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Gray Matters
28 April 2015

As an animal lover with a special affinity for cats, every few weeks I receive an article from a concerned friend, claiming that the Toxoplasma parasite in cats is making us crazy and killing more than a million people each year by driving them to car crashes, pushing them to violent suicides, boosting their risk of brain cancer, or destining their brains for schizophrenia or neurosis.

So cats are obviously the devil and turning me into a crazy person.

But I've always been too proud of the incredibly complex human brain to buy into this idea. And I've always had a nagging skepticism ­­— this just sounds too bad to be true. Like anything else in science, we need extraordinary evidence for such extraordinary claims about a mind-controlling parasite being the source of all evil.

So how certain are we that the Toxoplasma parasite is really able to invade our brains and take control?

"This indeed is a controversial area of investigation," said David J. Bzik, a professor of microbiology and immunology at Geisel School of Medicine at Dartmouth College in New Hampshire. "The evidence that Toxoplasma affects human behavior is extremely dubious and sketchy at this time, with the exception of an immunocompromised person."

As it turns out, even when it comes to mice and rats, what the Toxoplasma parasite actually does to its host is unclear and remains a matter of debate among researchers in the field. Some argue that theories about this parasite need a "rethink," and some go as far as asking whether the widespread narrative of the Toxoplasma parasite is merely fiction.

The story of Toxoplasma, and what it really does to rats

Here's what we know about the single-celled parasite Toxoplasma gondii (T. gondii): it lives and reproduces in cats' intestines, but it can infect other animals and humans who eat undercooked or raw contaminated pork, lamb or other meat, or come in contact with feces from an infected cat. It's estimated to infect 30 percent of the world's population. In unborn babies and in people with compromised immune systems, the infection can be devastating, but among healthy people, very few show any symptoms because their immune system efficiently attacks the parasite and keeps it in a "latent form" inside cysts, unable to cause illness, according to the Centers for Disease Control and Prevention.

From here, a huge debate begins over a controversial theory. The most outspoken advocate on one side is Jaroslav Flegr, a Czech scientist who suspects our minds have been taken over by parasites. The theory Flegr ascribes to holds that if Toxoplasma parasite finds itself in a rat, it wants to get back into a cat's intestines, because that's the only place it can reproduce. So in a stride for survival, the parasite manipulates the behavior of the infected rat in order to increase its chances of being caught and eaten by a cat. For example, it changes the rats' brains in a way that they get less terrified of cats and become even attracted to feline odor.

This is an appealing story for sure, and a widely accepted view, but it lacks solid evidence.

"In rodents, one of the theories has been that dopamine levels are increased in the brain following infection. The evidence for this is sketchy at best, and a recent paper from a prominent Toxoplasma lab, by Dr. David Sibley at Washington University in St. Louis, could not replicate these findings," Bzik said. Moreover, it's been proposed that the effects of Toxoplasma cysts on the brain's dopamine system are due to an increase in an enzyme called tyrosine hydroxylase, but Sibley's study didn't find evidence for this connection.

So what does the Toxoplasma parasite really do to rats? In an article published in Trends in Parasitology in 2013, Andrew Thompson and his colleagues from School of Veterinary and Biomedical Science at Murdoch University in Australia present a round-up of the findings about Toxoplasma infection in rats.

They found that studies have reported a range of behavioral changes in rats infected by the Toxoplasma parasite. Some of these changes increased rodents' risk of getting hunted by cats, including increased activity level, decreased anxiety, impaired motor performance and reaction time, and inappropriate responses to cat odors.

However, the researchers found that these findings are not consistent across all studies. Some studies didn't find a change in rodents' behavior that would turn them into easier prey for cats.

Moreover, some studies also observed behavioral changes that are not related to enhanced predation, including impaired learning and memory, and changes in dominance, social interaction and mate choice. (The researchers provide a complete list of these observations in a reader-friendly table in the article.)

Could these behavioral changes be coincidental? The "perfect" story of the Toxoplasma parasite and how it makes rodents less afraid of cats, has made it tempting to believe that a logical evolutionary mechanism is behind the phenomenon. But in fact, given the inconsistency of observations, there's reason to think that what Toxoplasma does is by pure chance, the researchers said.

Another interesting piece of evidence comes from a different parasite, called Eimeria vermiformis. Studies have found that mice infected with E. vermiformis, too, seem less afraid of of cat odor. But in this case, unlike the Toxoplasma parasite, E. vermiformis doesn't need to get back to cats to reproduce. In fact, if the mouse is caught by a cat, the parasite will die too.

