Dealing with negative thinking

Is it ‘normal’ to think about pushing someone in front of a train or to fantasise about driving your car into oncoming traffic?

The answer is yes says Victoria University of Wellington researcher Dr Kirsty Fraser who graduated with a PhD in Psychology last week.

“It’s common for people to occasionally have those kind of negative thoughts, but then most of us realise it’s a bit ridiculous and move on,” says Dr Fraser.

For some people, however, those negative thoughts may persist, leading to anxiety and depression.

“It’s how we react to, and process, those negative intrusions that can make the difference between brushing them off and developing obsessive compulsive symptoms, such as severe anxiety and depression.

“For example, some people could be so anxious about those kind of thoughts that they go out of their way to avoid catching a train or driving.”

Dr Fraser’s thesis focused on two ways of processing negative thoughts—inflated responsibility (IR) and thought action fusion (TAF), and the way each relates to mental disorders.

“TAF is when you believe that thinking about an action is equivalent to actually carrying out that action, while IR is one of the driving forces behind obsessive compulsive disorder (OCD), where you believe you can prevent something happening by what you do or don’t do.

“My research demonstrates that both types of beliefs play important roles in the development and maintenance of psychological symptoms related to anxiety, depression and OCD.”

Dr Fraser’s research also looked at how childhood experiences, critical events in one’s life and religious beliefs could impact upon thoughts.

She surveyed more than 1,000 people and divided them into four groups: undergraduate students, so called ‘normal’ citizens, patients from an anxiety clinic and those with religious and atheist beliefs.

“Overall,” she says, “my research provided strong support for existing theories about the role of cognitive processes in the maintenance of symptoms and distress.”

When Kirsty arrived at Victoria in 2002, she began studying human resources. She took a psychology paper out of interest and “never left”.

“The lecturer was John McDowall, who introduced me to how interesting the subject is. He ended up being my supervisor for my PhD.”

For the past three years, Kirsty has combined doctoral study with teaching a second year psychology paper at Victoria, marking for another tertiary institution and being a full-time mother.

“Now I’m starting to think about other challenges, including possible research positions. I’d like to publish my PhD research and continue lecturing.”

Mice with ‘mohawks’ help scientists link autism to 2 biological pathways in brain

"Aha" moments are rare in medical research, scientists say. As rare, they add, as finding mice with Mohawk-like hairstyles.

But both events happened in a lab at NYU Langone Medical Center, months after an international team of neuroscientists bred hundreds of mice with a suspect genetic mutation tied to autism spectrum disorders.

Almost all the grown mice, the NYU Langone team observed, had sideways,”overgroomed” hair with a highly stylized center hairline between their ears and hardly a tuft elsewhere. Mice typically groom each other’s hair.

Researchers say they knew instantly they were on to something, as the telltale overgrooming — a repetitive motor behavior — had been linked in other experiments in mice to the brain condition that prevents children from developing normal social, behavioral, cognitive, and motor skills. People with autism, the researchers point out, exhibit noticeably dysfunctional behaviors, such as withdrawal, and stereotypical, repetitive movements, including constant hand-flapping, or rocking.

Now and for what NYU Langone researchers believe to be the first time, an autistic motor behavior has been traced to specific biological pathways that are genetically determined.

The findings, says senior study investigator Gordon Fishell, PhD, the Julius Raynes Professor of Neuroscience and Physiology at NYU Langone, could with additional testing in humans lead to new treatments for some autism, assuming the pathways’ effects as seen in mice are reversible.

In the study, to be published in the journal Nature online May 25, researchers knocked out production in mice of a protein called Cntnap4. This protein had been found in earlier studies in specialized brain cells, known as interneurons, in people with a history of autism.

Researchers found that knocking out Cntnap4 affected two highly specialized chemical messengers in the brain, GABA and dopamine. Both are so-called neurotransmitters, chemical signals released from one nerve cell to the next to stimulate similar sensations throughout the body. GABA, short for gamma-aminobutyric acid, is the main inhibitory neurotransmitter in the brain. It not only helps control brain impulses, but also helps regulate muscle tone. Dopamine is a well-known hormonal stimulant, highly touted for producing soothing, pleasing sensations.

Among the researchers’ key findings was that in Mohawk-coiffed mice, reduced Cntnap4 production led to depressed GABA signaling and overstimulation with dopamine. Researchers say the lost protein had opposite effects on the neurotransmitters because GABA is fast acting and quickly released, so interfering with its action decreases signaling, while dopamine’s signaling is longer-acting, so impairing its action increases its release.

"Our study tells us that to design better tools for treating a disease like autism, you have to get to the underlying genetic roots of its dysfunctional behaviors, whether it is overgrooming in mice or repetitive motor behaviors in humans," says Dr. Fishell. "There have been many candidate genes implicated in contributing to autism, but animal and human studies to identify their action have so far not led to any therapies. Our research suggests that reversing the disease’s effects in signaling pathways like GABA and dopamine are potential treatment options."

The U.S. Centers for Disease Control and Prevention estimate that one in 68 American children under age 8 has some form of autism, with five times as many boys as girls suffering from the spectrum of disorders.

