Available via license: CC BY 4.0
Content may be subject to copyright.
RESEARCH ARTICLE
Is Toxoplasma Gondii Infection Related to
Brain and Behavior Impairments in Humans?
Evidence from a Population-Representative
Birth Cohort
Karen Sugden
1,2
*, Terrie E. Moffitt
1,2,3,4
, Lauriane Pinto
2
, Richie Poulton
5
, Benjamin
S. Williams
1,2
, Avshalom Caspi
1,2,3,4
1Department of Psychology & Neuroscience, Duke University, Durham, North Carolina, United States of
America, 2Duke Center for Genomic & Computational Biology, Duke University, Durham, North Carolina,
United States of America, 3Department of Psychiatry and Behavioral Sciences, School of Medicine, Duke
University, Durham, North Carolina, United States of America, 4Social, Genetic, and Developmental
Psychiatry Centre, Institute of Psychiatry, King’s College London, London, United Kingdom, 5Department of
Psychology, University of Otago, Dunedin, New Zealand
*karen.sugden@duke.edu
Abstract
Background
Toxoplasma gondii (T.gondii) is a protozoan parasite present in around a third of the human
population. Infected individuals are commonly asymptomatic, though recent reports have
suggested that infection might influence aspects of the host’s behavior. In particular, Toxo-
plasma infection has been linked to schizophrenia, suicide attempt, differences in aspects
of personality and poorer neurocognitive performance. However, these studies are often
conducted in clinical samples or convenience samples.
Methods/Results
In a population-representative birth-cohort of individuals tested for presence of antibodies to
T.gondii (N = 837) we investigated the association between infection and four facets of
human behavior: neuropsychiatric disorder (schizophrenia and major depression), poor
impulse control (suicidal behavior and criminality), personality, and neurocognitive perfor-
mance. Suicide attempt was marginally more frequent among individuals with T.gondii
seropositivity (p= .06). Seropositive individuals also performed worse on one out of 14 mea-
sures of neuropsychological function.
Conclusion
On the whole, there was little evidence that T.gondii was related to increased risk of psychi-
atric disorder, poor impulse control, personality aberrations or neurocognitive impairment.
PLOS ONE | DOI:10.1371/journal.pone.0148435 February 17, 2016 1/14
a11111
OPEN ACCESS
Citation: Sugden K, Moffitt TE, Pinto L, Poulton R,
Williams BS, Caspi A (2016) Is Toxoplasma Gondii
Infection Related to Brain and Behavior Impairments
in Humans? Evidence from a Population-
Representative Birth Cohort. PLoS ONE 11(2):
e0148435. doi:10.1371/journal.pone.0148435
Editor: Herbert B. Tanowitz, Albert Einstein College
of Medicine, UNITED STATES
Received: June 17, 2015
Accepted: January 18, 2016
Published: February 17, 2016
Copyright: © 2016 Sugden et al. This is an open
access article distributed under the terms of the
Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any
medium, provided the original author and source are
credited.
Data Availability Statement: Due to restrictions set
by the University of Otago IRB, data are available
upon request. Requests for the data may be made to
the corresponding author (karen.sugden@duke.edu).
Funding: The Dunedin Multidisciplinary Health and
Development Research Unit is supported by the New
Zealand Health Research Council (http://www.hrc.
govt.nz/; RP). This research received support from
US National Institute on Aging (NIA: https://www.nia.
nih.gov/) grants AG032282, AG048895 (AC and
TEM), and UK Medical Research Council (http://www.
mrc.ac.uk/) grant MR/K00381X (AC and TEM).
Introduction
Toxoplasma gondii (T.gondii) is an obligate protozoan parasite of all warm-blooded mammals
including humans, where infection has been linked to schizophrenia, suicide attempt, differ-
ences in aspects of personality and poorer neurocognitive performance. In humans, the pri-
mary source of infection is through contact with the feces of infected animals, especially
domestic cats, the definitive host in which the T.gondii protozoan completes its life cycle.
