Imaging Biomarker Predicts Response to Rapid Antidepressant

A telltale boost of activity at the back of the brain while processing emotional information predicted whether depressed patients would respond to an experimental rapid-acting antidepressant, a National Institutes of Health study has found.

“We have discovered a potential neuroimaging biomarker that may eventually help to personalize treatment selection by revealing brain-based differences between patients,” explained Maura Furey, Ph.D., of NIH’s National Institute of Mental Health (NIMH).

Furey, NIMH’s Carlos Zarate, M.D., and colleagues, reported on their functional magnetic resonance imaging (fMRI) study of a pre-treatment biomarker for the antidepressant response to scopolamine, Jan. 30, 2013, online in JAMA Psychiatry.

Scopolamine, better known as a treatment for motion sickness, has been under study since Furey and colleagues discovered its fast-acting antidepressant properties in 2006. Unlike ketamine, scopolamine works through the brain’s acetylcholine chemical messenger system. The NIMH team’s research has demonstrated that by blocking receptors for acetylcholine on neurons, scopolamine can lift depression in many patients within a few days; conventional antidepressants typically take weeks to work. But not all patients respond, spurring interest in a predictive biomarker.

The acetylcholine system plays a pivotal role in working memory, holding information in mind temporarily, but appears to act by influencing the processing of information rather than through memory. Imaging studies suggest that visual working memory performance can be enhanced by modulating acetylcholine-induced activity in the brain’s visual processing area, called the visual cortex, when processing information that is important to the task. Since working memory performance can predict response to conventional antidepressants and ketamine, Furey and colleagues turned to a working memory task and imaging visual cortex activity as potential tools to identify a biomarker for scopolamine response.

Depressed patients have a well-known tendency to process and remember negative emotional information. The researchers propose that this bias stems from dysregulated acetylcholine systems in some patients. They reasoned that such patients would show aberrant visual cortex activity in response to negative emotional features of a working memory task. They also expected to find that patients with more dysfunctional acetylcholine systems would respond better to scopolamine treatment.

The zebrafish revealed a central regulator for the development of the brain histamine system

Research has shown that mutations in the psen1 gene are common in the familial forms of Alzheimer’s disease, and the Presenilin-1 protein that the gene encodes is known to be involved in the cleavage of the amyloid precursor protein. In Alzheimer’s disease the amyloid precursor protein is not cleaved the normal way, and the protein accumulates in the brain damaging neuronal tracts and neurons. It is still unknown if the psen1 gene is involved in the etiology of Alzheimer’s disease via another mechanism.

Professor Pertti Panula’s research team at the University of Helsinki has elucidated the role of psen1 gene in the development of the neuronal histamine system and its modulation. Histamine is one of the neurotransmitters, which all are essential for cognitive functions, which in turn are impaired in Alzheimer’s disease. The histamine system is altered during the progression of Alzheimer’s disease.

In the study the zebrafish was used as a model organism. The rapidly developing zebrafish is suitable as a model organism, as its transparency allows researchers to study the development and function of vital organs. To study the function of psen1 gene, zebrafish that did not produce functional Presenilin-1 protein were generated. Despite the fact that the fish lacked functional Presenilin-1 they were viable and developed until adulthood.

The lack of Presenilin-1 protein induced a change in the behavior of the larval zebrafish, they did not as normal fish react to fast changes in the light intensity. “Based on previous research we know that this change in behavior is associated with lack of histamine in the brain”, Panula explains.

In adulthood the motor behavior of the mutant zebrafish differed from the normal fish: the fish swam by the edges of the arena that was available and avoided the inner part. Previous studies from the group have shown that this behavioral alteration also is due to changes in the histamine system.

The researchers found that larval fish lacking Presenilin-1 protein had significantly fewer histamine neurons; in adulthood the histamine neuron number was significantly increased in these fish when compared with normal fish.

"These results reveal that the psen1 gene is a central regulator of the development of the histamine neurons and that the mutation can cause a persistent lifelong change in the neuronal histamine system. This is a very interesting finding", Panula states.

One interesting remaining question is from where the new histamine neurons arise in the brains of adult zebrafish. Are they newly differentiated stem cells or do other cells become histamine neurons? The answer is not known, but based on these results it is advisable to elucidate the role of Presenilin-1 protein in differentiation of stem cells also in the brains of mammals. “Mammals have stem cells in the hypothalamus, in the same area where the histamine neurons are located in all studied vertebrates”, Panula comments.

Panula empathizes that the published study does not tell about an Alzheimer’s disease mechanism in humans. The new knowledge on the function of psen1 gene and the development of the brain histamine system provided by the study is one step forward to understanding the etiology of the disease.

"We perform basic research on molecular level, from where it is a long way to treatment of human diseases. This type of research provides the findings on which the treatments are finally based", Panula says.

