Effects T. gondii On Behavior and Psychiatric Symptoms
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 (1). Much subsequent work has been carried out in rodents (2).
Behavioral manipulation by T. gondii in animals
(see also section VI. Neurotransmitters and T. gondii)
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 (3). 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 (4). Webster and Glenn McConkey have also speculated about specific mechanisms that may explain the parasite manipulation (5-7).
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” (8). They also speculated regarding possible pathophysiological mechanisms (9) and showed that one of the mechanisms used by T.gondii is to activate sexual arousal pathways of the rats (10) Other research has suggested that T. gondii exerts its effect through epigenetic modulation of the host’s amygdala (11).
Since these early demonstrations of the ability of T. gondii to manipulate behavior were carried out in rodents, the question of their relevance to humans remained. A study published in 2016 addressed this question. Normally chimpanzees are repelled by the scent of a leopard, which is a predator of chimps. In Gabon 33 chimps held in captivity were investigated regarding their reaction to leopard urine. The 24 chimps not infected with T. gondii demonstrated the expected aversion to the leopard urine but the 9 chimps infected with T. gondii did not. The reactions were specific to leopard urine and not for lion or tiger urine, neither of which is a natural predator of chimps since they don’t live in the rainforest where chimps live. Since T. gondii can manipulate the behavior of chimpanzees, it seems likely that it can also manipulate the behavior of humans (12).
As 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 (13). 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” (14).
Another interesting example of the effects of T. gondii on animal behavior is the sea otters who live off the coast of California. Many have become infected with T. gondii, presumably because of rainwater runoff from cat-infested areas carrying the oocysts into the ocean. A 2004 study reported that sea otters with toxoplasmosis were 3.7 times more likely to be attacked by sharks than others who were not infected (15).
Effects of T. gondii on personality traits of humans
Jaroslav Flegr 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 (16-17). An article describing Flegr’s research was also published in the Atlantic magazine (18). In a separate study T. gondii infection was associated with increased aggressive traits in women but not in men (19).
Effects of T. gondii on cognition in humans
The effect of T. gondii on human cognition was initially noted in 1947 by Eichenwald reported mental retardation to be one outcome of severe congenital toxoplasmosis (20). Following the 1947 report, additional studies were undertaken to assess the prevalence of antibodies to T. gondii in individuals with moderate and severe retardation. Many, but not all such studies were negative although these older studies used antibody measurements of varying sensitivity and the control groups were often poorly matched (21-22).
Beginning in the 1970s, researchers initiated long-term follow-up studies of individuals with serological evidence of having been infected with T. gondii in utero, the majority of whom had no clinical manifestation at birth. A 20-year follow-up of 12 children in the Netherlands reported no major effects on intelligence, although several children had developed progressive chorioretinitis (23). An ongoing American study of 120 children with congenital toxoplasmosis who were treated for one year with anti-toxoplasmosis drugs has also reported no significant drop in IQ scores (24). Of concern, however, was a subset of these children who had IQ scores within a normal range but which were significantly lower than their sibling controls (25). In another large American study of children born to women infected with T. gondii during pregnancy, the children of the women with the highest titres had delayed mental development in their first year and an increased risk of having an IQ less than 70 at 7 years (26). In summary, regarding the effect of toxoplasmosis on IQ, the statement by Remington, et al in 2001 appears to still be applicable: “The total contribution of congenital toxoplasmosis, including the less severe and clinically unapparent forms at birth, to mental retardation is uncertain” (20, p. 255).
In addition to congenital infections with T. gondii, postnatal infections may also affect human cognition and behavior. Two recent studies were carried out on schoolchildren. In Brazil 100 children ages 6-13 were tested for T. gondii antibodies and the results compared to their test results for reading, writing, and mathematics. Toxopositive children had a higher proportion of poor results on the mathematics subtest (p=0.009) but not on the other tests (27). In Florida, 1,755 schoolchildren were tested for T. gondii antibodies and given a series of cognitive tests. Seropositivity was associated with lower reading skills (p=0.029) and memory capacities (p=0.017) (28).
Six studies, all published since 2014, have reported on cognitive effects of toxoplasma seropositivity in adults. A study of 352 adults with a mean age of 32.2 years, being used as healthy controls in a psychiatric study, reported an association between toxo IgM, but not IgG, and impaired immediate memory (p=0.04); language (p=0.004); and visuospatial construction (p=0.001) (29). Another study of 180 adults with a mean age of 40.1, also being used as healthy controls in a psychiatric study, reported an effect of T. gondii on working memory (30).