Alternate sources of infection occur through contact and ingestion of infected meat (especially
pork), maternal-fetal transmission and exposure to soil and water contaminated with oocytes.
T.gondii is geographically omnipresent, and it is estimated that age-adjusted country-level
seroprevalence ranges from around 3% in South Korea to 76% in Costa Rica [1].
In rare cases, Toxoplasmosis can present with severe pathological symptoms, including reti-
nochoroiditis, myocarditis and meningoencephalitis, potentially leading to death [2]. However,
most infected humans are asymptomatic, exhibiting few or no physiological symptoms. Because
of this asymptomatic nature, it was long thought that latent T.gondii infection was of little pub-
lic health significance except in cases of concurrent immunosuppression, such as HIV infection.
However, recent reports have suggested that infection with T.gondii might have previously
unrecognized consequences in humans.
One such consequence concerns host behavioral manipulation. In terms of the relationship
between the intermediate and the definitive host, modifying normal interactions between the
two would be advantageous to the parasites’transmission and reproduction. In other words,
modification of a rodent’s normal aversive reaction to felines would be advantageous to the
parasite, since it would generate a higher chance of it being consumed by the cat, the organism
in which the parasite’s life cycle is completed [3]. Indeed, evidence exists that infection of mice
by T.gondii predicts innate loss of fear of cat urine [4] and impaired working memory [5].
These observations have led to the hypothesis that such manipulations might not be unique to
rodent hosts. As such, extrapolations of these phenomena to correlates of human behavior are
gaining attention.
In line with observed effects of infection on rodents’behavior, most human research has
focused on behavioral domains involving psychiatric illness, impulsivity and aberrant neuro-
cognitive processes. The most heavily researched correlate of T.gondii infection is schizophre-
nia. Interestingly, some acute cases of T.gondii infection result in hallucinations, a key feature
of schizophrenia, and reports of inflated numbers of T.gondii positive individuals in samples
of psychiatric inpatients were made as early as the 1950’s[
6]. The culmination of these findings
is a recent meta-analysis of 38 studies, which suggests that T.gondii infection increases the
odds of developing schizophrenia 2.7 times (OR, 2.71, 95%CI 1.93–3.80) [7]. In addition, links
with T.gondii have also been suggested with major depressive disorder; however, these sugges-
tions have been more hyperbolic. One case report demonstrated alleviation of depressive symp-
toms upon successful T.gondii treatment [8], whilst another reported a correlation between cat
bites and depression in women [9]. However, association studies of T.gondii infection with
depression have been inconsistent [10,11].
Poor impulse regulation, including violent and risk-taking behavior, is another potential
consequence of infection. Latent T.gondii infection has been associated with increased human
trait aggression in females and increased impulsivity in males [12]. Other studies have reported
links between T.gondii antibody titer and suicide attempt [13–15]. Complementing these indi-
vidual-level studies, cross-national comparisons have documented that national seroprevalence
rates of T.gondii antibodies titers are positively correlated with higher nation-wide rates of
both suicide and homicide [1,16,17]. Yet another study has reported higher incidence in sero-
positivity amongst prison inmates compared to controls [18]. Further reports show that T.
Toxoplasma Gondii and Neuropsychological Outcomes
PLOS ONE | DOI:10.1371/journal.pone.0148435 February 17, 2016 2/14
Additional support was provided by the Jacobs
Foundation (http://jacobsfoundation.org/) Jacobs
Prize 2010 (AC and TEM). The funders had no role in
study design, data collection and analysis, decision to
publish, or preparation of the manuscript.
Competing Interests: The authors have declared
that no competing interests exist.
gondii seropositivity is related to both fatal and non-fatal traffic road accidents [19,20], pre-
sumably reflecting poor impulse regulation.
Finally, there is some evidence that neurocognitive and personality differences exist between
seropositive and seronegative individuals. In particular, slower reaction times [21,22] and
poor attention [23] appear to be associated with T.gondii seropositivity, along with lower
scores of Novelty Seeking [24].
