Neuroscience

A new mechanism for guiding the growth of nerves that involves cell-death machinery has been found by scientists at the University of Nevada, Reno that may bring advances in neurological medicine and research. The team obtained the evidence in studies of fruit flies and reported their discovery in an article published in the prestigious science publication Cell Reports.

"Although the fly is a relatively simple organism, almost every gene identified in this species appears to be carrying out similar functions in humans," said Thomas Kidd, associate professor in the University’s biology department in whose lab the work was performed.

The Kidd lab is part of a $10 million Center for Biomedical Research Excellence Project in Cell Biology of Signaling at the University, which is funded by the National Institute of Health’s Institute of General Medical Sciences. The project is also funded by the National Science Foundation.

"Flies are useful because the neural mechanisms we are studying are similar to those in mammals," said Gunnar Newquist, lead author of the Cell Reports article and a post-doctoral neuroscience researcher in Kidd’s lab. "We’ve found something no one has seen before, that blocking the cell-death pathway can make nerves deprived of guidance cues figure out the right way to connect with other neurons. This was completely unexpected and novel, but really exciting because it changes the way we look at nerve growth.

"Neurons have a natural ability to die, if they fail to make the right connections they usually die. Neurons, like most other cell types, have the capacity to commit suicide and many do so during the formation of the nervous system."

The wiring of nervous systems is composed of axons, specialized extensions of neurons that transmit electrical impulses. During development axons navigate long distances to their targets by using signals in their environment. Netrin-B is one of those signals.  Kidd, Newquist and colleagues have shown that Netrin-B also keeps neurons alive.

"Take away the Netrin-B and growth and cell death goes haywire," Newquist said.

This led them to the discovery that the cell-death machinery is active in growing nerves, and appears to be an integral part of the navigation mechanism.

"We use fruit fly genetics to study how these axons navigate these long distances correctly when developing," Kidd said. "Understanding the mechanisms they use to navigate is of great interest, not only for understanding how our brains form, but also as a starting point to devise ways to stimulate the re-growth of axons after injury, especially spinal cord injuries.

"Our work suggests that therapeutics designed to keep neurons alive after injury may be able to stimulate neurons to start re-growing or sprouting new connections."

"I am very pleased to see Tom’s and Gunnar’s hard work come to fruition," said Chris von Bartheld, director of the University’s cell-biology COBRE and a professor in the University of Nevada School of Medicine. "Linking axonal path finding and cell death signaling opens exciting new venues to better understand both topics. It also shows that our recently established center in cell biology is achieving its goals of producing top-level biomedical research."

A drug widely used to treat Parkinson’s Disease can help to reverse age-related impairments in decision making in some older people, a study from researchers at the Wellcome Trust Centre for Neuroimaging has shown.

The study, published today in the journal Nature Neuroscience, also describes changes in the patterns of brain activity of adults in their seventies that help to explain why they are worse at making decisions than younger people.

Poorer decision-making is a natural part of the ageing process that stems from a decline in our brains’ ability to learn from our experiences. Part of the decision-making process involves learning to predict the likelihood of getting a reward from the choices that we make.

An area of the brain called the nucleus accumbens is responsible for interpreting the difference between the reward that we’re expecting to get from a decision and the reward that is actually received. These so called ‘prediction errors’, reported by a brain chemical called dopamine, help us to learn from our actions and modify our behaviour to make better choices the next time.

Dr Rumana Chowdhury, who led the study at the Wellcome Trust Centre for Neuroimaging at UCL, said: “We know that dopamine decline is part of the normal aging process so we wanted to see whether it had any effect on reward-based decision making. We found that when we treated older people who were particularly bad at making decisions with a drug that increases dopamine in the brain, their ability to learn from rewards improved to a level comparable to somebody in their twenties and enabled them to make better decisions.”

The team used a combination of behavioural testing and brain imaging techniques, to investigate the decision-making process in 32 healthy volunteers aged in their early seventies compared with 22 volunteers in their mid-twenties. Older participants were tested on and off L-DOPA, a drug that increases levels of dopamine in the brain. L-DOPA, more commonly known as Levodopa, is widely used in the clinic to treat Parkinson’s.

The participants were asked to complete a behavioural learning task called the two-arm bandit, which mimics the decisions that gamblers make while playing slot machines. Players were shown two images and had to choose the one that they thought would give them the biggest reward. Their performance before and after drug treatment was assessed by the amount of money they won in the task.

"The older volunteers who were less able to predict the likelihood of a reward from their decisions, and so performed worst in the task, showed a significant improvement following drug treatment," Dr Chowdhury explains.