Together, these findings suggest it's possible that if infected rodents become less afraid of cat odor, it's just a coincidental side effect of a general reduction in anxiety and fearfulness, the researchers said. It may have nothing to do with Toxoplasma's master plan for survival.

Mice and men are somewhat different

Virtually all we know about Toxoplasma infection effects in the brain comes from studies in rodents.

Humans and rodents have a lot in common, but findings from animal studies don't always directly translate to humans. Moreover, Toxoplasma infection looks quite different in rodents. It visibly takes over their brain tissue, and their immune system doesn't seem to do a great job at keeping the parasite at bay.

"There is no doubt that Toxoplasma infection of mice alters their behavior but it does need to be kept in mind that Toxoplasma infections in rodents can be severe and chronic and this can cause abnormal brain pathology from primary infection or from the recurrent infections that can and do occur in the brain of rodents," Bzik said.

In contrast, humans with a healthy immune system control Toxoplasma infections extremely well, Bzik said. "Immune control of Toxoplasma in human brains is excellent and you only see re-emergent infections in severe immune deficiency," he said. Even in HIV/AIDS, in which the virus takes gradual control over the immune system, Toxoplasma is actually one of the latest infections to occur. A reinfection in a person with compromised immune system causes dangerous, often lethal encephalitis, and patients can show behavioral effects due to direct brain damage.

In a person with normal immune control, the parasite continues to exist in a latent form, in small cysts inside body tissues, such as muscles and the brain. But it is unclear to what extent such cysts reside in brain tissue of asymptomatic people, because, as one researcher put it, it is hard to find healthy volunteers for brain biopsy.

"There is usually no reason to look so it would have to be a retrospective study," said Gustavo Arrizabalaga, an assistant professor at Indiana University.

Some evidence that latent parasites exist in the brain comes from occasional case reports of people who get an infection when their immune system gets temporarily shut down for an organ transplant or cancer treatment.

"The fact that these individuals get toxoplasmosis in the brain would indicate that these people harbored the cysts when they were healthy," Arrizabalaga said.

What about observational studies?

Consistent with Flegr's argument, there's a host of studies linking Toxoplasma infection with outcomes in humans, such as higher risk for car accidents, brain cancer, schizophrenia and suicide. (One study linked the parasite with a positive outcome, having better control of actions.)

However, the findings of these studies are correlational, and don't prove a cause-and-effect relationship, which makes it difficult to draw definitive conclusions. For example, someone with schizophrenia might struggle to keep up good hygiene and so may be more likely to acquire Toxoplasmosis.

Also, there may be other factors behind the link.

"People who are infected with Toxoplasma are most likely the ones who are more likely to eat raw meat and to be infected," Bzik said. "So the behavior association is just as likely to be due to a pre-existing behavioral change linked to the desire to eat raw meat."

Moreover, some of the studies suffer from quality issues in the methods, such as having a small size or not controlling for confounding factors. And the results are sometimes up for different interpretations. For example, in a study that linked the parasite to suicide risk in people, researchers looked at 517 women who had tried to kill themselves, with 78 of these women attempting violent methods such as guns. The researchers found that women who were once infected with Toxoplasma were 1.8 times more likely to attempt suicide by violent means than uninfected women. Eighteen of the women in the whole sample succeeded at killing themselves, and eight of them had once been infected.

"The scientific problem with every one of these studies is that the populations studied are too small to gain meaningful insights," Bzik said. "With the human stories, there currently is no hard or definitive evidence that Toxoplasma causes behavioral changes at this time. But it makes for really nice and sometimes fearful stories that are widely publicized."

It could be that these findings are true. It could be that my cat-controlled brain is trying to convince you otherwise. And remember that Toxoplasma is a nasty parasite that can cause severe disease in vulnerable people. But clearly, before making a final call on how it affects our brains, we should pursue more evidence. And before understanding the effects of Toxoplasma on human psychology, at the very least, its behavior in rodents should be better studied, researchers argue.

"In light of the questionable assumptions and the inconsistent evidence that underlie the accepted dogma, we believe the effect of T. gondii on rodent behavior is not yet well understood," Thompson and his colleagues wrote.

"Given that research into human behavior is based at least partly on findings in rodents, it is vital that we have a good understanding of how rodent behavior is affected by T. gondii, before we extrapolate to other species."