This study tested the hypothesis that T.gondii infection is related to impairment in brain
and behavior, as measured by a range of phenotypes encompassing neuropsychiatric disorders,
poor impulse control, personality and neurocognitive deficits. We tested the hypothesis in a
population-representative birth cohort of adults enrolled in the Dunedin Longitudinal Study.
We drew on data derived from psychiatric interviews, neuropsychological testing, and a search
of administrative records to conduct, to our knowledge, the most comprehensive evaluation to
date of the link between T.Gondii infection and the full panoply of presumptive impairments.
Materials and Methods
Participants
Participants are members of the Dunedin Multidisciplinary Health and Development Study, a
longitudinal investigation of health and behavior in a population-representative birth cohort
[25]. Study members (N = 1,037; 91% of eligible births; 52% male, 48% female) were all individ-
uals born between April 1972 and March 1973 in Dunedin, New Zealand, who were eligible for
the longitudinal study based on residence in the province at age 3 and who participated in the
first follow-up assessment at age 3. The cohort represents the full range of socioeconomic status
in the general population of New Zealand’s South Island and matches the NZ National Health
and Nutrition Survey on adult health indicators (e.g. BMI, smoking, GP visits)[26]. The major-
ity of cohort members are White. Assessments were carried out at ages 3, 5, 7, 9, 11, 13, 15, 18,
21, 26, 32, and most recently, 38 years, when we assessed 95% of the 1,007 study members who
were still alive. At each assessment wave, Study members (including emigrants and prisoners)
were brought to the Dunedin Multidisciplinary Health and Development Research Unit for a
full day of interviews and examinations. These data are supplemented by searches of official
records, and by questionnaires that were mailed to informants nominated by the Study mem-
bers themselves. Written informed consent was obtained from all Study members. The Univer-
sity of Otago Ethics Committee approved each phase of the Study and the consent procedure.
Blood collection and processing
Venous blood samples were collected from Study members at age 38 by a trained phlebotomist
using standard blood collection apparatus. Blood was collected into 10ml K
2
EDTA Vacutainer
tubes (BD, Franklin Lakes, NJ). After the necessary initial inversion, tubes were processed by
centrifugation at 2,000g for 10 minutes (K
2
EDTA) and the plasma fraction was transferred
into 2ml cryovials. All plasma was stored at -80°C until analysis.
T.gondii IgG level measurement
Levels of IgG antibodies to T.gondii were determined using a Toxoplasma IgG Immunosimpli-
city EIA kit (Diamedix, FL., USA). Briefly, plasma was diluted 1 in 100 in sample diluent prior
to assaying, and 100μL of diluted samples, standards (0 IU/ml, 50 IU/ml and 250IU/ml), con-
trols (high positive, low positive and negative) and blank (sample diluent only) were placed in
the reaction plate. Reactions were performed following the manufacturer’s instructions. All
EIA reactions were performed in duplicate. Upon completion of the reactions, OD readings at
Toxoplasma Gondii and Neuropsychological Outcomes
PLOS ONE | DOI:10.1371/journal.pone.0148435 February 17, 2016 3/14
450nm (correcting for background at 600nm) were read using a Spectramax-384 spectropho-
tometer (Molecular Devices, Sunnydale, CA) and data acquired using SoftMax Pro software
(Molecular Devices). Raw OD units were transformed by subtracting the mean OD value of the
sample blank, and a standard curve was calculated using a point-point curve fit of the stan-
dards. The resulting equation was used to extrapolate sample OD values into IU/ml units.
These values were multiplied by the initial dilution factor (1 in 100) to derive an estimate of
plasma IU/ml. Duplicate values were then averaged to derive a mean IU/ml per sample. The
manufacturer-recommended cut-off value for seropositivity for anti-Toxoplasma IgG using
this EIA assay was 50 IU/ml, based on the WHO 3rd International Standard for Anti-Toxo-
plasma; Values above 50 IU/ml were designated positive for anti-Toxoplasma IgG; all other
values were designated negative. The mean within-assay coefficient of variation (%CV) was
11.3%.