Journal of Neuroscience published the study that was conducted at University of Helsinki Neuroscience center, and Institute of Biomedicine.

(Image: Charles Badland, Florida State University)

Human memory study adds to global debate

An international study involving researchers from the University of Adelaide has made a major contribution to the ongoing scientific debate about how processes in the human brain support memory and recognition.

The study used a rare technique in which data was obtained from within the brain itself, using electrodes placed inside the brains of surgery patients.

Obtained in Germany, the data was sent to the University of Adelaide’s School of Psychology for further analysis using new techniques developed there. The results are published today in the Proceedings of the National Academy of Sciences (PNAS).

"Being able to understand how human memory works is important because there is a range of conditions that affect memory, such as Alzheimer’s disease, head injury, and ageing," says Professor John Dunn, Head of the School of Psychology at the University of Adelaide and a co-author of the study, which was led by researchers at the universities of Cambridge, UK, and Bonn, Germany.

"Scientists know a lot about memory from years of study, but there is an ongoing debate about how certain mechanisms in the brain process memory, and how those mechanisms work together.

"What we’re looking at is how the human brain processes ‘recognition memory’, which is our ability to recognise people, objects or events that we’ve encountered in the past."

The debate has centered on two key regions in the brain:

• the hippocampus, which is very important to memory and is one of the first regions of the brain to suffer damage from Alzheimer’s disease; and
• the perirhinal cortex, which receives sensory information from all of the body’s sensory regions.

"The debate is whether or not these two regions work in the same or different ways to support memory and recognition Studies over the years have led to both conclusions," Professor Dunn says.

He says this new study, which uses data from inside the brain instead of from electrodes on the scalp, far from the critical regions, revealed that different processes are at work in the hippocampus and the perirhinal cortex.

"Our analysis shows that these regions are responding to and processing memory in two very different ways. The activity levels in those regions changed in different ways according to the amount of information that could be remembered," Professor Dunn says.

"This study won’t settle the debate once and for all, but it does add weight to those scientists who believe that these two distinct parts of the brain respond to memory in different ways," he says.

Response and recovery in the brain may predict well-being

It has long been known that the part of the brain called the amygdala is responsible for recognition of a threat and knowing whether to fight or flee from the danger.

Now, using functional magnetic resonance imaging, or fMRI, scientists at the Center for Investigating Healthy Minds at the University of Wisconsin-Madison Waisman Center are watching the duration of the amygdala response in the brains of healthy people when exposed to negative images. How long the recovery takes may be an indicator of personality traits like neuroticism.

Recently published in the journal Social Cognitive and Affective Neuroscience, the study specifically examines how the amygdala responds and recovers from negative stimuli. One of the more primitive parts of the mammalian brain, the amygdala is central to processing emotion, including activating changes in the body that often accompany emotion. In terms of its evolutionary function, this region of the brain is part of a circuit that is key to our sense of fear recognition and alertness to danger.

While the role of the amygdala has been understood and well documented, the time course for the response-recovery process has never been investigated, nor observed, until the recent advance of fMRI analysis methods.

"Past studies looking at the temporal unfolding of emotional responses have focused on reports of emotional experience obtained from interviews and questionnaires," says Tammi Kral, research specialist at the Center for Investigating Healthy Minds and an author of the paper. "This study is different because it looks at the temporal activity in the brain via fMRI."

Through the lens of fMRI, scientists can measure the activation in the amygdala as it reacts to negative stimuli, and the subsequent recovery after the stimulus ends. This study shows that while the initial reactivity of the amygdala does not predict personality traits, a sluggish response-recovery time may be a predictor of neuroticism.

"People’s responses to negative emotional stimuli, and their ability to regulate those responses, can be a major factor in depression, anxiety and other psychological disorders," says Kral. "In the case of depression, the person is often ruminating, perseverating — they’re unable to let go of the negative experience."

The study could have clinical applications because it implies that changing the way people recover from negative occurrences may be a good way to improve their emotional well-being. Research from other groups also supports the idea that individual differences in emotional recovery affect overall well-being.

Yale researchers spot attention deficits in babies who later develop autism

Researchers at Yale School of Medicine are able to detect deficits in social attention in infants as young as six months of age who later develop Autism Spectrum Disorders (ASD). Published in the current issue of Biological Psychiatry, the results showed that these infants paid less attention to people and their activities than typically developing babies.

Katarzyna Chawarska, associate professor at the Yale Child Study Center, and her colleagues investigated whether six-month-old infants later diagnosed with ASD showed prodromal symptoms — early signs of ASD such as an impaired ability to attend to social overtures and activities of others. Before this study, it had not been clear whether these prodromal symptoms were present in the first year of life.

“This study highlights the possibility of identifying certain features linked to visual attention that can be used for pinpointing infants at greatest risk for ASD in the first year of life,” said Chawarska. “This could make earlier interventions and treatments possible.”

