Posts tagged neuroscience

Clinical trials of drug treatments for neurological diseases such as Alzheimer’s and Parkinson’s often fail because the animal studies that preceded them were poorly designed or biased in their interpretation, according to a new study from an international team of researchers. More stringent requirements are needed to assess the significance of animal studies before testing the treatments in human patients, the researchers say.

The team — led by John Ioannidis, MD, DSc, a professor of medicine at the Stanford University School of Medicine and an expert in clinical trial design — assessed the results of more than 4,000 animal studies in 160 meta-analyses of potential treatments for neurological disorders from Alzheimer’s disease, Parkinson’s disease, stroke, spinal-cord injury and a form of multiple sclerosis. (A meta-analysis is a study that compiles and assesses information and conclusions from many independent experiments of a treatment, or intervention, for a particular condition.).

They determined that only eight of the 160 studies of potential treatments yielded the statistically significant, unbiased data necessary to support advancing the treatment to clinical trials. In contrast, 108 of the treatments were deemed at least somewhat effective at the time they were published.

Ioannidis and his collaborators at the University of Edinburgh in Scotland and the University of Ioannina School of Medicine in Greece say that animal studies of potential interventions can be made more efficient and reliable by increasing average sample size, being aware of statistical bias, publishing negative results and making all the results of all experiments on the effectiveness of a particular treatment — regardless of their outcome — freely accessible to scientists.

"Some researchers have postulated that animals may not be good models for human diseases," said Ioannidis. "I don’t agree. I think animal studies can be useful and perfectly fine. The problem is more likely to be related to the selective availability of information about the studies conducted on animals." Although the researchers focused here on neurological disorders, they believe it is likely that similar bias exists in animal studies of other types of disorders.

Ioannidis, who directs the Stanford Prevention Research Center, is the senior author of the research, published online in PLoS Biology on July 16. Lecturer Konstantinos Tsilidis, PhD, and postgraduate fellow Orestis Panagiotou, MD, of the University of Ioannina share lead authorship of the study. Panagiotou is currently a researcher at the National Cancer Institute’s Division of Cancer Epidemiology and Genetics.

Ioannidis is known for his efforts to strengthen the way that research is planned, carried out and reported. He was called “one of the world’s foremost experts on the credibility of medical research” in a profile published in The Atlantic magazine in 2010. He outlined some of the problems he observed in a 2005 essay in PLoS-Medicine titled, “Why most published research findings are false.” The essay is one of the most-downloaded articles in the history of the Public Library of Science, according to the journal’s media relations office.

For the new study, Ioannidis and his colleagues evaluated results in a database of the thousands of animal studies compiled over the years through the CAMARADES initiative (Collaborative Approach to Meta-Analysis and Review of Animal Data in Experimental Studies), led by professor Malcolm MacLeod, PhD, from the University of Edinburgh, who is also a co-author of the study.

The team compared the number of experiments in the meta-analyses that would have been expected to yield positive results (based on their predicted statistical power) with the actual number of experiments with published positive results. The difference was striking: 919 expected versus the 1,719 that were published, implying that either negative results were not published, or that the results of the experiments were interpreted too optimistically.

"We saw that it was very common for these interventions to have published evidence that they would work," said Ioannidis. "It was extremely common to have results that suggest they would be effective in humans."

Furthermore, nearly half (46 percent) of the 160 meta-analyses showed evidence of small-study effects — a term used to describe the fact that a small study using fewer numbers of animals is more likely to find the intervention more effective than a larger study with many animals.

Ioannidis speculated that a reluctance to publish negative findings (that is, those that conclude that a particular intervention did not work any better than the control treatment) and a perhaps unconscious desire on the part of researchers to find a promising treatment has colored the field of neurological research. Obscuring access to studies that conclude a particular treatment is ineffective, while also publishing positive results that are likely to be statistically flawed, tilts the perception toward the potential effectiveness of an intervention and encourages unwarranted human clinical trials.

"There are no standard rules that guide a decision to move from animal studies into human clinical trials," said Ioannidis, who also holds C.F. Rehnborg Professorship at Stanford. "Sometimes interventions are tested in humans with very little evidence that they may be effective. Of the 160 analyses we studied, only eight had what we would call strong evidence of potential effectiveness with no hint of bias in the preliminary animal studies. And of these eight, only two have given positive results in humans."

