Why Serotonin Can Cause Depression And Anxiety

Daily Science Journal (Feb. 5, 2008) — Mood disorders could be caused by a loss of our inherent, reflexive avoidance of aversive events, according to a new study. Researchers from UCL in London and Columbia University in New York used computational modeling techniques to integrate what appeared to be blatant contradictions between serotonin's roles in different states of health.

Serotonin appears to be one of the major players in mood and a variety of other disorders. But exactly how remains an open question. Imagine walking past a dark alleyway in a dangerous part of some city; although it might be a shortcut, most people wouldn't consider taking it. In healthy subjects, serotonin appears important for this automatic avoidance.

It has long been suggested that over-activity of the serotonin system may relate to mood disorders such as depression and anxiety, as these seem characterized by too much withdrawal and avoidance. However, the new modeling study simply suggests that we think about what happens when these reflexes fail--suddenly you have to think hard to avoid things that used to be avoided reflexively You might for example consider walking down the dangerous alley, be robbed and thus be reminded and taught by additional experience that dark alleys are to be avoided.

In this study Prof. Peter Dayan and Dr. Quentin Huys built a reinforcement learning model of reflexive choices. Agents take actions and as a result of these move through a set of states, some of which are rewarded or punished. As agents progress through this space, they learn the value of each state--how much punishment or reward is to be expected from this state onwards.

It turns out that adding to the agent's behavioural repertoire a simple reflex, which guides the agent away from an action with potential for poor consequences, does two things: it increases the rewards reaped overall, but, because bad states are now not explored any more, it also prevents them from learning exactly how bad these bad states are. When serotonin drops, say in depression or anxiety, agents have no more recourse to the reflexive avoidance and have to rely on what they learned. Because they have not learned how bad the bad states are, they start exploring states that don't look too bad to them, but in reality are much worse. Serotonin enhancing drugs, such as Prozac, are then suggested to reinstate the reflexive avoidance, and thus to redress the balance.

This study gives insight into some puzzling findings--for example, it argues that the association of depression with aggression may have to do with a lack of reflexive avoidance of it. In addition, stress not only causes depression, but people with depression experience more stressors. Again, this may be related to a dysfunctional reflexive avoidance system. The study, however, vastly oversimplifies a number of issues, such as the flexibility of reflexive actions, and the effect of non-reflexive action choice. These provide interesting avenues for further research, and may in fact give some insight into the co-morbidity of different mood disorders.

Journal citation: Dayan P, Huys QJM (2008) Serotonin, inhibition, and negative mood. PLoS Comput Biol 4(1): e4. doi:10.1371/journal.pcbi.0040004. http://compbiol.plosjournals.org/perlserv/?request=get-document&doi=10.1371/journal.pcbi.0040004

Adapted from materials provided by PLoS Computational Biology, via EurekAlert!, a service of AAAS.

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Why Scratching Relieves An Itch

Daily Science Journal (Feb. 1, 2008) — In the first study to use imaging technology to see what goes on in the brain when we scratch, researchers at Wake Forest University Baptist Medical Center have uncovered new clues about why scratching may be so relieving -- and why it can be hard to stop.

"Our study shows for the first time how scratching may relieve itch," said lead author Gil Yosipovitch, M.D., a dermatologist who specializes in itch. "It's important to understand the mechanism of relief so we can develop more effective treatments. For some people, itch is a chronic condition that affects overall health."

The study involved 13 healthy participants who underwent testing with functional magnetic resonance imaging (MRI) technology that highlights areas of the brain activated during an activity. Participants were scratched on the lower leg with a small brush. The scratching went on for 30 seconds and was then stopped for 30 seconds -- for a total of about five minutes.

"To our surprise, we found that areas of the brain associated with unpleasant or aversive emotions and memories became significantly less active during the scratching," said Yosipovitch. "We know scratching is pleasurable, but we haven't known why. It's possible that scratching may suppress the emotional components of itch and bring about its relief."

The reduced brain activity occurred in the anterior cingulate cortex, an area associated with aversion to unpleasant sensory experiences, and the posterior cingulate cortex, which is associated with memory. When participants reported that the scratching felt most intense, activation in these areas was lowest.

Yosipovitch said patients occasionally report that intense scratching -- to the point of drawing blood -- is the only thing that relieves chronic itch.

"This is the first real scientific evidence showing that itch may be inhibited by scratching," he said. "Of course, scratching is not recommended because it can damage the skin. But understanding how the process works could lead to new treatments. For example, drugs that deactivate this part of the brain might be effective."

The imaging studies also showed that some areas of the brain were made more active by the scratching, including the secondary somatosensory cortex, a sensory area involved in pain, and the prefrontal cortex, which is associated with compulsive behavior.

"This could explain the compulsion to continue scratching," said Yosipovitch.

One drawback to the study is that the scratching occurred in the absence of itch. Yosipovitch's team is continuing the research by evaluating whether the findings will apply to chronic itch.

