Neuroscience

Research identifies the mechanism that protects our brains from turning stress and trauma into post-traumatic stress disorder

Researchers from the University of Exeter Medical School have for the first time identified the mechanism that protects us from developing uncontrollable fear.

Our brains have the extraordinary capacity to adapt to changing environments – experts call this ‘plasticity’. Plasticity protects us from developing mental disorders as the result of stress and trauma.

Researchers found that stressful events re-programme certain receptors in the emotional centre of the brain (the amygdala), which the receptors then determine how the brain reacts to the next traumatic event.

These receptors (called protease-activated receptor 1 or PAR1) act in the same way as a command centre, telling neurons whether they should stop or accelerate their activity.

Before a traumatic event, PAR1s usually tell amygdala neurons to remain active and produce vivid emotions. However, after trauma they command these neurons to stop activating and stop producing emotions – so protecting us from developing uncontrollable fear.

This helps us to keep our fear under control, and not to develop exaggerated responses to mild or irrelevant fear triggers – for example, someone who may have witnessed a road traffic accident who develops a fear of cars or someone who may have had a dog jump up on them as a child and who now panics when they see another dog.

The research team used mice in which the PAR1 receptors were genetically de-activated and found that the animals developed a pathological fear in response to even mild, aversive stimuli.

The study was led by Professor Robert Pawlak of University of Exeter Medical School. He said: “The discovery that the same receptor can either awaken neurons or ‘switch them off’ depending on previous trauma and stress experience, adds an entirely new dimension to our knowledge of how the brain operates and emotions are formed.”

Professor Pawlak added: “We are now planning to extend our study to investigate if the above mechanisms, or genetic defects of the PAR1 receptor, are responsible for the development of anxiety disorders and depression in human patients. There is more work to be done, but the potential for the development of future therapies based on our findings is both exciting and intriguing.”

The article describing the above findings has recently been published in one of the most prestigious psychiatry journals, Molecular Psychiatry.

By exploring parts of the brain that trigger during periods of daydreaming and mind-wandering, neuroscientists from Western University have made a significant breakthrough in understanding what physically happens in the brain to cause vegetative state and other so-called “disorders of consciousness.”
Vegetative state and related disorders such as the minimally conscious state are amongst the least understood conditions in modern medicine because there is no particular type of brain damage that is known to cause them. This lack of knowledge leads to an alarmingly high level of misdiagnosis.

In support of the study titled, “A role for the default mode network in the bases of disorders of consciousness,” Davinia Fernandez-Espejo, a post doctoral fellow at Western’s Brain and Mind Institute, utilized a technique called diffusion tensor imaging tractography to investigate more than 50 patients suffering from varying degrees of brain injury.

This state-of-the-art magnetic resonance imaging (MRI) technique allows researchers to virtually reconstruct the pathways that connect different parts of the brain in the patients while detecting subtle differences in their brain damage.

Specifically, Fernandez-Espejo was able to show that in vegetative state patients, a group of brain regions known as the default mode network that are known to activate during periods of daydreaming and mind-wandering were significantly disconnected, relative to healthy individuals.

"These findings are a first step towards identifying biomarkers that will help us to improve diagnosis and to find possible therapies for these patients" says Fernandez-Espejo. "But they also give us new information about how the healthy brain generates consciousness."

Strokes often cause loss or impairment of vital brain functions – such as speech, movement, vision or attention. Restoration of these functions is often possible, but difficult. One of the factors impeding brain plasticity is inflammation.  A study on rats, carried out at the Nencki Institute in Warsaw, suggests that effectiveness of neurorehabilitation after a stroke can be improved by anti-inflammatory drugs.

Post-stroke inflammation slows down recovery and impairs brain plasticity, reveal the results from the lab of Professor Małgorzata Kossut at the Nencki Institute in Warsaw. The popular anti-inflammatory drug ibuprofen restores the ability of brain cortex to reorganize – a process necessary for recovery of stroke-damaged functions. “Our research was conducted on rats, but we have good reasons to suppose that in future our results will help improve effectiveness of rehabilitation of stroke patients”, says Prof. Kossut.