The team then looked at brain activity in the participants as they played the game using functional Magnetic Resonance Imaging (fMRI), and measured connections between areas of the brain that are involved in reward prediction using a technique called Diffusor Tensor Imaging (DTI).

The findings reveal that the older adults who performed best in the gambling game before drug treatment had greater integrity of their dopamine pathways. Older adults who performed poorly before drug treatment were not able to adequately signal reward expectation in the brain – this was corrected by L-DOPA and their performance improved on the drug.

Dr John Williams, Head of Neuroscience and Mental Health at the Wellcome Trust, said: “This careful investigation into the subtle cognitive changes that take place as we age offers important insights into what may happen at both a functional and anatomical level in older people who have problems with making decisions. That the team were able to reverse these changes by manipulating dopamine levels offers the hope of therapeutic approaches that could allow older people to function more effectively in the wider community.”

The strongest predictor of whether a man is developing dementia with Lewy bodies — the second most common form of dementia in the elderly — is whether he acts out his dreams while sleeping, Mayo Clinic researchers have discovered. Patients are five times more likely to have dementia with Lewy bodies if they experience a condition known as rapid eye movement (REM) sleep behavior disorder than if they have one of the risk factors now used to make a diagnosis, such as fluctuating cognition or hallucinations, the study found.

The findings were being presented at the annual meeting of the American Academy of Neurology in San Diego. REM sleep behavior disorder is caused by loss of the normal muscle paralysis that occurs during REM sleep. It can appear three decades or more before a diagnosis of dementia with Lewy bodies is made in males, the researchers say. The link between dementia with Lewy bodies and the sleep disorder is not as strong in women, they add.

"While it is, of course, true that not everyone who has this sleep disorder develops dementia with Lewy bodies, as many as 75 to 80 percent of men with dementia with Lewy bodies in our Mayo database did experience REM sleep behavior disorder. So it is a very powerful marker for the disease," says lead investigator Melissa Murray, Ph.D., a neuroscientist at Mayo Clinic in Florida.

The study’s findings could improve diagnosis of this dementia, which can lead to beneficial treatment, Dr. Murray says.

"Screening for the sleep disorder in a patient with dementia could help clinicians diagnose either dementia with Lewy bodies or Alzheimer’s disease," she says. "It can sometimes be very difficult to tell the difference between these two dementias, especially in the early stages, but we have found that only 2 to 3 percent of patients with Alzheimer’s disease have a history of this sleep disorder."

Once the diagnosis of dementia with Lewy bodies is made, patients can use drugs that can treat cognitive issues, Dr. Murray says. No cure is currently available.

Researchers at Mayo Clinic in Minnesota and Florida, led by Dr. Murray, examined magnetic resonance imaging, or MRI, scans of the brains of 75 patients diagnosed with probable dementia with Lewy bodies. A low-to-high likelihood of dementia was made upon an autopsy examination of the brain.

The researchers checked the patients’ histories to see if the sleep disorder had been diagnosed while under Mayo care. Using this data and the brain scans, they matched a definitive diagnosis of the sleep disorder with a definite diagnosis of dementia with Lewy bodies five times more often than they could match risk factors, such as loss of brain volume, now used to aid in the diagnosis. The researchers also showed that low-probability dementia with Lewy bodies patients who did not have the sleep disorder had findings characteristic of Alzheimer’s disease.

"When there is greater certainty in the diagnosis, we can treat patients accordingly. Dementia with Lewy bodies patients who lack Alzheimer’s-like atrophy on an MRI scan are more likely to respond to therapy — certain classes of drugs — than those who have some Alzheimer’s pathology," Dr. Murray says.

One ion channel, many diseases

A dysfunction of a certain Calcium channel, the so called P/Q-type channel, in neurons of the cerebellum is sufficient to cause different motor diseases as well as a special type of epilepsy. This is reported by the research team of Dr. Melanie Mark and Prof. Dr. Stefan Herlitze from the Ruhr-Universität Bochum. They investigated mice that lacked the ion channel of the P/Q-type in the modulatory input neurons of the cerebellum. “We expect that our results will contribute to the development of treatments for in particular children and young adults suffering from absence epilepsy”, Melanie Mark says. The research team from the Department of General Zoology and Neurobiology reports in the “Journal of Neuroscience”.