Outcome measures
The measures used as outcome variables in this study are described in Table 1. Briefly, we
assessed four facets of human behavior: neuropsychiatric disorder (DSM diagnosis of schizo-
phrenia and depression), indicators of poor impulse control (non-suicidal self-injury,
attempted suicide, criminal convictions, and accident claims), Big-five personality traits
(Openness to Experience, Conscientiousness, Extraversion, Agreeableness, and Neuroticism),
and neurocognitive performance (e.g., general intelligence, executive functions, memory, and
processing speed).
Statistical analysis
The association between T.gondii infection status and the various phenotypes were tested
using SPSS version 22 (IBM, New York, NY) and SAS (SAS Institute Inc., Cary, NC). We tested
associations between T.gondii infection and outcomes in a regression of the form: A=a+b1
(T.gondii)+b2(sex) + e, where Ais one of the 27 outcome measures. The form of regression
varied depending on whether the outcome under consideration represented binary or continu-
ous data.
Results
Plasma samples were available for 837 individuals at age 38 (423 male, 50.4%). Of these indi-
viduals, 236 (28.2%) had T.gondii IgG antibodies above 50 UI/ml, indicating a positive T.
gondii infection status. This is similar to seroprevalence rates in other developed Western
countries [1]. Males (32.6%) were significantly more likely to test positive for T.gondii than
females (23.7%) (χ2(df) = 8.28(1), p<0.01). All subsequent inferential tests included a statisti-
cal control for sex. T.gondii infection status was not related to socioeconomic status (SES); pro-
portions of individuals testing positive for T.gondii IgG in low, medium and high SES groups
were 32.2%, 29.4% and 23.4%, respectively (χ2(df) = 4.41(1), p= 0.11). We compared people
with missing (N = 200) versus non-missing (N = 837) T.gondii seroprevalence data at age 38.
Seroprevalence data were missing because a) for cultural reasons, Maori-ancestry cohort mem-
bers’blood was not studied (7% of cohort), b) Study members either did not consent to phle-
botomy (2%), did not take part at age-38 assessment (5%), or died before age 38 (3%), or c)
immunoassay data did not pass quality control (2%). Across all 27 outcome variables tested in
our analysis, we found only three differences: Study members with missing T.gondii data were
more likely to meet a diagnosis of schizophrenia (N = 13, 10.7%; OR (95% CI) = 4.07 (2.01–
8.24), p<.01), a diagnosis of major depression (N = 28, 24.1%; OR (95% CI) = 1.77 (1.11–
Toxoplasma Gondii and Neuropsychological Outcomes
PLOS ONE | DOI:10.1371/journal.pone.0148435 February 17, 2016 4/14
Table 1. Brief description of neuropsychiatric, impulse control, personality and neurocognitive outcome measures used in the study.
Outcome measure Description
Neuropsychiatric disorders
Schizophrenia Our assessment of schizophrenia has been previously described [27]. Briefly, schizophrenia was assessed with
the Diagnostic Interview Schedule (DIS) following the Diagnostic and Statistical Manual of Mental Disorders
(DSM). Diagnoses required hallucinations (which are not substance use-related) in addition to at least two other
positive symptoms. In addition, objective evidence of impairment resulting from psychosis was required, as
reported by informants and as recorded in the Study’s life-history calendars.
Major depression Depression was diagnosed at age 38 using the DIS following diagnostic criteria for the DSM-IV. The reporting
period was the past year.
Indicators of Poor Impulse Control
Non-suicidal self-injury Self-reported engagement in self-injury behaviors (e.g., cutting wrists, burning self) since assessment at age 32
were ascertained at age 38 during standardized clinical interviews as well as via the Life History Calendar [28].
Behaviors only counted as non-suicidal self-injury if not accompanied by the intent to die.
Attempted suicide Self-reported suicide attempt(s) since assessment at age 32 were ascertained during standardized clinical
interviews at age 38 as well as via the Life History Calendar [28]. Examples of behaviors considered attempted
suicide include cutting or stabbing oneself, overdosing on pills, attempting to hang or strangle oneself, or
attempting to drown. Behaviors counted as attempted suicide only if accompanied by self-reported intent to die.