The Nencki Institute team stresses that so far there are no proofs that the treatment will be effective in humans and that they did not investigate if the ibuprofen therapy prevents strokes, but concentrated on post-stroke recovery.

The most frequent cause of stroke is blocking of brain arteries. Without supply of oxygen, neurons die quckly. In the region of stroke-induced damage pathological changes cause decrease of brain tissue metabolism, impairment of neurotransmission and edema.

Brain control over physiological and voluntary functions may be lost, depending on the localization of the infarct. Impairments of movement, vision, speech and attention are frequent. In most cases these functions return either partially or completely. Sometimes they return spontaneously, more often after neurorehabilitation.

“In both instances recovery is based on neuroplasticity, the ability of the brain to reorganize, that is to change the properties of neurons and to alter the connections between them”, says Dr. Monika Liguz-Lęcznar (Nencki Institute).

After a stroke, neuroplasticity is impaired. Scientists from the Nencki Institute suppose that this may be due to inflammation developing at the site of the stroke. The proof that decreasing inflammation helps neurorehabilitation came from experiments done on rats with experimentally induced stroke. The stroke was localized in a special region of the brain cortex, receiving information from whiskers.

The whiskers are important sensory organs of rodents, allowing the animals to orient themselves in their environment in darkness. Every whisker activates a small, precisely delineated chunk of brain cortex.

In healthy rats neuroplastic changes can be induced by cutting off some of the whiskers, that is by eliminating part of the sensory input to the brain. The brain reacts to that by letting the remaining whiskers take over more cortical space, expand their cortical representation, at the expense of the cut off ones.

“This plastic change does not occur when the site of stroke-induced damage is near the region of cortex ‘belonging’ to the whiskers. We showed that application of ibuprofen decreases inflammation and restores neuroplasticity – the brain cortex reorganizes like in healthy animals”, says Prof. Kossut.

New research suggests that a mother’s high blood pressure during pregnancy may have an effect on her child’s thinking skills all the way into old age. The study is published in the October 3, 2012, online issue of Neurology®, the medical journal of the American Academy of Neurology.

“High blood pressure and related conditions such as preeclampsia complicate about 10 percent of all pregnancies and can affect a baby’s environment in the womb,” said study author Katri Räikönen, PhD, with the University of Helsinki in Finland. “Our study suggests that even declines in thinking abilities in old age could have originated during the prenatal period when the majority of the development of brain structure and function occurs.”

Researchers looked at medical records for the mother’s blood pressure in pregnancy for 398 men who were born between 1934 and 1944. The men’s thinking abilities were tested at age 20 and then again at an average age of 69. Tests measured language skills, math reasoning and visual and spatial relationships.

The study found that men whose mothers had high blood pressure while pregnant scored 4.36 points lower on thinking ability tests at age 69 compared to men whose mothers did not have high blood pressure. The group also scored lower at the age of 20 and had a greater decline in their scores over the decades than those whose mothers did not have problems with blood pressure. The finding was strongest for math-related reasoning.

The researchers also looked at whether premature birth affected these findings and found no change. Whether the baby’s father was a manual laborer or an office worker also did not change the results.

Efforts to treat disorders like Lou Gehrig’s disease, Paget’s disease, inclusion body myopathy and dementiawill receive a considerable boost from a new research model created by UC Irvine scientists.

The team, led by pediatrician Dr. Virginia Kimonis, has developed a genetically modified mouse that exhibits many of the clinical features of human diseases largely triggered by mutations in the valosin-containing protein.

The mouse model will let researchers study how these now-incurable, degenerative disorders progress in vivo and will provide a platform for translational studies that could lead to lifesaving treatments.