P/Q-type channel defects cause a range of diseases

“One of the main challenging questions in neurobiology related to brain disease is in which neuronal circuit or cell-type the diseases originate,” Melanie Mark says. The Bochum researchers aimed at answering this question for certain motor disorders that are caused by cerebellar dysfunction. More specifically, they investigated potential causes of motor incoordination, also known as ataxia, and motor seizures, i.e., dyskinesia. In a previous study in 2011, the researchers showed that a certain Calcium channel type, called P/Q-type channel, in cerebellar neurons can be the origin of the diseases. The channel is expressed throughout the brain, and mutations in this channel cause migraines, different forms of epilepsy, dyskinesia, and ataxia in humans.

Disturbing cerebellar output is sufficient to cause different diseases

“Surprisingly, we found in 2011 that the loss of P/Q-type channels, specifically in the sole output pathway of the cerebellar cortex, the Purkinje cells, not only leads to ataxia and dyskinesia, but also to a disease often occurring in children and young adults, absence epilepsy,” Dr. Mark says. The research team thus hypothesized that disturbing the output signals of the cerebellum is sufficient to cause the major disease phenotypes associated with the P/Q-type channel. In other words, P/Q-type channel mutations in the cerebellum alone can elicit a range of diseases, even when the same channels in other brain regions are intact.

Disturbing the input to the cerebellum has similar effects as disturbing the output

Mark’s team has now found further evidence for this hypothesis. In the present study, the biologists did not disturb the output signals, i.e., the Purkinje cells, directly, but rather the input to these cells. The Purkinje cells are modulated by signals from other neurons, amongst others from the granule cells. “This modulatory input to the Purkinje cells is important for the proper communication between neurons in the cerebellum,” Melanie Mark explains. In mice, the researchers disturbed the input signals by genetically altering the granule cells so that they did not express the P/Q-type channel. Like disturbing the cerebellar output in the 2011 study, this manipulation resulted in ataxia, dyskinesia, and absence epilepsy. “The results provide additional evidence that the cerebellum is involved in initiating and/or propagating neurological deficits”, Mark sums up. “They also provide an animal model for identifying the specific pathways and molecules in the cerebellum responsible for causing these human diseases.”

Researchers at Georgetown University Medical Center (GUMC) have found what they say is evidence that veterans who suffer from “Gulf War Illness” have physical changes in their brains not seen in unaffected individuals. Brain scans of 31 veterans with the illness, compared to 20 control subjects, revealed anomalies in the bundles of nerve fibers that connect brain areas involved in the processing and perception of pain and fatigue.

The discovery, published online March 20 in PLOS ONE, could provide insight into the mysterious medical symptoms reported by more than one-fourth of the 697,000 veterans deployed to the 1990-1991 Persian Gulf War, the researchers say. These symptoms, termed Gulf War Illness, range from mild to debilitating and can include widespread pain, fatigue, and headache, as well as cognitive and gastrointestinal dysfunctions.

Although these veterans were exposed to nerve agents, pesticides and herbicides, among other toxic chemicals, no one has definitively linked any single exposure or underlying mechanism to Gulf War Illness according to the scientists.

This is the first study to show veterans, compared to unaffected subjects, have significant axonal damage. Bundles of axons, which form the brain white matter, are akin to telephone wires that carry nerve impulses between different parts of the gray matter in the brain. The researchers found that damage to the right inferior fronto-occipital fasciculus was significantly correlated with the severity of pain, fatigue, and tenderness.

“This tract of axons links cortical gray matter regions involved in fatigue, pain, emotional and reward processing.  This bundle also supports activity in the ventral attention network, which searches for unexpected signals in the surrounding environment that may be inappropriately interpreted as causing pain or being dangerous. Altered function in this tract may explain the increased vigilance and distractibility observed in veterans.” says lead author Rakib Rayhan, MS, a researcher in the lab of the study’s senior investigator, James Baraniuk, MD, a professor of medicine at GUMC.

In this Department of Defense-funded study, the research team used a form of functional magnetic resonance imaging (fMRI) called diffusion tensor imaging. This imaging method examines patterns of water diffusion in the brain to look for changes in the integrity of white matter, which is not seen on regular MRI scans. “This provides a completely new perspective on Gulf War Illness,” says Baraniuk. “While we can’t exactly tell how this tract is affected at the molecular level — the scans tell us these axons are not working in a normal fashion.”

Although preliminary, “the changes appear distinct from multiple sclerosis, major depression, Alzheimer’s disease and other neurodegenerative diseases,” says Rayhan. “These novel findings are really exciting because they provide validation for many veterans who have long said that no one believes them.”

The results must be replicated, say its authors, but for the first time a potential biomarker for Gulf War Illness may be on the horizon as well as a possible target for therapy aimed at regenerating these neurons.

“Pain and fatigue are perceptions, just like other sensory input, and Gulf War Illness could be due to extensive damage to the structures that facilitate them,” says Rayhan. “Some of the veterans we studied feel pain when doing something as simple as putting on a shirt. Now we have something to tell them about why their lives have been so greatly affected.”

