’ previous exposure to music in everyday life, and expertise as a result of formal musical training, play a role in making expressive timing judgments in music. This was investigated by using a Web-based listening experiment in which listeners with a wide range of musical backgrounds were asked to compare two different recordings of the same composition (fifteen pairs, grouped in three musical genres), one of which was tempo-transformed. The results show that expressive timing judgments are not influenced by expertise levels, as suggested by the expertise hypothesis, but by exposure to a certain musical idiom, as suggested by the exposure hypothesis. Apparently, frequent listening to a certain musical genre allows listeners, with and without formal musical training, to implicitly learn the timing patterns that are characteristic for that style, and to use this (implicit) knowledge to discriminate between a real and a tempo-transformed recording. As such, and in addition to what has recently been shown in the pitch domain (Bigand & Poulin-Charronnat, 2006), the current study provides evidence in the temporal domain for the idea that some musical capabilities are acquired through exposure to music, and that these abilities are more likely enhanced by active listening (exposure) than by formal musical training (expertise).
In a study that sheds new light on how memory and spatial cognition are related to each other in the brain, researchers at the University of California, San Diego School of Medicine and the Veteran Affairs (VA) San Diego Healthcare System studied memory-impaired patients as they navigated their environment.
Path integration, or the ability of the brain to compute the distance and direction of a traveled path, is an important aspect of spatial cognition – an ability long-thought to be dependent on the medial temporal lobe structures of the brain.
However, the researchers discovered that the hippocampus and entorhinal cortex – two major medial temporal lobe structures – are not essential for path integration. Their findings will be published in the early on line edition of Proceedings of the National Academy of Sciences (PNAS) the week of August 4.
The study, led by Larry R. Squire, Ph.D., professor of psychiatry, neurosciences and psychology at UCSD School of Medicine and research career scientist at the VA San Diego Healthcare System, was designed to measure whether these structures of the brain are essential for spatial cognition.
“For decades, the medial temporal lobe structures have been linked to both memory and spatial cognition,” said Squire. One important aspect of spatial cognition is keeping track of a reference location during movement by using internal cues, Squire explained, yet such tracking also relies on memory. “So we set out to test how these two abilities related to one another and to the temporal lobe area of the brain.”
The researchers looked at five memory-impaired patients with lesions of the medial temporal lobe along with seven matched controls, testing each for their path integration ability. Participants, who were blindfolded and wore noise-canceling earphones, were led by researchers on 16 paths and asked to keep their starting point in mind. After walking the path, participants were asked to point to their start location.
Due to their lesions, the five patients all had long-term memory impairment, so the paths were short enough that the task could be performed within the span of their working, or short-term, memory. Building on the idea that working memory is independent of the medial temporal lobe, the researchers theorized that these patients should succeed at the task if performed within the span of their short-term memory, unless this section of the brain was also necessary for spatial cognition.
The memory-impaired patients pointed to and estimated their distance from the start location as accurately as the controls.
“We concluded that the hippocampus and entorhinal cortex are not essential for path integration, since we showed that the tests could be successfully accomplished despite damage to these brain regions,” said Squire.
PNAS published ahead of print August 7, 2008, doi:10.1073/pnas.0805414105
Neural basis of the cognitive map: Path integration does not require hippocampus or entorhinal cortex
Yael Shrager, C. Brock Kirwan and Larry R. Squire
The hippocampus and entorhinal cortex have been linked to both memory functions and to spatial cognition, but it has been unclear how these ideas relate to each other. An important part of spatial cognition is the ability to keep track of a reference location using self-motion cues (sometimes referred to as path integration), and it has been suggested that the hippocampus or entorhinal cortex is essential for this ability. Patients with hippocampal lesions or larger lesions that also included entorhinal cortex were led on paths while blindfolded (up to 15 m in length) and were asked to actively maintain the path in mind. Patients pointed to and estimated their distance from the start location as accurately as controls. A rotation condition confirmed that performance was based on self-motion cues. When demands on long-term memory were increased, patients were impaired. Thus, in humans, the hippocampus and entorhinal cortex are not essential for path integration.
