IV. Effects of T. gondii on Behavior
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).
manipulation by T. gondii in rodents
also section VI. Neurotransmitters and T.
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.
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 behavior.
Microbes Infect. 2001;3:1037–1045). Webster and Glenn McConkey have also
speculated about specific mechanisms that may explain the parasite manipulation
(Webster JP, McConkey GA. Toxoplasma
gondii -altered behaviour: clues as to mechanism of action. Folia Parasitol.
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). They also speculated
regarding possible pathophysiological mechanisms (Vyas A, Sapolsky R.
Manipulation of host behaviour by Toxoplasma
gondii : what is the minimum a proposed proximate mechanism should explain?
Folia Parasitol. 2010;57:88–94) and showed that one of the mechanisms used by T.gondii is to activate sexual arousal pathways of the
rats (House PK, Vyas A, Sapolsky R. Predator cat odors activate sexual arousal
pathways in brains of Toxoplasma gondii infected rats. PLoS One. 2011;6:e23277).
suggested by the above findings, there is evidence that the effects of T. gondii on the brain are highly specific. For example,
in experiments in which mice have been infected, the mice may have profound and
widespread brain pathology and deficits in motor coordination and sensory
deficits, but their cognitive skills remain relatively intact (Gulinello M,
Acquarone M, Kim JH, et al., Acquired infection with Toxoplasma gondii in adult
mice results in sensorimotor deficits but normal cognitive behavior despite
widespread brain pathology. Microbes Infect. 2010;12:528-537). It has also been
shown that the effects of T. gondii in rodents is sex specific as assessed by
gene expression. A study of this specificity concluded that “the sex of the
host plays a major role in determining variable brain and behavior changes
following Toxoplasma infection” (Xiao J, Kannan G, Jones-Brando L,
et al. Sex-specific changes in gene expression and behavior induced by chronic Toxoplasma infection in mice.
of T. gondii on personality traits of humans
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. Thus, sex differences of the effect of T. gondii in humans have been shown, just as they
have been in rodents. Flegr has summarized these findings (Flegr J. Effects of Toxoplasma on human behavior. Schizophr
Bull. 2007;33:757–760; Flegr J. Influence of latent toxoplasmosis on the
phenotype of intermediate hosts. Folia Parasitol. 2010;57:81–87). An article
describing Flegr’s research was also published in the Atlantic magazine (McAuliff K. How your cat is making you crazy. March
of T. gondii on cognition in humans
effects of T. gondii on cognitive measures in humans has been
studied by our laboratory (Yolken RH, Dickerson FB, Torrey EF. Toxoplasma and schizophrenia. Parasite
Immunol. 2009;31:706–715). We measured Toxoplasma
IgG antibodies and cognitive functioning in 291 individuals between the ages of
19 and 60 who did not have a history of a psychiatric disorder. As depicted in
Figure 2, we found that individuals with serological evidence of Toxoplasma infection had significantly
worse performance in measures of delayed memory (p<0.002) and immediate
memory (p<0.05) and trends toward worse performance in other domains. On the
other hand, Toxoplasma serostatus was
not associated with demographic variables that might affect the results of
cognitive testing such as age, gender, race, or level of education. Additional
studies should be performed to further define the association between exposure
to Toxoplasma and cognitive
impairment in other populations, particularly ones containing older adults and
others at risk for cognitive impairment due to multiple genetic and
2. Cognitive functioning in individuals with and without serological evidence
of Toxoplasma infection.
total of 291 individuals between the ages of 19 and 60 without a history of a
psychiatric disease underwent cognitive testing and had their serum IgG
antibodies measured to Toxoplasma gondii.
A total of 39 (13.4%) of the individuals had serological evidence of Toxoplasma infection as defined by
antibody levels > 10 international units. The bars indicate the mean performance
on cognitive tasks with the results standardized so that the mean value in the Toxoplasma seronegative group is equal
to one. The error bars indicate the 95% confidence intervals of the mean
values. The tests performed are as follows: Del Mem, RBANS Delayed Memory; Imm
Mem, RBANS Immediate Memory; Vis Con, RBANS Visuospatial/Constructional;
Attent, RBANS Attention; Lang., RBANS Language; RBANS Tot, RBANS Total Score;
WCS Per Err, Wisconsin Card Sorting Task perseverative errors; WCS Comp,
Wisconsin Card Sorting Task categories completed; Let Num Sc, Letter Number
test scaled score; Trial Sc, Trail Making Test A scaled score. The indicated p
values are computed from linear regression models that include age, gender,
race, and level of education.
of T. gondii on the behavior of humans
et al. also compared his infected and uninfected human subjects 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.
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). This research
group subsequently replicated this finding in another driver cohort in the
Czech Republic (Flegr J, Klose J, Novotna M, et al. Increased incidence of
traffic accidents in Toxoplasma-infected
military drivers and protective effect RhD molecule revealed by a large-scale
prospective cohort study. BMC Infect Dis. 2009;9:e72).
Turkey, there have been two replications showing an association between
individuals involved in traffic accidents and infection with T. gondii. In a case-control study, Yereli
et al. 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). This study has been replicated by
another study in Turkey (Kocazeybek B, Oner YA, Turksoy R, et al. Higher
prevalence of toxoplasmosis in victims of traffic accidents suggest increased
risk of traffic accident in Toxoplasma-infected
inhabitants of Istanbul and its suburbs. Forensic Sci Int. 2009;187:103–108).
In view of this association between traffic accidents and T. gondii, researchers in Mexico assessed the T. gondii antibody status in
133 individuals involved in work-related industrial accidents and 266 controls.