Cognitive problems with memory and behavior experienced by individuals with schizophrenia are linked with changes in brain activity; however, it is difficult to test whether these changes are the underlying cause or consequence of these symptoms. By altering the brain activity in mice to mimic the decrease in activity seen in patients with schizophrenia, researchers reporting in the Cell Press journal Neuron on March 20 reveal that these changes in regional brain activity cause similar cognitive problems in otherwise normal mice. This direct demonstration of the link between changes in brain activity and the behaviors associated with schizophrenia could alter how the disease is treated.

"We artificially decreased activity of the mediodorsal thalamus region of the brain in the mouse and found that it is sufficient to lead to deficits in working memory and other schizophrenia-like cognitive deficits," says senior author Dr. Christoph Kellendonk of Columbia University in New York City. "Our findings further suggest that decreased thalamic activity interferes with cognition by disrupting communication between the thalamus and the prefrontal cortex, an area of the brain that has already been shown to be important for working memory," he added.

The researchers made their discovery by giving mice a drug that decreased activity selectively in the mediodorsal thalamus region of the brain. They then tested the animals in various cognitive tasks involving levers and mazes. The investigators found that even a subtle decrease in the activity of the mediodorsal thalamus led to altered connectivity between this brain region and the prefrontal cortex region and that the altered connectivity was associated with a variety of cognitive impairments experienced by patients with schizophrenia.

The findings likely apply to humans because patients with schizophrenia have decreased thalamic activity as well as altered connectivity between the thalamus and the prefrontal cortex. “Our work suggests that these two findings may be linked,” explains co-senior author Dr. Joshua Gordon, also of Columbia University. “One next step would be to examine this relationship in patients. For example, one could ask whether deficits in thalamic activity and connectivity between the thalamus and prefrontal cortex are correlated with each other.”

Cognitive symptoms of schizophrenia include problems with memory and behavioral flexibility, two processes that are essential for activities of daily living. These symptoms are resistant to current treatments, but this study’s findings provide new information for the design of potentially more effective therapies that target the neuronal mechanisms underlying patients’ cognitive problems.

The effects of antiepileptic drugs during pregnancy have long been a concern of clinicians and women of childbearing age whose seizures can only be controlled by medications. In 1999, a study called the Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) began following the children of women who were taking a single antiepileptic agent during pregnancy. The drugs included carbamazepine, lamotrigine, phenytoin or valproate.

Recently released final data from NEAD shows that at age 6, IQ is 7-10 points lower in children exposed in utero to the anti-epileptic drug valproate (Depakote) than those exposed to the other medications. The children exposed to valproate also did poorly on measures of verbal and memory abilities, and non-verbal and executive functions. The results were reported in the January 23, 2013, Lancet Neurology publication on line.

"Data published at ages 3 and 4.5 showed similar results in cognitive impairment," says lead study author Kimford Meador, MD, professor of neurology at Emory University School of Medicine. "Age 6 IQ was our primary outcome goal because it is standardized and predictive of school performance."

The NEAD study is the largest prospective study examining the cognitive effects of fetal antiepileptic drug exposure. The researchers monitored women through pregnancy and followed their children, performing cognitive testing at ages 2,3,4.5 and finally at 6. In addition to the effect on cognitive function, earlier data from NEAD showed an increase in the risk of anatomical birth defects.

Valproate is an anticonvulsant used in the treatment of epilepsy, migraines and bipolar disorder, and is particularly effective in the treatment of primary generalized seizures.  Except for a small number of women who only respond to valproate, there are alternative medications.

"These findings consistently show a substantial loss of developmental abilities for these children," says Meador. "Women of childbearing age who have epilepsy should talk with their doctors about their options, and possibly test the safer medications prior to pregnancy to find out if they work."

In order to avoid seizures with potentially serious consequences, Meador emphasizes that women who are already pregnant and taking valproate should not stop without consulting their physicians.

"For a woman who has significant seizures, the risk from the seizure itself is worse than the risk of taking the drugs," he points out.  "The number one reason for miscarriage late in pregnancy for women with epilepsy is trauma resulting from a seizure."

Meador will co-lead a follow-up study with Page Pennell, MD, from Harvard. The new study funded by the National Institutes of Health is called Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD), and will investigate the risks of these same drugs to both the mother and the child. The study will be conducted at 19 sites, enrolling 350 women with epilepsy during pregnancy. An additional 100 women with epilepsy who are not pregnant, and 100 healthy pregnant women will serve as controls.