Criminal conviction Linked New Zealand (NZ) government records (via the New Zealand Police) were used to determine whether
Study members were convicted of any crime in adulthood, including property (e.g., theft of property of value
greater than $500, receipt of stolen property, burglary, breaking and entering, shoplifting, credit car theft), court
order violations (e.g., obstructing or resisting police, breaching parole, escaping prison, misleading welfare
officer, failing to pay fines, failing to answer summons), drugs (e.g., possessing drug paraphernalia, supplying or
procuring hard drugs or prescription medications, selling cannabis), violence (e.g., aggravated cruelty to animal,
common assault, assault with intent to injure with weapon, assault of police officer, robbery, robbery aggravated
with firearm, manslaughter, rape, common assault domestic) and driving convictions (including excess blood
alcohol, speeding, driving without a license, causing injury, hit and run, but not including traffic infringements).
Accident claims The number of accepted accident claims per Study member from ages 21 to 38 were determined via the New
Zealand Accident Compensation Corporation (ACC). The ACC provides comprehensive, no-fault personal injury
coverage for all residents and visitors in New Zealand.
Personality at age 38
At age 38, Study members nominated people "who knew them well." These informants were mailed
questionnaires and asked to describe each Study member using a 25-item version of the Big Five Inventory
measuring the personality traits of Extraversion, Agreeableness, Conscientiousness, Neuroticism, and
Openness to Experience.
Description of a Typical High Scorer Description of a Typical Low Scorer
Openness to experience Imaginative, creative, aesthetically sensitive,
quick to learn, clever, insightful, attentive and
aware of feelings
Resistant to change, conventional, prefers the plain,
straightforward, and routine over the complex, subtle, and
abstract
Conscientiousness Responsible, attentive, careful, persistent,
orderly, planful, and future-oriented
Irresponsible, unreliable, careless, distractible, and
impulsive
Extraversion Outgoing, expressive, energetic, dominant Quiet, lethargic, content to follow others’lead
Agreeableness Cooperative, considerate, empathic, generous,
polite, and kind
Aggressive, rude, spiteful, stubborn, cynical, and
manipulative
Neuroticism Anxious, vulnerable to stress, guilt-prone,
lacking in confidence, moody, angry, easily
frustrated, and insecure in relationships
Emotionally stable, adaptable, and sturdy
Neurocognition at age 38
Domain Tested Description
Wechsler Adult Intelligence Scale–
IV (WAIS-IV)
The WAIS-IV [29] was administered to Study members
individually according to standard protocol at age 38 years.
IQ at 38 General Intelligence Derived from ten subtests using the method recommended
in the test manual.
(Continued)
Toxoplasma Gondii and Neuropsychological Outcomes
PLOS ONE | DOI:10.1371/journal.pone.0148435 February 17, 2016 5/14
Table 1. (Continued)
Verbal comprehension Verbal Comprehension Verbal Comprehension Index comprises the Information,
Similarities, and Vocabulary subtests. The Information
subtest is a test of general knowledge and reflects the ability
to acquire and store knowledge in long-term memory, to
access it, and to express it verbally. The Similarities subtest
is a test of verbal concept formation, abstraction, and
reasoning. It captures the ability to categorize and
conceptualize information available in long-term memory.
The Vocabulary subset is a test of language skills and
includes questions about the meaning of words (e.g., What
does winter mean?). It captures language processes such
as the ability to acquire word meaning, recall it, and
effectively express it.
Perceptual reasoning Perceptual reasoning Perceptual Reasoning Index comprises the Block Design,
Picture Completion, and Matrix Reasoning subtests. The
Block Design subtest is a test of visual-spatial organization,
executive planning, and problem solving skills. The test
requires putting together two, four, or nine red and white
blocks in a pattern according to specific designs being
displayed. The Picture Completion subtest is a test of visual
discrimination and reasoning. The test involves looking at an
incomplete picture of common objects or scenes and
determining which part is missing. Test items are arranged
in order of difficulty and have time limits. The Matrix
Reasoning subtest is a test of visual-perceptual organization
and reasoning ability. The test requires viewing design
patterns with a missing part and selecting, from a set of five
options, the part that completes the design.