Overall there was no association except among workers who also had low
socioeconomic status (Alvarado-Esquivel C, Torres-Castorena A, Liesenfeld O, et
al. High seroprevalence of Toxoplasma
gondii infection in a subset of
Mexican patients with work accidents and low socioeconomic status. Parasites
& Vectors. 2012;5:13).
manifestations of congenital T. gondii infections
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).
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).
manifestations of adult T. gondii infections
may become infected with T. gondii at any time in life. In immunocompetent
individuals, the infection is asymptomatic 90 percent of the time. In the other
10 percent, the "primary infections cause a mild, mononucleosis-like
illness with low-grade fever, malaise, headache, and cervical
lymphadenopathy" (Kravetz JD. Toxoplasma
gondii. In: Fratamico PM, Smith JL, Brogden KA, eds, Sequelae and Long-Term
Consequences of Infectious Diseases. Washington, D.C.: ASM Press; 2009:217–228).
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.
in the Netherlands summarized 114 cases of symptomatic 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).
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).
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).
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.
possible psychiatric manifestation of T.
gondii infection in immunocompetent
hosts is suicidal ideation. One
study in the United States assessed T.
gondii antibodies in 99 individuals
who had made a suicide attempt; 119 individuals with a recurrent mood disorder
but no history of suicide attempts; and 39 unaffected controls. There was no
significant difference in T. gondii seropositivity, but those who had attempted
suicide had higher T. gondii antibody titres (p=0.004) (Arling TA, Yolken
RH, Lapidus M, et al. Toxoplasma gondii antibody titers and history of suicide
attempts in patients with recurrent mood disorders. J Nerv Ment Dis.
2009;197:905–908). The association between suicide attempts and higher titre to
T. gondii antibodies was replicated by a study in Turkey
(Yagmur F, Yazar S, Temel HO, et al. May Toxoplasma
gondii increase suicide
attempt-preliminary results in Turkish subjects? Forensic Sci Int.
2010;199:15-17). A third study reported an association between suicide attempts
and T. gondii seropositivity in patients with schizophrenia,
but the association was only significant in younger patients (Okusaga O,
Langenberg P, Sleemi A, et al. Toxoplasma
gondii antibody titers and history
of suicide attempts in patients with schizophrenia. Schizophr Res. 2011;133:150-155).
Finally, in 2012 a Danish study reported that women who were infected with T.gondii were significantly more likely to be suicidal
and twice as likely to successfully commit suicide, compared to women not
infected (Pedersen MG, Mortensen PB, Norgaard-Pedersen B, Postolache TT. Toxoplasma gondii infection and self-directed violence in
mothers. Arch Gen Psychiatry. 2012;doi:10.1001/archgenpsychiatry.2012.668).
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.
effects of different strains of T. gondii
at least 15 distinct strains of T. gondii
are known, most isolates of T. gondii in Europe and North America belong to one of
three strains: I, II, or III. Despite having more than 98 percent genetic
identity, the effects of the three strains are quite different in rodents and
are assumed to be so in humans as well. In mice, for example, the three strains
produce significantly different gene expression (Hill RD, Gouffon JS, Saxton AM,
Su C. Differential gene expression in mice infected with distinct Toxoplasma strains. Infect Immun.
2012;80(3):968-74). Studies of the three strains on gene expression in human
neuroepithelial cells also show markedly different effects on gene expression,
with type I exhibiting the highest level of gene expression (Xiao J,
Jones-Brando L, Talbot CC Jr, et al. Differential effects of three canonical Toxoplasma strains on gene expression in
human neuroepithelial cells. Infect Immun. 2011;79:1363–1373). It has also been
shown that different strains of T. gondii
produce different effects on mouse
behavior (Kannan G, Moldovan K, Xiao J-C, et al. Toxoplasma gondii strain-dependent effects on mouse behavior.
Folia Parasitol. 2010;57:151–155). Similarly, it is known that type I T. gondii is much more lethal in mice than type II or
type III, but it was not known whether or not this also applies to human
infections. A recent study from our laboratory suggests that type I T. gondii, compared to type II or III, is
more likely to produce psychotic symptoms, especially for affective psychoses
(Xiao J, Buka SL, Cannon TD, et al. Serological pattern consistent with
infection with type I Toxoplasma gondii in mothers and risk of psychosis among adult
offspring. Microbes Infect. 2009;11:1011–1018). In a related study, in human
congenital T. gondii infections, different strains of T. gondii were found to produce differences in the
incidence of premature births and eye disease (McLeod R, Boyer KM, Lee D, et
al. Prematurity and severity are associated with Toxoplasma gondii alleles
(NCCCTS, 1981-2009). Clin Infect Dis. 2012;54:1595-605).
effects of the timing of the initial T.
In mice it has been shown that the
timing of the initial T. gondii infection is an important determinant of
outcome. For example, the outcome in mice infected at 4 weeks of age is very
different from mice infected at 9 weeks of age. Additional research on this
problem is in progress by Dr. Misha Pletnikov and his colleagues at John
Hopkins University Medical Center.
OTHER SPECIFIC TOPICS
I. All about Cats
II. Transmission of T. gondii
III. Epidemiological Similarities and Differences between Toxoplasmosis and Schizophrenia
IV. Effects of T. gondii on Behavior and Psychiatric Symptoms
V. Studies of T. gondii Antibodies in Schizophrenia
VI. Neurotransmitters and T. gondii
VII. Neuropathology of T. gondii
VIII. Treatment Approaches to Toxoplasmosis and Schizophrenia