In a double-blind, placebo-controlled clinical trial to assess the impact of smoked medical cannabis, or marijuana, on the neuropathic pain associated with HIV, researchers at the University of California, San Diego School of Medicine found that reported pain relief was greater with cannabis than with a placebo.
The study, sponsored by the University of California Center for Medical Cannabis Research (CMCR) based at UC San Diego, will be published on line, August 6 in the journal Neuropsychopharmacology.
Led by Ronald J. Ellis, M.D., Ph.D., associate professor of neurosciences at UCSD School of Medicine, the study looked at 28 HIV patients with neuropathic pain not adequately controlled by other pain-relievers, including opiates. They took part in the controlled study as outpatients at the UCSD Medical Center. The proportion of subjects achieving pain reduction of 30 percent or more was greater for those smoking cannabis than those smoking the placebo.
“Neuropathy is a chronic and significant problem in HIV patients as there are few existing treatments that offer adequate pain management to sufferers,” Ellis said. “We found that smoked cannabis was generally well-tolerated and effective when added to the patient’s existing pain medication, resulting in increased pain relief.”
Each trial participant participated in five study phases over seven weeks. During two five-day phases, randomly selected participants smoked either cannabis or placebo cigarettes made from whole plant material with cannabinoids (the psychoactive compound found in marijuana) removed, both provided by the National Institute on Drug Abuse. Outcome was tested by standardized tests measuring analgesia (lessened pain sensation), improvement in function and relief of pain-associated emotional distress.
Using verbal descriptors of pain magnitude, cannabis was associated with an average reduction of pain intensity from ‘strong’ ‘to mild-to-moderate’ in cannabis smokers, according to Ellis. Also, cannabis was associated with a sizeable (46% versus 18% for placebo) proportion of patients reporting clinically meaningful pain relief.
The study’s findings are consistent with and extend other recent research supporting the short-term efficacy of cannabis for neuropathic pain, also sponsored by the CMCR.
“This study adds to a growing body of evidence that indicates that cannabis is effective, in the short-term at least, in the management of neuropathic pain,” commented Igor Grant, M.D., professor of psychiatry and director of the CMCR.
Grant noted that this is the fourth CMCR sponsored study to provide convergent evidence that cannabis can help in relieving these types of pain. The previous studies were conducted with CMCR support by Donald I. Abrams, M.D., Professor of Clinical Medicine at UCSF, who reported efficacy in short-term treatment of HIV neuropathy (Neurology, 2007, 68:515-521); by Mark Wallace, M.D., Program Director for the UCSD Center for Pain Medicine, who found that normal volunteers subjected to chemically induced pain which mimics neuropathy also responded to medium doses of cannabis (Anesthesiology, 2007, 107(5):785-796); and by Barth Wilsey, M.D., Director of the UC Davis Analgesic Research Center, who also reported benefit from smoked cannabis in a group of patients with neuropathy of multiple origins (Journal of Pain, 2008 Jun;9(6):506-21).