Ioannidis believes the development of consortiums of groups of researchers studying a particular intervention, coupled with the free sharing of all data about its effectiveness, or lack thereof, is a good first step in reducing bias in animal studies.

"Under the current conditions, only a tiny proportion of interventions that have published some promising results in animals have shown to be at all effective in humans. For example, while dozens of treatments on ischemic or hemorrhagic stroke seem to work in the animal literature, almost none of them have worked in humans," said Ioannidis. "It is hard to believe we could not improve upon that translation record. If we raise the bar for moving into human trials, centralize researchers’ efforts and make all results available, it will be much easier for researchers to know whether they have a potential winner, and it would increase the efficiency of human clinical trials enormously."

(Source: med.stanford.edu)

Premenopausal women who aren’t interested in sex and are unhappy about this reality have distinctive blood flow patterns in their brains in response to explicit videos compared to women with normal sexual function, researchers report.

A study of 16 women – six with normal sexual function and 10 with clear symptoms of dysfunction – showed distinct differences in activation of brain regions involved in making and retrieving memories, and determining how attentive they are to their response to sexual stimuli, researchers report in the journal Fertility and Sterility.

Up to 20 percent of women may have this form of sexual dysfunction, called hypoactive sexual desire disorder, for which there are no proven therapies, said Dr. Michael P. Diamond, Chairman of the Department of Obstetrics and Gynecology at the Medical College of Georgia at Georgia Regents University.

Researchers hope that a clearer understanding of physiological differences in these women will provide novel therapy targets as well as a method to objectively assess therapies, said Diamond, the study’s senior author.

"There are site-specific alterations in blood flow in the brains of individuals with hypoactive sexual disorders versus those with normal sexual function," Diamond said. "This tells me there is a physiologic means of assessing hypoactive sexual desire and that as we move forward with therapeutics, whether it’s counseling or medications, we can look to see whether changes occur in those regions."

Viagra, developed in the 1990s as way to increase the heart rate of sick babies, was approved by the Food and Drug Administration in 1998 to also treat male impotence, a major cause of sexual dysfunction. While several more options for men have been developed since, no FDA-approved options are available for women experiencing hypoactive sexual desire, Diamond said. He notes that a possible critical flaw in developing and evaluating therapies for women may be the inability to objectively measure results, other than with a woman’s self-reporting of its impact on sexual activity.

Years ago, Diamond, a reproductive endocrinologist, became frustrated by the inability to help these women. In fact, many women did not bother discussing the issue with their physicians, possibly because it’s an awkward problem with no clear solutions, he said.

While still at Wayne State University, he and his colleagues began looking for objective measures of a woman’s sexual response, identifying sexually explicit film clips, then using functional magnetic resonance imaging, which measures real-time brain activation in response to a stimulus, to look at responses.

Their latest study links acquired hypoactive sexual desire disorder to a distinct pattern of blood flow in the brain, with significant activation of cortical structures involved in attention and reflection about emotion and mental state. Researchers noted that paying more attention to response to sexual stimuli already is implicated in sexual dysfunction. They also note activation of the anterior cingulate gyrus, an area involved in a broad range of emotions including homeostasis, pain, depression, and apathy. Another key area was the amygdala, which has a central role in processing emotion, learning, and memory.

Women with normal sexual function showed significantly greater activation of areas such as the right thalamus - a sort of relay station for handling sensory and motor input – that also plays a role in sexual arousal. They also experienced activation of the parahippocampal gyrus, involved in making and recalling memories. Interestingly, this area has been found to be more significantly activated in women with surgical menopause receiving hormone therapy.

Diamond notes that the official diagnosis of the sexual disorder requires distress regarding persistent disinterest in sex. Study participants were heterosexual, in stable relationships and had previously viewed sexually explicit images. Those with sexual dysfunction had a mean age of 37 versus 29 in the control group. Part of assessing blood flow patterns included also measuring baseline responses to neutral videos.

Next steps include taking these measurements in a larger number of women and beginning to use brain blood flow patterns to assess therapies, Diamond said.