As part of their study, researchers performed dozens of genetic, behavioral, and neural tests with growing mice to isolate and pinpoint where Cntnap4 acted in their brains, and how it affected chemical signaling among specific interneuron brain cells, which help relay and filter chemical signals between neurons in localized areas of the brain.

They found that Cntnap4 in mature interneurons strengthened GABA signaling, but did not do so in younger interneurons. When researchers traced where Cntnap4 acted in immature brain cells, Dr. Fishell says tests showed that it stimulated “a big bolus of dopamine.”

As part of testing to confirm the hereditary link among Cntnap4, the two pathways, and grooming behaviors, researchers exposed young mice with normal levels of Cntnap4, who did not groom each other, to mature mice with and without Cntnap4. Only mature mice deficient in Cntnap4 preened the hairstyle on other mice. Further tests in young mice without Cntnap4 showed that other, mature mice with normal amounts of Cntnap4 largely let them be, without any particular grooming or hairstyle.

Dr. Fishell and his team plan further analyses of how GABA and dopamine production changes as brain cells mature, and precisely what cellular mechanisms are involved in autism. Their goal is to control and rebalance any biological systems that go awry, as a possible future therapy for the disease.

The control of dendritic branching by mitochondria

A fundamental difference between neurons in real brains and those in artificial neural networks is the way the neurons in each are connected. In artificial nets, the synapses between neurons often have adjustable strengths, but the structure and scale of the input dendritic field generally counts for little. For real neurons, where a “connection” between cells is not just a synapse but rather a whole net unto itself, structure and scale are everything. The architect of this dendritic structure is neither a DNA code nor a spontaneous developmental physics that condenses order from a protein-lipid chaos. This structure is in fact the byproduct of competitive, yet cooperative mitochondria that administer that code to themselves and to their host to control its interaction with other similarly controlled hosts.

Reseachers from Osaku University have found that if mitochondria are depleted from developing dendrites in pyramidal cells, there is increased branching in the proximal region of the dendrites. In their paper last week in the Journal of Neuroscience, they also show that these dendrites grow longer. Since mitochondria distribute not just energy but also metabolites, proteins, and mRNAs throughout the cell, these results may be somewhat surprising. However depending on what manipulations have been done to alter the mitochondria, many things might be expected to happen to dendrites and the cell in general.

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Brain imaging reveals clues about chronic fatigue syndrome

A brain imaging study shows that patients with chronic fatigue syndrome may have reduced responses, compared with healthy controls, in a region of the brain connected with fatigue. The findings suggest that chronic fatigue syndrome is associated with changes in the brain involving brain circuits that regulate motor activity and motivation.

Compared with healthy controls, patients with chronic fatigue syndrome had less activation of the basal ganglia, as measured by fMRI (functional magnetic resonance imaging). This reduction of basal ganglia activity was also linked with the severity of fatigue symptoms.

According to the Centers for Disease Control and Prevention, chronic fatigue syndrome is a debilitating and complex disorder characterized by intense fatigue that is not improved by bed rest and that may be worsened by exercise or mental stress.

The results are scheduled for publication in the journal PLOS One.

"We chose the basal ganglia because they are primary targets of inflammation in the brain," says lead author Andrew Miller, MD. "Results from a number of previous studies suggest that increased inflammation may be a contributing factor to fatigue in CFS patients, and may even be the cause in some patients."

Miller is William P. Timmie professor of psychiatry and behavioral sciences at Emory University School of Medicine. The study was a collaboration among researchers at Emory University School of Medicine, the CDC’s Chronic Viral Diseases Branch, and the University of Modena and Reggio Emilia in Italy. The study was funded by the CDC.

The basal ganglia are structures deep within the brain, thought to be responsible for control of movements and responses to rewards as well as cognitive functions. Several neurological disorders involve dysfunction of the basal ganglia, including Parkinson’s disease and Huntington’s disease, for example.

In previous published studies by Emory researchers, people taking interferon alpha as a treatment for hepatitis C, which can induce severe fatigue, also show reduced activity in the basal ganglia. Interferon alpha is a protein naturally produced by the body, as part of the inflammatory response to viral infection. Inflammation has also been linked to fatigue in other groups such as breast cancer survivors.

"A number of previous studies have suggested that responses to viruses may underlie some cases of CFS," Miller says. "Our data supports the idea that the body’s immune response to viruses could be associated with fatigue by affecting the brain through inflammation. We are continuing to study how inflammation affects the basal ganglia and what effects that has on other brain regions and brain function. These future studies could help inform new treatments."

Treatment implications might include the potential utility of medications to alter the body’s immune response by blocking inflammation, or providing drugs that enhance basal ganglia function, he says.

The researchers compared 18 patients diagnosed with chronic fatigue syndrome with 41 healthy volunteers. The 18 patients were recruited [not referred] based on an initial telephone survey followed by extensive clinical evaluations. The clinical evaluations, which came in two phases, were completed by hundreds of Georgia residents. People with major depression or who were taking antidepressants were excluded from the imaging study, although those with anxiety disorders were not.