Neuropsychopharmacology advance online publication, August 6, 2008; doi:10.1038/npp.2008.120
Smoked Medicinal Cannabis for Neuropathic Pain in HIV: A Randomized, Crossover Clinical Trial
Ronald J Ellis, Will Toperoff, Florin Vaida, Geoffrey van den Brande, James Gonzales, Ben Gouaux, Heather Bentley and J Hampton Atkinson
Despite management with opioids and other pain modifying therapies, neuropathic pain continues to reduce the quality of life and daily functioning in HIV-infected individuals. Cannabinoid receptors in the central and peripheral nervous systems have been shown to modulate pain perception. We conducted a clinical trial to assess the impact of smoked cannabis on neuropathic pain in HIV. This was a phase II, double-blind, placebo-controlled, crossover trial of analgesia with smoked cannabis in HIV-associated distal sensory predominant polyneuropathy (DSPN). Eligible subjects had neuropathic pain refractory to at least two previous analgesic classes; they continued on their prestudy analgesic regimens throughout the trial. Regulatory considerations dictated that subjects smoke under direct observation in a hospital setting. Treatments were placebo and active cannabis ranging in potency between 1 and 8% Delta-9-tetrahydrocannabinol, four times daily for 5 consecutive days during each of 2 treatment weeks, separated by a 2-week washout. The primary outcome was change in pain intensity as measured by the Descriptor Differential Scale (DDS) from a pretreatment baseline to the end of each treatment week. Secondary measures included assessments of mood and daily functioning. Of 127 volunteers screened, 34 eligible subjects enrolled and 28 completed both cannabis and placebo treatments. Among the completers, pain relief was greater with cannabis than placebo (median difference in DDS pain intensity change, 3.3 points, effect size=0.60; p=0.016). The proportions of subjects achieving at least 30% pain relief with cannabis versus placebo were 0.46 (95%CI 0.28, 0.65) and 0.18 (0.03, 0.32). Mood and daily functioning improved to a similar extent during both treatment periods. Although most side effects were mild and self-limited, two subjects experienced treatment-limiting toxicities. Smoked cannabis was generally well tolerated and effective when added to concomitant analgesic therapy in patients with medically refractory pain due to HIV DSPN.
New research from The University of Western Ontario reveals how the brain processes the ‘rewarding’ and addictive properties of nicotine, providing a better understanding of why some people seemingly become hooked with their first smoke.
The research, led by Steven Laviolette of the Department of Anatomy and Cell Biology at the Schulich School of Medicine & Dentistry could lead to new therapies to prevent nicotine dependence and to treat nicotine withdrawal when smokers try to quit.
“Nicotine interacts with a variety of neurochemical pathways within the brain to produce its rewarding and addictive effects,” explains Laviolette. “However, during the early phase of tobacco exposure, many individuals find nicotine highly unpleasant and aversive, whereas others may become rapidly dependent on nicotine and find it highly rewarding. We wanted to explore that difference.”
The researchers found one brain pathway in particular uses the neurotransmitter ‘dopamine’ to transmit signals related to nicotine’s rewarding properties. This pathway is called the ‘mesolimbic’ dopamine system and is involved in the addictive properties of many drugs of abuse, including cocaine, alcohol and nicotine.
“While much progress has been made in understanding how the brain processes the rewarding effects of nicotine after the dependence is established, very little is known about how the mesolimbic dopamine system may control the initial vulnerability to nicotine; that is, why do some individuals become quickly addicted to nicotine while others do not, and in some cases, even find nicotine to be highly aversive.”
The scientists identified which specific dopamine receptor subtype controlled the brain’s initial sensitivity to nicotine’s rewarding and addictive properties and were able to manipulate these receptors to control whether the nicotine is processed as rewarding or aversive.
“Importantly, our findings may explain an individual’s vulnerability to nicotine addiction, and may point to new pharmacological treatments for the prevention of it, and the treatment of nicotine withdrawal,” says Laviolette. The research was funded by the Canadian Institutes of Health Research and the Canadian Psychiatric Research Foundation.
