IV. Effects of T. gondii on Behavior and Psychiatric Symptoms
• Early research
Beginning in the late 1970s, G. Piekarski (1978) and P.-A. Witting (1979) in Bonn began investigations to ascertain possible effects of latent T. gondii on mice and rats. The impetus for their research appears to have been the reported behavioral effects of other parasitic infections and the known association of congenital T. gondii with mental retardation. Piekarski and Witting reported that T. gondii caused impaired learning in mice and rats and impaired memory in mice. Based on these findings, Hutchinson, Hay et al. in Glasgow studied T. gondii–infected mice and reported that, compared to uninfected controls, the infected mice had increased activity, especially in exploring novel environments. Holliman summarized this early research (Holliman RE, Toxoplasmosis, behaviour and personality, J Infect 1997;35:105–110).
• Behavioral manipulation by T. gondii in rodents
The manipulation hypothesis states that a parasite may alter the behavior of its host in order to improve its transmission rate. Carl Zimmer’s Parasite Rex provides wonderful illustrations of this phenomenon.
Joanne Webster (SMRI grantee) and her colleagues, initially at Oxford and now at Imperial College London, noted the early research cited above and carried it forward. Beginning in 1994, they published a series of studies demonstrating that rats infected with T. gondii were more active and less neophobic of cat urine than controls rats (Berdoy M, Webster JP, Macdonald DW, Fatal attraction in rats infected with Toxoplasma gondii, Proc R Soc Lond B 2000;267:1591–1594). Both changes would make it more likely that the rat would be eaten by a cat, thus completing the life cycle of T. gondii and being an example of the manipulation hypothesis. These studies were summarized by Dr. Webster (Webster JP, Rats, cats, people and parasites: the impact of latent toxoplasmosis on behaviour, Microbes Infect 2001;3:1037–1045).
Given the findings of Webster et al., Ajai Vyas (SMRI grantee) and his colleagues at Stanford University sought to replicate them. They did so, showing in both mice and rats that T. gondii infection reverses the rodents’ natural aversion to the smell of cat urine and causes them to instead “develop an actual attraction to the pheromones” (Vyas A, Kim S-K, Giacomini N et al., Behavioral changes induced by Toxoplasma infection of rodents are highly specific to aversion of cat odors, Proc Natl Acad Sci USA 2007;104:6442–6447, copyright 2007, the National Academy of Sciences of the USA; linked to PDF file with permission).
• Effects of T. gondii on personality traits of humans
Jaroslav Flegr (SMRI grantee) and his colleagues at Charles University in Prague have, since 1992, been studying the effects of T. gondii infection on human personality traits and behavior. Utilizing university students, military recruits, and blood donors, Flegr et al. have administered a series of personality questionnaires and compared individuals with and without antibodies to T. gondii. Infected men were shown to be more expedient, suspicious, jealous, and dogmatic, whereas infected women had more warmth and superego strength. Flegr has summarized these findings (Flegr J, Effects of Toxoplasma on human behavior, Schizophr Bull 2007;33:757–760).
• Effects of T. gondii on the behavior of humans
Flegr et al. also compared his infected and uninfected groups on reaction time as measured by a standard computerized test. Infected individuals performed significantly more poorly and appeared to lose their concentration more quickly (Havlicek J, Gasova Z, Smith AP et al., Decrease in psychomotor performance in subjects with latent ‘asymptomatic’ toxoplasmosis, Parasitology 2001;122:515–520).
Flegr et al. also compared the sera of 146 individuals deemed to have been responsible for causing a motor vehicle accident, with 446 controls. Those individuals who had antibodies to T. gondii, compared with those without antibodies, had more than twice the risk of having caused a motor vehicle accident (Flegr J, Havlicek J, Kodym P et al., Increased risk of traffic accidents in subjects with latent toxoplasmosis: a retrospective case-control study, BMC Infect Dis 2002;2:11).
In Turkey, Yereli et al. replicated the association between traffic accidents and T. gondii infection. In a case-control study, they compared 185 individuals “who were involved in a traffic accident while driving,” with 185 matched controls. T. gondii antibodies were found in 24 percent of those involved in traffic accidents, compared with 6 percent of the controls (p<0.05) (Yereli K, Balcioglu IC, Ozbilgin A, Is Toxoplasma gondii a potential risk for traffic accidents in Turkey? Forensic Sci Int 2006;163:34–37).
• Psychiatric manifestations of congenital T. gondii infections
It is clearly established that congenital infections with T. gondii, especially early in pregnancy, can produce intracranial calcifications, mental retardation, deafness, seizures, and retinal damage. Less clearly established are the long-term effects of congenital infection that occur late in pregnancy and that are often latent at birth. Two research groups have reported late effects, especially lower IQ, following latent congenital infections (Alford A, Stagno S, Reynolds DW, Congenital toxoplasmosis: clinical, laboratory, and therapeutic considerations, with special reference to subclinical disease, Bull NY Acad Med 1974;50:160–181; Wilson CB, Remington JS, Stagno S et al., Development of adverse sequelae in children born with subclinical congenital Toxoplasma infection, Pediatrics 1980;66:767–774). However, long-term follow-up of a similar cohort in Europe reported no loss of IQ or other significant sequelae (Koppe JG, Rothova A, Congenital toxoplasmosis: a long-term follow-up of 20 years, Int Ophthalmol 1989;13:387–390).