For the brain imaging portion of the study, participants were told they’d win a dollar if they correctly guessed whether a preselected card was red or black. After they made a guess, the color of the card was revealed, and at that point researchers measured blood flow to the basal ganglia.

The key measurement was: how big is the difference in activity between a win or a loss? Participants’ scores on a survey gauging their levels of fatigue were tied to the difference in basal ganglia activity between winning and losing. Those with the most fatigue had the smallest changes, especially in the right caudate and the right globus pallidus, both parts of the basal ganglia.

Ongoing studies at Emory are further investigating the impact of inflammation on the basal ganglia, including studies using anti-inflammatory treatments to reduce fatigue and loss of motivation in patients with depression and other disorders with inflammation including cancer.

Healthcare professionals must be aware of the signs, symptoms and appropriate response to rarer causes of headaches in pregnancy, suggests new review

Most headaches in pregnancy and the postnatal period are benign, but healthcare professionals must be alert to the rarer and more severe causes of headaches, suggests a new review published in The Obstetrician & Gynaecologist (TOG).

(Image caption: Given an opportunity to spread in cells, prion-like proteins taken from the brains of patients with (from top) Alzheimer’s disease, corticobasal degeneration and Pick’s disease form distinctly shaped clumps (green in this image) in different parts of the cells. Credit: David W. Sanders)

Alzheimer’s disease, other conditions linked to prion-like proteins

A new theory about disorders that attack the brain and spinal column has received a significant boost from scientists at Washington University School of Medicine in St. Louis.

The theory attributes these disorders to proteins that act like prions, which are copies of a normal protein that have been corrupted in ways that cause diseases. Scientists previously thought that only one particular protein could be corrupted in this fashion, but researchers in the laboratory of Marc Diamond, MD, report that another protein linked to Alzheimer’s disease and many other neurodegenerative conditions also behaves very much like a prion.

The findings appear online May 22 in Neuron.

Diamond’s lab found that the protein, known as tau, could be corrupted in different ways, and that these different forms of corruption — known as strains — were linked to distinct forms of damage to the brain.

“If we think of these different tau strains as different pathogens, then we can begin to describe many human disorders linked to tau based on the strains that underlie them,” said senior author Diamond, the David Clayson Professor of Neurology. “This may mean that certain antibodies or drugs, for example, will work better against certain disorders than others.”

The study was led by co-first authors David Sanders and Sarah Kaufman, who are graduate students.

Prions are composed of normal proteins that have folded into an abnormal shape. They aren’t alive, but their effects can be similar to infectious microbes such as bacteria or viruses. Their unusual structure lets prions replicate themselves through a kind of molecular peer pressure: When a prion interacts with identical but normally folded proteins, it can cause these proteins to become prions, which are small aggregates, or clumps, that can spread from cell to cell.

Prions first came to popular attention in the 1990s with the emergence of mad cow disease, a disorder that destroys the brains of cattle. Scientists linked a few cases of a similar condition in people to consumption of meat from infected cows. Researchers eventually determined that the disorder was caused by a distinct strain of prions made by the sickened cattle.

Scientists had suspected that prion-like forms of a protein called alpha-synuclein contribute to Parkinson’s disease and other conditions, and prion-like versions of proteins known as SOD1 and TDP43 may cause amyotrophic lateral sclerosis, commonly known as Lou Gehrig’s disease.

Scientists also had identified tau clumps in 25 different neurodegenerative disorders, known collectively as tauopathies. This hinted at potential prion-like behavior on the part of tau. In 2009, Diamond’s group found that tau misfolds into several different shapes in a test tube.

“When we infected a cell with one of these misshapen copies of tau and allowed the cell to reproduce, the daughter cells contained copies of tau misfolded in the same fashion as the parent cell,” Diamond said. “Further, if we extracted the tau from an affected cell, we could reintroduce it to a naïve cell, where it would recreate the same aggregate shape. This proves that each of these differently shaped copies of the tau protein can form stable prion strains, like a virus or a bacteria, that can be passed on indefinitely.”

Diamond used the tau prions made in cells to infect mouse brains, showing that differently shaped strains caused different levels of brain damage. He isolated the prions from the mice, grew them in cell culture, and then infected other mice. Throughout these transfers, each particular prion strain continued to be misfolded in the same shape and to cause damage in the same fashion.

Finally, the researchers examined clumps of tau from the brains of 28 patients after they died. Each of the patients was known to have one of five forms of tauopathy.

“Each disease had a unique tau prion strain or combination of strains associated with it,” he said. “For example, we isolated the same tau prion strain from nearly every patient with Alzheimer’s disease we examined.”

Brain samples from patients with the progressive neurological disorderscorticobasal degeneration and Pick’s disease also typically had the same tau prion strains or mixtures of strains.

Diamond and others now are working to find a way to isolate tau prions non-invasively from individuals for diagnostic purposes.

Options for stopping prions include monoclonal antibodies, which could label prions for inactivation or immune system attack and removal (described in a paper by Diamond and David Holtzman, MD, Chair of Neurology (Neuron, 2013)). Diamond and others also are developing ways to block tau prion movement between cells and to stop cells from making new copies of the prion proteins.