Working memory Working memory Working Memory Index comprises the Arithmetic and Digit
Span subtests. The Arithmetic subtest is a test that requires
working memory processes to be applied to orally-presented
verbal information. It involves numerical knowledge, short-
term memory, attention, and concentration. Arithmetic
problems are presented in story format (e.g., Four men can
finish a job in eight hours. How many men will be needed to
finish it in one-half hour?). Performance requires holding
information in short-term memory, accessing long-term
memory to retrieve numerical rules of mathematical
operation, and using the rules to manipulate the stored data.
The Digit Span subtest is a test of memory span, attention/
concentration, and ability to mentally manipulate information.
The test requires listening to a sequence of digits read aloud
and repeating them in forward, backward, and ascending
order.
Processing speed Processing speed Processing Speed Index comprises the Digit Symbol Coding
and Symbol Search subtests. The Digit Symbol Coding
subtest is a test of processing speed, psychomotor speed
and coordination, and attention/concentration. Better
performance also depends on incidental learning. A key that
pairs symbols and numbers is presented. The test requires
filling in rows containing blank squares (each with a
randomly assigned number above it) using the key. The
Symbol Search subtest is a test of visual processing speed,
psychomotor speed and attention/ concentration. Better
performance also depends on incidental learning. The test
requires determining whether target symbols appear in a
row of symbols.
Trail Making Test B time Executive Functions Test of scanning and tracking, divided attention, and mental
flexibility [30]. The test involves drawing lines to connect
consecutively numbered and lettered circles, alternating
between numbers and letters. Scores represent the time, in
seconds, to complete the test.
(Continued)
Toxoplasma Gondii and Neuropsychological Outcomes
PLOS ONE | DOI:10.1371/journal.pone.0148435 February 17, 2016 6/14
Table 1. (Continued)
The Cambridge
Neuropsychological Test Automated
Battery (CANTAB)
The CANTAB [31] is a computerized test battery of
neuropsychological functioning that uses touch-screen
technology. The tests for the CANTAB have been selected
based on validation in primate/rodent models and/or
neuroimaging paradigms.
Rapid Visual Information
Processing: A Prime
Executive Functions Measure of sustained attention and vigilance. A white
box appears in the center of the computer screen, inside
which digits, from 2 to 9, appear in a pseudo-random order,
at the rate of 100 digits per minute. Subjects are requested
to detect target sequences of digits (for example, 2-4-6, 3-5-
7, 4-6-8) and to register responses using the press pad. The
signal detection measure of sensitivity to the target,
regardless of response tendency (range 0.00 to 1.00; bad to
good), is a measure of how good the subject is at detecting
target sequences using "Probability of Hit" and "Probability
of False Alarm."
Reaction Time: 5-choice Reaction
time
Motor Test Test of processing speed. The task is divided into five
stages, which require increasingly complex chains of
responses. In each case, the subject must react as soon as
a yellow dot appears. The subject must respond by lifting
their finger from the press-pad and touching the yellow dot
on the screen. In some stages the dot may appear in one of
five locations. The speed with which the subject releases the
press pad button in response to a stimulus in any one of five
randomly presented locations. Choice reaction time latency,
averaged across all correct trials, is measured in
milliseconds and tends toward a positive skew.
Visual Paired Associates Learning:
Total errors, adjusted
Memory Test of visual memory and new learning. Boxes are
displayed on the screen and are opened in a random order.
One or more of them will contain a pattern. The patterns are
then displayed in the middle of the screen, one at a time,
and the subject must touch the box where the pattern was
originally located. If the subject makes an error, the patterns
are re -presented to remind the subject of their locations.