Understanding more about chronic itch is important, Yosipovitch said, noting that more than 30 million Americans suffer from eczema and that almost half (42 percent) of kidney dialysis patients are bothered by moderate to severe itch. In fact, those kidney dialysis patients with itch have a 17 percent higher mortality rate, likely from a loss of sleep, according to a report in Nephrology Dialysis Transplantation.

The work is reported online in the Journal of Investigative Dermatology and will appear in a future print issue.

The study was supported by the National Institutes of Health and the Center for Biomolecular Imaging of Wake Forest. Co-researchers were Yozo Ishuiji,MD, Tajesh Patel, M.D., Maria Isabel Hicks, M.D., Yoshitetsu Oshiro, M.D., Robert Kraft, Ph.D., Erica Winnicki, M.D., and Robert C. Coghill, Ph.D., senior author, all from Wake Forest.

Adapted from materials provided by Wake Forest University Baptist Medical Center, via EurekAlert!, a service of AAAS.

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Brain Differences Found In People With Migraine ; Scientists Identify Protein That May Promote Migraines

Daily Science Journal (Nov. 19, 2007) — People with migraines have differences in an area of the brain that helps process sensory information, including pain, according to a new study.

The study found that part of the cortex area of the brain is thicker in people with migraine than in people who do not have the neurological disorder.

Comparing 24 people with migraine to 12 people without migraine, the study found that the somatosensory cortex area of the brain was an average of 21 percent thicker in those with migraine.

"Repeated migraine attacks may lead to, or be the result of, these structural changes in the brain," said study author Nouchine Hadjikhani, MD, of The Martinos Center for Biomedical Imaging at Massachusetts General Hospital in Boston. "Most of these people had been suffering from migraines since childhood, so the long-term overstimulation of the sensory fields in the cortex could explain these changes. It's also possible that people who develop migraines are naturally more sensitive to stimulation."

Hadjikhani said the results indicate that the brain's sensory mechanisms are important components in migraine. "This may explain why people with migraines often also have other pain disorders such as back pain, jaw pain, and other sensory problems such as allodynia, where the skin becomes so sensitive that even a gentle breeze can be painful."

Other studies have shown changes in the cortex. The area becomes thinner in neurological disorders such as multiple sclerosis and Alzheimer's disease. But the area thickens with extensive motor training and learning.

This research is published in the November 20, 2007, issue of Neurology®, the medical journal of the American Academy of Neurology.

The study was supported by grants from the National Institutes of Health, the Swiss Heart Foundation, and the Harvard School of Dental Medicine Dean's Award.

Adapted from materials provided by American Academy of Neurology, via EurekAlert!, a service of AAAS.

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Scientists Identify Protein That May Promote Migraines

A University of Iowa study may provide an explanation for why some people get migraine headaches while others do not. The researchers found that too much of a small protein called RAMP1 appears to "turn up the volume" of a nerve cell receptor's response to a neuropeptide thought to cause migraines.

The neuropeptide is called CGRP (calcitonin gene-related peptide) and studies have shown that it plays a key role in migraine headaches. In particular, CGRP levels are elevated in the blood during migraine, and drugs that either reduce the levels of CGRP or block its action significantly reduce the pain of migraine headaches. Also, if CGRP is injected into people who are susceptible to migraines, they get a severe headache or a full migraine.

"We have shown that this RAMP protein is a key regulator for the action of CGRP," said Andrew Russo, Ph.D., UI professor of molecular physiology and biophysics. "Our study suggests that people who get migraines may have higher levels of RAMP1 than people who don't get migraines."

RAMP1 is a normal, required subunit of the CGRP receptor. Russo and his colleagues found that overexpression of RAMP1 protein in nerve cells increased the sensitivity and responsiveness of CGRP receptors to the neuropeptide -- more RAMP1 made CGRP receptors react to much lower concentrations of CGRP than usual and caused the receptors to respond more vigorously to the neuropeptide.

The UI team also engineered mice to express human RAMP1 in their nervous system in addition to the normal mouse version of the protein. These mice had double the amount of inflammation in response to CGRP than did normal mice. Nerve-induced inflammation is one of the effects associated with migraine headache.

Russo explained that his study raises the possibility that people who have migraines may have subtle genetic differences in the RAMP1 gene that result in increased levels of RAMP1 protein.

"There is clearly a genetic difference between people who get migraines and those who do not, and we think that difference could be RAMP1. Our studies provide a reason to look for variations in the DNA that encodes RAMP1 in humans," he said.

The study also suggests that the mice engineered to produce elevated levels of RAMP1 protein may be a good model for studying migraine and specifically trying to understand how the neuropeptide, CGRP, is working.

The UI team investigated CGRP receptors in the trigeminal nerve, which is responsible for relaying almost all sensory perception, including pain and touch, for the front of the head. The UI findings reinforce the emerging view that CGRP receptors in the trigeminal nerve play a key role in migraine headache.

However, there are other CGRP receptors throughout the body, and elevated CGRP levels are implicated in other types of pain, including arthritis. Russo predicts that his group's findings about RAMP1 will have implications for pain research beyond migraine headaches.

The study was funded by the National Institutes of Health and published in the Journal of Neuroscience.

Adapted from materials provided by University of Iowa.

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