J. Neurosci. 2008 28: 8025-8033; doi:10.1523/JNEUROSCI.1371-08.2008
Dopamine Signaling through D1-Like versus D2-Like Receptors in the Nucleus Accumbens Core versus Shell Differentially Modulates Nicotine Reward Sensitivity
Steven R. Laviolette, Nicole M. Lauzon, Stephanie F. Bishop, Ninglei Sun, and Huibing Tan
Considerable evidence implicates the mesolimbic dopamine (DA) system in the processing of nicotine’s reinforcing properties, specifically the ventral tegmental area (VTA) and the terminal fields of VTA DAergic projections to the “core” (NAcore) and “shell” (NAshell) subdivisions of the nucleus accumbens (NAc). However, the specific roles of DA D1-like and D2-like receptor subtypes in nicotine reward processing within these NAc subregions have not been elucidated. We report that microinfusions of DA D1-like or D2-like receptor-specific antagonists into NAcore or NAshell double dissociate the rewarding and aversive properties of systemic or intra-VTA nicotine, and differentially regulate sensitivity to the rewarding properties as well as the motivational valence of either intra-VTA or systemic nicotine administration. Using a place conditioning procedure, NAshell infusions of a D2-like receptor antagonist switched the motivational valence of intra-VTA nicotine from aversive to rewarding and potentiated nicotine reward sensitivity to sub-reward threshold intra-VTA nicotine doses. In contrast, NAcore infusions of a D1-like receptor antagonist switched intra-VTA nicotine aversion to reward, and potentiated reward sensitivity to sub-reward threshold nicotine doses. Thus, D1-like versus D2-like receptors in NAcore versus NAshell subdivisions play functionally dissociable roles in modulating systemic or intra-VTA nicotine motivational processing.
Argos Therapeutics and Université de Montréal today announced the presentation of new information on Argos’process for developing dendritic cell-based immunotherapies for HIV.
Results from the study demonstrate that loading monocyte-derived dendritic cells with combinations of HIV antigen RNA stimulates the expansion of HIV-specific T cells, which attack and kill HIV-infected cells.
Argos’ immunotherapies are generated by the Company’s Arcelis™ technology, which is a platform for creating autologous, RNA-loaded dendritic cell-based therapies perfectly matched to each patient’s unique virus. These data were presented in an oral poster discussion August 5, 2008 at the XVII International AIDS Conference in Mexico City.
“A key step in the durable control of HIV infection requires enhancing the development of memory immune responses and the stimulation of potent cytotoxic T cells through therapeutic vaccination,” said Charles Nicolette, Ph.D., Chief Scientific Officer of Argos. “Working with our colleagues at the Université de Montréal, we have shown that Argos’ approach of transfecting dendritic cells with autologous, HIV-specific antigens effectively activates dendritic cells and enhances the HIV-specific T cell response. We believe that these results support our methods of developing potent immunotherapies that help patients’ immune systems more effectively fight HIV infection.”
The inability of the immune system to effectively mount a response against HIV may be caused by a defect in the maturation of T cell memory. To explore this hypothesis, researchers from Dr. Rafick-Pierre Sékaly’s laboratory at the Université de Montréal and Argos tested whether modified dendritic cells, derived from monocytes of HIV-infected individuals, could correct the defective maturation of HIV-specific CD8 T-cells responsible for virus eradication. To potentially improve the magnitude and quality of the anti-HIV T-cell response, maturing dendritic cells were transfected with mRNA-encoding autologous HIV sequences combined with mRNA encoding immune modulatory molecules. These modified dendritic cells were then tested for their ability to expand and mature T cell responses in vitro.
The results of these recent assessments, presented for the first time at the International AIDS Conference in Mexico, show that this novel product induces greater proliferation, maturation and differentiation of HIV-specific CD8 cells in vitro. These properties, especially expanding memory cells, required for long term protection against pathogens, may represent an improvement worthy of future of clinical development.
“We believe that this improvement may represent a significant step forward,” said Dr. Sékaly, professor of immunology at the Université de Montréal. “The fact that we can stimulate a specific, long-term immune response gives us great hope that, with additional development, we will be able to give people infected with HIV a new option to battle the virus.”
The abstract, titled, “The co-transfection of monocyte derived dendritic cells (DC) by different combinations of HIV antigen RNA and molecular adjuvant RNA enhanced the response of HIV-specific CD8+ T cells,” was authored by Oleg Yegorov, Bader Yassine-Diab, Tom Baumgartner, Harris Carpenter, Irina Tcherepanova, Don Healey, Charles Nicolette, and Rafick-Pierre Sékaly.