The difficulty level increases through the test. The number of
patterns increases across eight stages (i.e., two 1 -pattern
stage s, two 2 -pattern stages, two 3 -pattern stages, one 6
-pattern stage, one 8 -pattern stage), which challenges even
very able subjects. For each stage, up to 10 trials are
presented until all the patterns are located correctly. Score is
the total number of errors (with an adjustment for each stage
not attempted due to previous failure).
Rey Auditory Verbal Learning Test Test of verbal learning and memory [32]. The test involves a
five-trial presentation of a 15- word list and a one-time
presentation of an interference list.
Total Recall Memory The total number of words (0–60) recalled over four trials
(the sum of words recalled across trials 1–4).
Delayed recall Memory The total number of words (0–15) recalled after a 25–30
minute delay.
Wechsler Memory Scale-III
(WMS-III)
The WMS-III [33] was administered individually according to
standard protocol.
Mental Control Executive Functions Test of attention and tracking. It requires reciting the months
of the year in backwards order, starting with December.
Responses were scored according to the instructions in the
WMS-III manual. Scores ranged from 1 (poor performance)
to 5 (good performance) and reflect both accuracy and
speed.
(Continued)
Toxoplasma Gondii and Neuropsychological Outcomes
PLOS ONE | DOI:10.1371/journal.pone.0148435 February 17, 2016 7/14
2.83), p= .02), and were more likely to have an adult criminal conviction (N = 54, 39.1%; OR
(95% CI) = 1.60 (1.04–2.46), p= .03).
1. Is T.gondii infection status related to neuropsychiatric conditions?
We tested whether T.gondii seropositivity was associated with increased prevalence of two
neuropsychiatric disorders; schizophrenia and major depression. T.gondii seropositivity was
not significantly associated to either of these conditions (Table 2).
2. Is T.gondii infection status related to poor impulse control?
We tested whether T.gondii seropositivity was associated with poor impulse control, as
reflected in four phenotypes: non-suicidal self-injury, suicide attempt, criminal convictions,
and traffic-related offences and accidents. T.gondii was not significantly associated with non-
suicidal self-injury, but there was a suggestive link between latent infection and suicide attempt
(Table 2). In regards to criminal behavior, there was no significant association between T.gon-
dii seropositivity and criminal convictions, as reflected in official conviction records (Table 2).
We further probed this non-significant association by testing whether T.gondii seropositivity
was linked to certain types of criminal offenses (e.g., violence, driving) that have been previ-
ously examined in studies of T.gondii infection. T.gondii seropositivity was not significantly
associated with increased risk of any type of criminal offending (Table 2).
3. Is T.gondii infection status related to personality differences?
In order to summarize the possible psychological differences that are associated with infection
by T.gondii, we examined the personality profiles of individuals who tested positive versus neg-
ative for T.gondii antibodies. To do this, we measured the Five-Factor Model of personality.
The past two decades have led to a consensus among psychologists that personality differences
can be organized along five broad dimensions: Openness to Experience, Conscientiousness,
Extraversion, Agreeableness, and Neuroticism [34]. Table 2 describes the mean scores across
all traits for seropositive and seronegative individuals. The personality profiles of individuals
who tested positive for T.gondii antibodies were indistinguishable from the personality profiles
of individuals who tested negative.
4. Is T.gondii infection status related to poorer neurocognitive
performance?
Lastly, we assessed the relationship between T.gondii seropositivity and a comprehensive
range of neurocognitive functions at age 38 (Table 3). We tested whether performance on the
WAIS-IV test of general intelligence at age 38 was associated with T.gondii seropositivity.
Table 1. (Continued)
Paired associates: Total Recall Memory Test of verbal learning and memory. Eight pairs of unrelated
words (e.g., truck-arrow) are read aloud and followed by a
recall task (one of the words from each word pair is given,
and the associated word must be recalled). Four trials of the
eight word-pairs are presented. Presentation of the word-
pairs is randomized across trials. The total recall score
represents the total number of words (0–32) recalled across
four trials.