Reflex control could improve walking after incomplete spinal injuries

A training regimen to adjust the body’s motor reflexes may help improve mobility for some people with incomplete spinal cord injuries, according to a study supported by the National Institutes of Health.

During training, the participants were instructed to suppress a knee jerk-like reflex elicited by a small shock to the leg. Those who were able to calm hyperactive reflexes – a common effect of spinal cord injuries – saw improvements in their walking.

The study was led by Aiko Thompson, Ph.D., and Jonathan Wolpaw, M.D., both of whom hold appointments at the New York state Department of Health and the State University of New York in Albany, and at Columbia University in New York City. The study took place at Helen Hayes Hospital in West Haverstraw, N. Y. It was funded in part by NIH’s National Institute of Neurological Disorders and Stroke (NINDS), and published in the Journal of Neuroscience.

"People tend to think of reflexes as fixed, but in reality, normal movement requires constant fine tuning of reflexes by the brain. Loss of that fine-tuning is an important part of the disability that comes with a spinal cord injury," said Dr. Wolpaw, a research physician and professor at the Wadsworth Center, the state health department’s public health laboratory.

When the brain makes a decision to move, it sends signals that travel through the spinal cord to the appropriate muscles. Spinal reflexes – controlled by local circuits of nerve cells in the spinal cord – provide a way for the body to react and move quickly without a conscious decision from the brain. “They enable you to jerk your hand away from a hot stove before you’ve registered the pain and experienced severe burns,” Dr. Wolpaw said. “The brain can gradually enhance or suppress reflexes as needed,” he said.

Vitamin D, omega-3 may help clear amyloid plaques found in Alzheimer’s

A team of academic researchers has pinpointed how vitamin D3 and omega-3 fatty acids may enhance the immune system’s ability to clear the brain of amyloid plaques, one of the hallmarks of Alzheimer’s disease.

In a small pilot study published in the Feb. 5 issue of the Journal of Alzheimer’s Disease, the scientists identified key genes and signaling networks regulated by vitamin D3 and the omega-3 fatty acid DHA (docosahexaenoic acid) that may help control inflammation and improve plaque clearance.

Previous laboratory work by the team helped clarify key mechanisms involved in helping vitamin D3 clear amyloid-beta, the abnormal protein found in the plaque. The new study extends the previous findings with vitamin D3 and highlights the role of omega-3 DHA.

"Our new study sheds further light on a possible role for nutritional substances such as vitamin D3 and omega-3 in boosting immunity to help fight Alzheimer’s," said study author Dr. Milan Fiala, a researcher at the David Geffen School of Medicine at UCLA.

Stroke Damage in Mice Overcome by Training that ‘Rewires’ Brain Centers

Johns Hopkins researchers have found that mice can recover from physically debilitating strokes that damage the primary motor cortex, the region of the brain that controls most movement in the body, if the rodents are quickly subjected to physical conditioning that rapidly “rewires” a different part of the brain to take over lost function.

Their research, featuring precise, intense and early treatment, and tantalizing clues to the role of a specific brain area in stroke recovery, is described online in the journal Stroke.

"Despite all of our approved therapies, stroke patients still have a high likelihood of ending up with deficits," says study leader Steven R. Zeiler, M.D., Ph.D., an assistant professor of neurology at the Johns Hopkins University School of Medicine. "This research allows us the opportunity to test meaningful training and pharmacological ways to encourage recovery of function, and should impact the care of patients."

With improved acute care for stroke, more patients are surviving. Still, as many as 60 percent are left with diminished use of an arm or leg, and one-third need placement in a long-term care facility. The economic cost of disability translates to more than $30 billion in annual care.

Evidence That at Least One Mammal Can Smell in Stereo

Most mammals, including humans, see in stereo and hear in stereo. But whether they can also smell in stereo is the subject of a long-standing scientific controversy.

Now, a new study shows definitively that the common mole (Scalopus aquaticus) – the same critter that disrupts the lawns and gardens of homeowners throughout the eastern United States, Canada and Mexico – relies on stereo sniffing to locate its prey. The paper that describes this research, “Stereo and Serial Sniffing Guide Navigation to an Odor Source in a Mammals,” was published on Feb. 5 in the journal Nature Communications.

“I came at this as a skeptic. I thought the moles’ nostrils were too close together to effectively detect odor gradients,” said Kenneth Catania, the Stevenson Professor of Biological Sciences at Vanderbilt University, who conducted the research.

What he found turned his assumptions upside down and opened new areas for potential future research. “The fact that moles use stereo odor cues to locate food suggests other mammals that rely heavily on their sense of smell, like dogs and pigs might also have this ability,” Catania said.

New 3D printing technique could speed up progress towards creation of artificial organs