This work was funded in part with Federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under Contract No. N01-AI-60019.
About the Arcelis™ Technology
Arcelis is Argos’ proprietary technology for personalizing RNA-loaded dendritic cell immunotherapies for HIV, other infectious diseases, and cancer. This platform is based on optimizing a patient’s own (autologous) dendritic cells to trigger a pathogen- or tumor-specific immune response. To address the challenge of the unique genetic profile of each patient’s disease and the genetic mutations of that disease, Argos loads the autologous dendritic cells with a sample of messenger RNA (“mRNA”) isolated from their disease. Through this process, dendritic cells can potentially prime immune responses to the entire antigenic repertoire, resulting in an immunotherapeutic that is customized to the patient’s specific disease. The development of the Arcelis platform is part of Argos’ broad collaboration with Kirin Pharma Company, Ltd.
PLoS ONE. 2008 Jan 30;3(1):e1489.
Multiplex RT-PCR amplification of HIV genes to create a completely autologous DC-based immunotherapy for the treatment of HIV infection.
Tcherepanova I, Harris J, Starr A, Cleveland J, Ketteringham H, Calderhead D, Horvatinovich J, Healey D, Nicolette CA.
Research and Development Department, Argos Therapeutics, Inc., Durham, North Carolina, USA. email@example.com
BACKGROUND: Effective therapy for HIV-infected individuals remains an unmet medical need. Promising clinical trials with dendritic cell (DC)-based immunotherapy consisting of autologous DC loaded with autologous virus have been reported, however, these approaches depend on large numbers of HIV virions to generate sufficient doses for even limited treatment regimens. METHODOLOGY/PRINCIPAL FINDINGS: The present study describes a novel approach for RT-PCR amplification of HIV antigens. Previously, RT-PCR amplification of autologous viral sequences has been confounded by the high mutation rate of the virus which results in unreliable primer-template binding. To resolve this problem we developed a multiplex RT-PCR strategy that allows reliable strain-independent amplification of highly polymorphic target antigens from any patient and requires neither viral sequence data nor custom-designed PCR primers for each individual. We demonstrate the application of our RT-PCR process to amplify translationally-competent RNA encoding regions of Gag, Vpr, Rev and Nef. The products amplified using this method represent a complex mixture of autologous antigens encoded by viral quasispecies. We further demonstrate that DCs electroporated with in vitro-transcribed HIV RNAs are capable of stimulating poly-antigen-specific CD8+ T cell responses in vitro. CONCLUSION/SIGNIFICANCE: This study describes a strategy to overcome patient to patient viral diversity enabling strain-independent RT-PCR amplification of RNAs encoding sequence divergent quasispecies of Gag, Vpr, Rev and Nef from small volumes of infectious plasma. The approach allows creation of a completely autologous therapy that does not require advance knowledge of the HIV genomic sequences, does not have yield limitations and has no intact virus in the final product. The simultaneous use of autologous viral antigens and DCs may provoke broad patient-specific immune responses that could potentially induce effective control of viral loads in the absence of conventional antiretroviral drug therapy.
Happiness does not heal, but happiness protects against falling ill. As a result, happy people live longer. The size of the effect on longevity is comparable to that of smoking or not.
This is concluded from an analysis of 30 follow-up studies published in a recent issue of the Journal of Happiness Studies.
There have been more reports of happy people living longer, but for long it was unclear whether happiness causes longevity, since it can also be that good health add both to happiness and longevity.
Scientists assess causality using long-term follow-up studies, taking initial health into account. The results of such studies seemed contradictory; several studies found the expected causal effect of happiness on longevity, but other studies found no effect and some observed even earlier death among the happy. The analysis of 30 follow-up studies showed that the difference is in the people under investigation.
