A novel mechanism regulating stress is identified

Neuroscience researchers from Tufts have demonstrated, for the first time, that the physiological response to stress depends on neurosteroids acting on specific receptors in the brain, and they have been able to block that response in mice. This breakthrough suggests that these critical receptors may be drug therapy targets for control of the stress-response pathway. This finding may pave the way for new approaches to manage a wide range of neurological disorders involving stress. 

The stress-control pathway, more technically known as the Hypothalamus-Pituitary-Adrenal (HPA) axis, determines the levels of cortisol and other stress hormones in the human body. In addition to being implicated in the types of emotional and psychological stress that can lead to major depression, disorders of the stress-control pathway are also associated with obesity, premenstrual syndrome, postpartum depression, Cushing's syndrome (hypercortisolism) and diseases including epilepsy and osteoporosis. 

"We have identified a novel mechanism regulating the body's response to stress by determining that neurosteroids are required to mount the physiological response to stress. Moreover, we were able to completely block the physiological response to stress as well as prevent stress-induced anxiety," said author Jamie Maguire, PhD, assistant professor in the department of neuroscience at Tufts University School of Medicine and a member of the Neuroscience and Pharmacology & Experimental Therapeutics program faculties at the Sackler School of Graduate Biomedical Sciences at Tufts. 

Using the brain tissues of adult mice, the research team identified mechanisms controlling the activity of Corticotrophin Releasing Hormone (CRH) neurons involved in the control of the stress pathway. By monitoring the activity of CRH neurons following stress and measuring levels of corticosterone in the blood, they found that the production of stress hormones required the action of neurosteroids on specific receptors on CRH neurons. 

Apart from the finding that stress causes a neurosteroid-induced increase in blood corticosterone levels, the researchers also found that blocking the synthesis of neurosteroids is sufficient to block the stress-induced elevations in corticosterone and prevent stress-induced, anxiety-like behavior in mice. Previous research had identified the presence of specialized CRH-nerve-cell receptors in the HPA axis, but the findings had been controversial because of limited studies showing any connection between these receptors and the regulation of the CRH nerve cells. 

"We have found a definite role of neurosteroids on the receptors regulating CRH nerve cells and the stress response. The data suggest that these receptors may be novel targets for control of the stress-control pathway. Our next work will focus on modulating these receptors to treat disorders associated with stress, including epilepsy and depression-like behaviors," said Maguire. 

Source: Tufts University, Health Sciences Campus [December 13, 2011]

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Brain stimulator shown to reduce 'untreatable' epileptic seizures

Brain stimulation, already approved by the U.S. Food and Drug Administration for the treatment of Parkinson's disease and essential tremor, has now been shown to offer significant relief to patients with intractable seizures for whom drugs and other treatments have not worked. 

This is the major finding of a first-of-its-kind study of responsive electric brain stimulation in adults with "medically refractory," or hard to treat, epilepsy. 

The NeuroPace Responsive Neurostimulation (RNS) System consists of a miniaturized, implanted computer which can detect seizures from electrodes implanted into or on the surface of the brain and deliver an electrical pulse to stop them. 

Henry Ford Hospital was the only site in Michigan to participate in this multicenter investigation, which was based in California. The study is published in the current issue of Neurology. 

"For the third of people who have tried two or three medications for their epilepsy, but are still having seizures, the standard of care is removing the abnormal part of the brain that is causing seizures. Over 50 percent of patients undergoing surgical removal of brain tissue causing seizures will be cured of their epilepsy," says Jason M. Schwalb, M.D., Director, Movement Disorder and Behavioral Neurosurgery at Henry Ford Health System. 

"However, there are people who are not candidates for this type of surgery because of potential side effects. Until now, we have not had great treatment options. The RNS system is an attractive option for these patients, especially since it is reversible." 

A total of 191 adults, ages 18 to 70, whose disabling epileptic seizures had not been controlled by at least two medications, were chosen. They were studied at 32 medical sites throughout the U.S. for three years, beginning in late 2005. 

All patients were implanted with electric leads attached to one or two seizure focal points in their brains. Their abnormal brain activity was recorded for a month, and then they were chosen at random either to receive electric stimulation or to be given "sham," or no treatment. 

The researchers found: 

• The 97 patients who were treated with the RNS system had 37.9 percent fewer seizures than before surgery. Those 94 patients in the sham, or untreated group, had only 17.3 fewer seizures than before surgery. 

• When those in the sham group had the RNS system turned on, seizures were significantly reduced. 

• There was no difference between the two groups in the number of adverse events associated with the treatment. 

• The effects of the treatment led to significant improvements in patients' quality of life. (Medically refractory epilepsy patients with frequent seizures are at risk of depression, suicidal thoughts and actions, memory loss, and SUDEP, or sudden unexplained death in epilepsy.)  

Source: Henry Ford Health System [November 08, 2011]

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