(Source: eurekalert.org)

Whether you’re reading the paper or thinking through your schedule for the day, chances are that you’re hearing yourself speak even if you’re not saying words out loud. This internal speech — the monologue you “hear” inside your head — is a ubiquitous but largely unexamined phenomenon. A new study looks at a possible brain mechanism that could explain how we hear this inner voice in the absence of actual sound.

In two experiments, researcher Mark Scott of the University of British Columbia found evidence that a brain signal called corollary discharge — asignal that helps us distinguish the sensory experiences we produce ourselves from those produced by external stimuli — plays an important role in our experiences of internal speech.

The findings from the two experiments are published in Psychological Science, a journal of the Association for Psychological Science.

Corollary discharge is a kind of predictive signal generated by the brain that helps to explain, for example, why other people can tickle us but we can’t tickle ourselves. The signal predicts our own movements and effectively cancels out the tickle sensation.

And the same mechanism plays a role in how our auditory system processes speech. When we speak, an internal copy of the sound of our voice is generated in parallel with the external sound we hear.

“We spend a lot of time speaking and that can swamp our auditory system, making it difficult for us to hear other sounds when we are speaking,” Scott explains. “By attenuating the impact our own voice has on our hearing — using the ‘corollary discharge’ prediction — our hearing can remain sensitive to other sounds.”

Scott speculated that the internal copy of our voice produced by corollary discharge can be generated even when there isn’t any external sound, meaning that the sound we hear when we talk inside our heads is actually the internal prediction of the sound of our own voice.

If corollary discharge does in fact underlie our experiences of inner speech, he hypothesized, then the sensory information coming from the outside world should be cancelled out by the internal copy produced by our brains if the two sets of information match, just like when we try to tickle ourselves.

And this is precisely what the data showed. The impact of an external sound was significantly reduced when participants said a syllable in their heads that matched the external sound. Their performance was not significantly affected, however, when the syllable they said in their head didn’t match the one they heard.

These findings provide evidence that internal speech makes use of a system that is primarily involved in processing external speech, and may help shed light on certain pathological conditions.

“This work is important because this theory of internal speech is closely related to theories of the auditory hallucinations associated with schizophrenia,” Scott concludes.

A new study from neuroscientists at the Wayne State University School of Medicine provides the first novel insights into the neural origins of hot flashes in menopausal women in years. The study may inform and eventually lead to new treatments for those who experience the sudden but temporary episodes of body warmth, flushing and sweating.

The paper, “Temporal Sequencing of Brain Activations During Naturally Occurring Thermoregulatory Events,” by Robert Freedman, Ph.D., professor of psychiatry and behavioral neurosciences, founder of the Behavioral Medicine Laboratory and a member at the C.S. Mott Center for Human Growth and Development, and his collaborator, Vaibhav Diwadkar, Ph.D., associate professor of psychiatry and behavioral neurosciences, appears in the June issue of Cerebral Cortex, an Oxford University Press journal.

“The idea of understanding brain responses during thermoregulatory events has spawned many studies where thermal stimuli were applied to the skin. But hot flashes are unique because they are internally generated, so studying them presents unique challenges,” said Freedman, the study’s principal investigator. “Our participants had to lie in the MRI scanner while being heated between two body-size heating pads for up to two hours while we waited for the onset of a hot flash. They were heroic in this regard and the study could not have been conducted without their incredible level of cooperation.”

“Menopause and hot flashes are a significant women’s health issue of widespread general interest,” Diwadkar added. “However, understanding of the neural origins of hot flashes has remained poor. The question has rarely been assessed with in vivo functional neuroimaging. In part, this paucity of studies reflects the technical limitations of objectively identifying hot flashes while symptomatic women are being scanned with MRI. Nothing like this has been published because this is a very difficult study to do.”

During the course of a single year, 20 healthy, symptomatic postmenopausal women ages 47 to 58 who reported six or more hot flashes a day were scanned at the School of Medicine’s Vaitkevicius Imaging Center, located in Detroit’s Harper University Hospital.