No study has reported psychosis or other symptoms of schizophrenia in children infected with congenital latent toxoplasmosis. However, a 30-year psychiatric follow-up of the European cohort cited above reported one case of major depression, one suicide, and one case of sex change among the eight cases on which clinical data were available (Selton J-P, Kahn RS, Schizophrenia after prenatal exposure to Toxomplasma gondii? Clin Infect Dis 2002;35:633–634).
• Psychiatric manifestations of adult T. gondii infections
Humans may become infected with T. gondii at any time in life. The clinical picture is nonspecific but often includes headache, fever, malaise, myalgia, and lymphadenopathy (Carme B, Demar M, Ajzenberg D et al., Severe acquired toxoplasmosis caused by wild cycle of Toxoplasma gondii, French Guiana, Emerg Infect Dis 2009;15:656-658; Silva CS, Neves ES, Benchimiol El et al., Postnatal acquired toxoplasmosis patients in an infectious disease reference center, Braz J Infect Dis 2008;12:438-441). In recent years, most clinical cases have been described in patients with AIDS, thus making it difficult to ascertain which clinical symptoms are due to the toxoplasmosis and which are due to AIDS. However, in 1966, prior the AIDS epidemic, two publications summarized the neurological and psychiatric symptoms found in T. gondii infection occurring in adults.
Kramer in the Netherlands summarized 114 cases of adult toxoplasmosis published between 1940 and 1964. Among these, he noted that “psychiatric disturbances were very frequent,” occurring in 24 cases. Some cases were described as having acute or subacute psychosis, and others as having “psychic alteration” (Kramer W, Frontiers of neurological diagnosis in acquired toxoplasmosis, Psychiatr Neurol Neurochir 1966;69:43–64). Ladee et al., also in the Netherlands, noted that “the literature not infrequently focuses attention on psychoses with schizophrenic or schizophreniform features that accompany chronic toxoplasmosis or that acquired in childhood or early in adult life. . . . In several instances a neurasthenic prodromal stage is followed by an initially suspected paranoid or paranoid-hallucinatory picture” (Ladee GA, Scholten JM, Meyes FEP, Diagnostic problems in psychiatry with regard to acquired toxoplasmosis, Psychiatr Neurol Neurochir 1966;69:65–82).
Many of these early reported cases are very interesting. For example, in 1951 Ström reported two cases of adult toxoplasmosis in laboratory workers. A 22-year-old woman who “often pipetted toxoplasma exudates” developed lyphadenopathy, headache, and fever. Diagnosis of toxoplasmosis was confirmed by skin test. Attempts to demonstrate T. gondii by microscopy of CSF or inoculation of CSF into mice was unsuccessful. She also had psychiatric symptoms: three months after the onset of infection, she “finds it difficult to concentrate,” “cannot follow a conversation when several people are present,” and “she feels far away, as if her body wasn’t there” (Ström J, Toxoplasmosis due to laboratory infection in two adults, Acta Med Scand 1951;139:244–252).
In another case, a 47-year-old woman who also worked in the laboratory with T. gondii presented “obviously delirious with delusions and hallucinations . . . the patients was irrational, spoke frequently to imaginary characters in the room and indicated she was going to die from toxoplasmosis.” In fact, she went into a coma and did die, and her diagnosis was confirmed at autopsy by animal inoculation of brain, liver, and spleen. Despite a normal CSF (no cells, normal protein and sugar), it was also positive for T. gondii by animal inoculation (Sexton RC, Eyles DE, Dillman RE, Adult toxoplasmosis, Am J Med 1953;14:366–377).
Since 1966, there have been occasional similar case reports, but except for patients with AIDS in whom psychiatric symptoms are prominent, this subject has received little attention. An example of a case report was a 20-year-old male who presented with delusions, auditory hallucinations, and catatonic symptoms but was then diagnosed with toxoplasmic encephalitis based on serological tests (Freytag HW, Haas H, Psychiatric aspects of acquired toxoplasmosis, Nervenarzt 1979;50:128–131, in German). The incidence of such cases is unknown.
Another approach to this question is to do a follow-up examination of individuals who are thought to have been infected by T. gondii during outbreaks of water-borne infection. Examples of such outbreaks include a 1979 outbreak among 39 U.S. military personnel (Benenson MW, Takafuji ET, Lemon SM et al., Oocyst-transmitted toxoplasmosis associated with ingestion of contaminated water, N Engl J Med 1982;307:666–669) and a 1995 outbreak among an estimated 2,900–7,700 people in Victoria, Canada (Bowie WR, King AS, Werker DH et al., Outbreak of toxoplasmosis associated with municipal drinking water, Lancet 1997;350:173–177). To date, such follow-up studies have not been done.
Current SMRI-funded research in this area
Rima McLeod, University of Chicago: A pilot study of toxoplasmosis, schizophrenia, and bipolar disorder: clinical follow-up of children with congenital toxoplasmosis with beginning analysis of neuroimaging and host-parasite genetics.