Happiness does not lengthen the life of seriously ill people, but it does prolong the life of healthy people. Happiness appears to protect against falling ill. One of the mechanisms behind that effect seems to be that chronic unhappiness causes stress, which on its turn reduces immune response.
Another possible mechanism is that happiness adds to the chance of adopting a healthy life style.
An implication of this finding is that public health can also be promoted by policies that aim at greater happiness for a greater number.
Journal of Happiness Studies Volume 9, Number 3 / September 2008
Healthy happiness: effects of happiness on physical health and the consequences for preventive health care
Is happiness good for your health? This common notion is tested in a synthetic analysis of 30 follow-up studies on happiness and longevity. It appears that happiness does not predict longevity in sick populations, but that it does predict longevity among healthy populations So, happiness does not cure illness but it does protect against becoming ill. The effect of happiness on longevity in healthy populations is remarkably strong. The size of the effect is comparable to that of smoking or not.
If so, public health can also be promoted by policies that aim at greater happiness of a greater number. That can be done by strengthening individual life-abilities and by improving the livability of the social environment. Some policies are proposed. Both ways of promoting health through happiness require more research on conditions for happiness.
UC Irvine researchers have identified the brain mechanism that switches off traumatic feelings associated with bad memories, a finding that could lead to the development of drugs to treat panic disorders.
Scientists from UCI and the University of Muenster in Germany found that a small brain protein called neuropeptide S is involved in erasing traumatic responses to adverse memories by working on a tiny group of neurons inside the amygdala where those memories are stored.
“The exciting part of this study is that we have discovered a completely new process that regulates the adverse responses to bad memories,” said Rainer Reinscheid, pharmacology and pharmaceutical sciences associate professor at UCI. “These findings can help the development of new drugs to treat conditions in which people are haunted by persistent fears, such as posttraumatic stress disorder or other panic disorders.” The study appears in the July 31 issue of Neuron.
In tests, scientists exposed mice to situations that caused adverse memories. The scientists saw that when NPS receptors in amygdala neurons are blocked, the traumatic responses to bad memories persisted longer. In turn, when scientists treated the mice with compounds activating these receptors, traumatic responses disappeared faster.
After a traumatic experience, environmental cues often become associated with the bad experience and re-exposure to the same environment can trigger fearful emotions or even panic attacks, according to Reinscheid.
Other research has shown that forgetting such negative experiences may require “new learning,” such as re-exposure to the place where the original experience occurred but this time without any harmful consequences. Reinscheid said this process, called the extinction of memories, occurs in both humans and laboratory animals such as mice. Until this study, scientists did not know about the specific neurons and molecules involved with extinction learning of fear memories in the brain.
Previous work by Reinscheid’s group has shown that NPS is involved in regulating wakefulness and anxiety. Last year, they found evidence that a particular genetic variant of the NPS receptor may increase vulnerability to panic disorder.
Neuron. 2008 Jul 31;59(2):298-310.
Neuropeptide S-mediated control of fear expression and extinction: role of intercalated GABAergic neurons in the amygdala.
A deficient extinction of memory is particularly important in the regime of fear, where it limits the beneficial outcomes of treatments of anxiety disorders. Fear extinction is thought to involve inhibitory influences of the prefrontal cortex on the amygdala, although the detailed synaptic mechanisms remain unknown. Here, we report that neuropeptide S (NPS), a recently discovered transmitter of ascending brainstem neurons, evokes anxiolytic effects and facilitates extinction of conditioned fear responses when administered into the amygdala in mice. An NPS receptor antagonist exerts functionally opposing responses, indicating that endogenous NPS is involved in anxiety behavior and extinction. Cellularly, NPS increases glutamatergic transmission to intercalated GABAergic neurons in the amygdala via presynaptic NPS receptors on connected principal neurons. These results identify mechanisms of NPS in the brain, a key role of intercalated neurons in the amygdala for fear extinction, and a potential pharmacological avenue for treating anxiety disorders.