The researchers collected skin conductance levels to identify the onset of flashes while the women were being scanned. Skin conductance is an electrical measure of sweating. The women were connected to a simple circuit passing a very small current across their chests, Diwadkar said. Changes in levels allowed researchers to identify a hot flash onset and analyze the concurrently acquired fMRI data to investigate the neural precedents and correlates of the event.

The researchers focused on regions like the brain stem because its sub regions, such as the medullary and dorsal raphe, are implicated in thermal regulation, while forebrain regions, such as the insula, have been implicated in the personal perception of how someone feels. They showed that activity in some brain areas, such as the brain stem, begins to rise before the actual onset of the hot flash.

“Frankly, evidence of fMRI-measured rise in the activity of the brain stem even before women experience a hot flash is a stunning result. When this finding is considered along with the fact that activity in the insula only rises after the experience of the hot flash, we gain some insight on the complexity of brain mechanisms that mediate basic regulatory functions,” Diwadkar said.

These results point to the plausible origins of hot flashes in specific brain regions. The researchers believe it is the first such demonstration in academic literature.

They are now evaluating the network-based interactions between the brain regions by using more complex modeling of the fMRI data. “We think that our study highlights the value of using well-designed fMRI paradigms and analyses in understanding clinically relevant questions,” Diwadkar said.

The researchers also are exploring possibilities for integrating imaging with treatment to examine whether specific pharmacotherapies for menopause might alter regional brain responses.

(Source: media.wayne.edu)

The trajectory of amyloid plaque buildup—clumps of abnormal proteins in the brain linked to Alzheimer’s disease—may serve as a more powerful biomarker for early detection of cognitive decline rather than using the total amount to gauge risk, researchers from Penn Medicine’s Department of Radiology suggest in a new study published online July 15 in the Journal of Neurobiology of Aging.

Amyloid plaque that starts to accumulate relatively early in the temporal lobe, compared to other areas and in particular to the frontal lobe, was associated with cognitively declining participants, the study found. “Knowing that certain brain abnormality patterns are associated with cognitive performance could have pivotal importance for the early detection and management of Alzheimer’s,” said senior author Christos Davatzikos, PhD, professor in the Department of Radiology, the Center for Biomedical Image Computing and Analytics, at the Perelman School of Medicine at the University of Pennsylvania.

Today, memory decline and Alzheimer’s—which 5.4 million Americans live with today—is often assessed with a variety of tools, including physical and bio fluid tests and neuroimaging of total amyloid plaque in the brain. Past studies have linked higher amounts of the plaque in dementia-free people with greater risk for developing the disorder. However, it’s more recently been shown that nearly a third of people with plaque on their brains never showed signs of cognitive decline, raising questions about its specific role in the disease.

Now, Dr. Davatzikos and his Penn colleagues, in collaboration with a team led by Susan M. Resnick, PhD, Chief, Laboratory of Behavioral Neuroscience at the National Institute on Aging (NIA), used Pittsburgh compound B (PiB) brain scans from the Baltimore Longitudinal Study of Aging’s Imaging Study and discovered a stronger association between memory decline and spatial patterns of amyloid plaque progression than the total amyloid burden.

“It appears to be more about the spatial pattern of this plaque progression, and not so much about the total amount found in brains. We saw a difference in the spatial distribution of plaques among cognitive declining and stable patients whose cognitive function had been measured over a 12-year period. They had similar amounts of amyloid plaque, just in different spots,” Dr. Davatzikos said. “This is important because it potentially answers questions about the variability seen in clinical research among patients presenting plaque. It accumulates in different spatial patterns for different patients, and it’s that pattern growth that may determine whether your memory declines.”

The team, including first author Rachel A. Yotter, PhD, a postdoctoral researcher in the Section for Biomedical Image Analysis, retrospectively analyzed the PET PiB scans of 64 patients from the NIA’s Baltimore Longitudinal Study of Aging whose average age was 76 years old. For the study, researchers created a unique picture of patients’ brains by combining and analyzing PET images measuring the density and volume of amyloid plaque and their spatial distribution within the brain. The radiotracer PiB allowed investigators to see amyloid temporal changes in deposition.

Those images were then compared to California Verbal Learning Test (CLVT) scores, among other tests, from the participants to determine the longitudinal cognitive decline. The group was then broken up into two subgroups: the most stable and the most declining individuals (26 participants).