“Currently, there are no effective therapies for VCP-associated diseases and related neurodegenerative disorders,” said Kimonis, a professor of pediatrics who specializes in genetics and metabolism. “This model will significantly spark new approaches to research directed toward the creation of novel treatment strategies.”

She and her team reported their discovery Sept. 28 online in PLOS ONE, a peer-reviewed, open-access journal.

The UCI researchers – from pediatrics, neurology, pathology and radiological sciences – specifically bred the first-ever “knock-in” mouse in which the normal VCP gene was substituted with one containing the common R155H mutation seen in humans with VCP-linked diseases. Subsequently, these mice exhibited the same muscle, brain and spinal cord pathology and bone abnormalities as these patients.

VCP is part of a system that maintains cell health by breaking down and clearing away old and damaged proteins that are no longer necessary. Mutations in the VCP gene disrupt the demolition process, and, as a result, excess and abnormal proteins may build up in muscle, bone and brain cells. These proteins form clumps that interfere with the cells’ normal functions and can lead to a range of disorders.

Another study carried out by members of this group – and published in August in the journal Cell Death & Disease – made use of these genetically altered mice to examine the development of Lou Gehrig’s disease, or ALS. The researchers, led by Dr. Hong Yin and Dr. John Weiss in UCI’s Department of Neurology, documented slow, extensive pathological changes in the spinal cord remarkably similar to changes observed in other animal models of ALS as well as in human patients. ALS research is currently limited by a paucity of animal models in which disease processes can be studied.

Genetically modified mice have become important research models in the effort to cure human ailments. Mice bred to exhibit the brain pathology of Alzheimer’s disease, for example, have dramatically sped up the race to advance new treatments – one such model was developed at UCI. And many cancer therapies were created and tested using genetically altered mice.

Parents should not worry that proposed changes to the medical criteria redefining a diagnosis of autism will leave their children excluded and deemed ineligible for psychiatric and medical care, says a team of researchers led by psychologists at Weill Cornell Medical College.

Their new study, published in the October 1 issue of the American Journal of Psychiatry, is the largest to date that has tried to unpack the differences between the diagnostic criteria for autism spectrum disorders in the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) and the proposed revision in the fifth edition (DSM-5), which is expected to be published in May 2013. These manuals provide diagnostic criteria for people seeking mental-health-related medical services.

"I know that parents worry, but I don’t believe there is any substantial reason to fear that children who need to be diagnosed with autism spectrum disorders, and provided with vital services, will not be included in the new criteria in this updated manual," says the study’s senior investigator, Dr. Catherine Lord, director of the Center for Autism and the Developing Brain at NewYork-Presbyterian Hospital’s Westchester campus, along with its affiliated medical schools Weill Cornell Medical College and Columbia University College of Physicians and Surgeons.

At issue is whether DSM-5 will “capture” the same individuals diagnosed with different forms of autism by the DSM-IV. The DSM-5 proposal redefines autism as a single category — autism spectrum disorder (ASD) — whereas DSM-IV had multiple categories and included Autistic Disorder, Asperger’s Disorder, and Pervasive Developmental Disorder, Not Otherwise Specified (PDD-NOS).

Critics have particularly worried that among the excluded will be children now diagnosed with PPD-NOS and Asperger’s disorder. That isn’t the case, says Dr. Lord, who is also a DeWitt Wallace Senior Scholar at Weill Cornell and an attending psychologist at NewYork-Presbyterian Hospital. The study, the largest to date and arguably, the most rigorous, finds that when relying on parent report, 91 percent of the 4,453 children in the sample currently diagnosed with a DSM-IV autism spectrum disorder would be diagnosed with ASD using DSM-V.

Many of the remaining nine percent would likely be reincluded once a clinician can offer input, says Dr. Lord, who is also a member of the American Psychiatric Association’s DSM-5 Neurodevelopmental Disorders Work Group.

The study researchers also concluded that DSM-5 has higher specificity than DSM-IV—in their study, DSM-5 criteria resulted in fewer misclassifications.

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