Four studies of older adults have all reported associations between toxo IgG positivity and cognitive problems. Eighty four volunteer adults with a mean age of 70.3 were divided into groups of 42 toxo IgG positive and negative. The toxo positive group showed significant impairment in working memory and verbal memory, both immediate and delayed recall, executive function were not affected (31). In a subset of this same cohort the toxo positive group displayed significant impairment in goal-directed behavior as assessed by an auditory distraction paradigm (32). Among 4,485 participants, mean age 69, in a national nutrition survey, toxo IgG seropositivity was associated with impairment of immediate memory (p=0.006) but not delayed memory (33). Finally, among 1,022 participants, mean age 77.5, in a longitudinal random population sample, toxo IgG seropositivity was significantly associated with a more rapid decline in executive function but not in decline of attention, memory, language or visuospatial function (34). However, a fifth study of 114 nondemented older adults reported “little evidence of an association between impaired memory function and T. gondii seropositivity (35).
Effects of T. gondii on the behavior of humans
Flegr 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 (36). Pearce et al. also demonstrated psychomotor slowing in healthy humans, as well as in those with schizophrenia, who were infected with T. gondii compared with those not infected (37).
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 (38). This research group subsequently replicated this finding in another driver cohort in the Czech Republic (39).
In 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) (40). This study has been replicated by another study in Turkey (41). 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 (42).
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 (43-44). However, long-term follow-up of a similar cohort in Europe reported no loss of IQ or other significant sequelae (45).
No study has reported psychosis or other symptoms of schizophrenia in children infected with congenital latent toxoplasmosis. Rima McLeod, who has followed large numbers of such children over many years, reported that among the congenitally-infected cases “there have been only rare persons with these neuropsychiatric or other disease” (46). 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 (47).
Psychiatric manifestations of adult T. gondii infections
Humans 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” (48). The clinical picture is nonspecific but often includes headache, fever, malaise, myalgia, and lymphadenopathy (49-50). 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 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” (51). 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” (52).
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” (53).
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 (54).
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 (55). The incidence of such cases is unknown.
Another 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) (56). A recent study of 156 suicide attempters and 127 controls in Mexico reported similar results. There was no statistical difference in seropositivity but the titers of the T. gondii antibody was significantly higher (p=0.04) in the suicide attempters (57). The association between suicide attempts and higher titre to T. gondii antibodies was replicated by a study in Turkey (58). 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 (59). 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 (60) and in Sweden, a study of 54 adult suicide attempters reported increased seropositivity of T. gondii (OR 7.12, p=0.08) compared to controls (61). Finally, a study of national suicide rates in 17 European nations reported a significant association between the prevalence of T. gondii and the suicide rate (62).
Three other studies are of interests regarding the effect of T. gondii on behavior and psychiatric symptoms. Holub and his colleagues in Prague divided individuals with schizophrenia into those with antibodies to T. gondii (n=57) and those without such antibodies (n=194), then retrospectively assessed their clinical histories. The patients with antibodies were found to have had an earlier onset of their illness for men, but not women; to have more severe symptoms; and to have been hospitalized for longer (63).
Another study of interest was the effect of seropositivity to T. gondii on the mortality rate of individuals with schizophrenia. In an earlier study, Dickerson et al. reported that antibodies for T. gondii were associated with an increased mortality (64). However, a later study reported that this relationship was no longer statistically significant when it was corrected for age and gender (65). Finally, a demographic study reported a correlation between the prevalence of T. gondii and the national homicide rate in 20 European nations for the year 2000 (66).
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 (67) and a 1995 outbreak among an estimated 2,900–7,700 people in Victoria, Canada (68). To date, such follow-up studies have not been done.
The effects of different strains of T. gondii
Although 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 (69). 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 (70). Rodent studies have also shown that immunity is strain specific; thus a person infected with one strain of T. gondii can become reinjected by a different strain (71).
It has also been shown that different strains of T. gondii produce different effects on mouse behavior (72). 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 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 (73). Another study from our laboratory showed that the different strains of T. gondii had very different effects on neurotrasmitters (74). 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 (75)
The question remains “whether or not different strains of T. gondii are responsible for different disease manifestations in humans” (76). Research on ocular toxoplasmosis suggests that this may indeed be the case (77). For another review of this issue see Rico-Torres (78).
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