Despite lack of significant difference in the total amount of amyloid in the brain, the spatial patterns between the two groups (stable and declining) were different, with the former showing relatively early accumulation in the frontal lobes and the latter in the temporal lobes.   

A particular area of the brain may be affected early or later depending on the amyloid trajectory, according to the authors, which in turn would affect cognitive impairment. Areas affected early with the plaque include the lateral temporal and parietal regions, with sparing of the occipital lobe and motor cortices until later in disease progression.

“This finding has broad implications for our understanding of the relationship between cognitive decline and resistance and amyloid plaque location, as well as the use of amyloid imaging as a biomarker in research and the clinic,” said Dr Davatzikos. “The next step is to investigate more individuals with mild cognitive impairment, and to further investigate the follow-up scans of these individuals via the BLSA study, which might shed further light on its relevance for early detection of Alzheimer’s.”

(Source: uphs.upenn.edu)

A little bit of learned fear is a good thing, keeping us from making risky, stupid decisions or falling over and over again into the same trap. But new research from neuroscientists and molecular biologists at USC shows that a missing brain protein may be the culprit in cases of severe over-worry, where the fear perseveres even when there’s nothing of which to be afraid.

In a study appearing the week of July 15 in the Proceedings of the National Academy of Sciences, the researchers examined mice without the enzymes monoamine oxidase A and B (MAO A/B), which sit next to each other in a human’s genetic code as well as on that of mice. Prior research has found an association between deficiencies of these enzymes in humans and developmental disabilities along the autism spectrum, such as clinical perseverance, the inability to change or modulate actions along with social context.

“These mice may serve as an interesting model to develop interventions to these neuropsychiatric disorders,” said University Professor and senior author Jean Shih, Boyd & Elsie Welin Professor of Pharmacology and Pharmaceutical Sciences at the USC School of Pharmacy and the Keck School of Medicine of USC. “The severity of the changes in the MAO A/B knockout mice compared to MAO A knockout mice supports the idea that the severity of autistic-like features may be correlated to the amounts of monoamine levels, particularly at early developmental stages.”

Shih is a world leader in understanding the neurobiological and biochemical mechanisms behind such behaviors as aggression and anxiety. In this latest study, Shih and her co-investigators — including lead author Chanpreet Singh, a USC doctoral student at the time of the research who is now at the California Institute of Technology (Caltech), and Richard Thompson, USC University Professor Emeritus and Keck Professor of Psychology and Biological Sciences at the USC Dornsife College of Letters, Arts and Sciences — expanded their past research on MAO A/B, which regulates neurotransmitters known as monoamines, including serotonin, norepinephrine and dopamine.

Comparing mice without MAO A/B with their wild-type littermates, the researchers found significant differences in how the mice without MAO A/B processed fear and other types of learning. Mice without MAO A/B and wild mice were put in a new, neutral environment and given a mild electric shock. All mice showed learned fear the next time they were tested in the same environment, with the MAO A/B knockout mice displaying a greater degree of fear.

But while wild mice continued to explore other new environments freely after the trauma, mice without the MAO A/B enzymes generalized their phobia to other contexts — their fear spilled over onto places where they should have no reason to be afraid.

“The neural substrates processing fear in the brain is very different in these mice,” Singh said. “Enhanced learning in the wrong context is a disorder and is exemplified by these mice. Their brain is not letting them forget. In a survival issue, you need to be able to forget things.”

The mice without MAO A and MAO B also learned eye-blink conditioning much more quickly than wild mice, which has also been noted in autistic patients but not in mice missing only one of these enzymes.

Importantly, the mice without MAO A/B did not display any differences in learning for spatial skills and object recognition, the researchers found, “but in their ability to learn an emotional event, the [MAO A/B knockout mice] are very different than wild types,” Singh said.

He continued: “When both enzymes are missing, it significantly increases the levels of neurotransmitters, which causes developmental changes, which leads to differential expression of receptors that are very important for synaptic plasticity — a measure of learning — and to behavior that is quite similar to what we see along the autism spectrum.”

(Source: news.usc.edu)