Paired associates: Delayed Recall Memory The delayed recall score represents the total number of
words (0–8) recalled after a 25–35 minute delay.
doi:10.1371/journal.pone.0148435.t001
Toxoplasma Gondii and Neuropsychological Outcomes
PLOS ONE | DOI:10.1371/journal.pone.0148435 February 17, 2016 8/14
There were no significant IQ differences between seropositive versus seronegative individuals.
We then tested whether T.gondii seropositivity was associated with poorer performance on a
range of functions encompassing verbal comprehension, perceptual reasoning, working mem-
ory, processing speed, executive functioning, motor functions and memory. T.gondii infection
status was associated with poorer memory performance on the Rey Auditory Verbal Learning
test. Associations between T.gondii infection status and all other tests of neurocognitive func-
tions were not significant.
Discussion
Our results suggest that a positive test for T.gondii antibodies does not result in increased sus-
ceptibility to neuropsychiatric disorders, poor impulse control or impaired neurocognitive
ability. Moreover, we found no association between seropositivity and aberrant personality
functions.
Some traits which have been linked previously to T.gondii seropositivity were marginally
associated in our cohort. For example, we found that recently-attempted suicide was more
common in seropositive individuals. This trend is consistent with previous studies, where his-
tory of suicide attempt, but not completion, has been related to both antibody titer [13] and
seropositivity [15]. Similarly, our seropositive individuals performed more poorly on one test
Table 2. The association between T.gondii infection status and the range of neuropsychiatric disorders, indicators of poor impulse control and
personality.
Outcome measure T.gondii positive T.gondii negative Test statistic pvalue Effect Size (Cohen’sd
(N = 236) (N = 601) (V
d
))
N (%) N (%) Odds Ratio (95% CI)
Neuropsychiatric disorders
Schizophrenia 8 (3.4) 16 (2.7) 1.31 (0.55–3.12) .54 .06 (0.01)
Major depression 35 (14.8) 92 (15.4) 1.01 (0.66–1.54) .98 .00 (0.00)
Impulsive behavior
Non-suicidal self-injury 10 (4.3) 19 (3.2) 1.44 (0.66–3.16) .36 .09 (0.01)
Suicide attempt 8 (3.4) 8 (1.3) 2.63 (0.97–7.14) .06 .23 (0.01)
Crime and accidents*
Criminal conviction 70 (29.7) 136 (22.7) 1.19 (0.82–1.71) .36 .04 (0.00)
Violent criminal conviction 28 (11.9) 46 (7.7) 1.36 (0.81–2.29) .25 .07 (0.00)
Driving conviction 51 (21.6) 89 (14.9) 1.30 (0.86–1.96) .22 .06 (0.00)
M (SD) M (SD) est
Number of Accident claims** 7.01 (6.73) 6.46 (7.59) 0.00 .99
Personality,assessed at age 38 EMM (95% CI) EMM (95% CI) F.00 (0.00)
Openness to experience -0.04 (-0.17–0.09) 0.02 (-0.06–0.10) 0.62 .43 .06 (0.01)
Conscientiousness 0.01 (-0.12–0.14) 0.03 (-0.05–0.11) 0.07 .79 .02 (0.01)
Extroversion 0.00 (-0.13–0.13) 0.04 (-0.04–0.12) 0.31 .58 .04 (0.01)
Agreeableness -0.03 (-0.16–0.09) 0.04 (-0.04–0.12) 0.82 .36 .07 (0.01)
Neuroticism -0.01 (-0.14–0.16) -0.01 (-0.08–0.08) 0.01 .93 .01 (0.01)
All tests are controlled for sex. N (%) represents the number and percent of individuals within each seropositivity group presenting with each phenotype.
Personality scores are standardized to Mean = 0 and Standard Deviation = 1.
*Criminal conviction and accident claim data are controlled for amount of time spent in New Zealand.
**Differences tested using a zero-inflated negative binomial model;
M (SD) = mean number (standard deviation) of accepted claims. EMM = Estimated Marginal Mean. 95% CI = 95% Confidence Interval. V
d
= Variance of
Cohen’sd
doi:10.1371/journal.pone.0148435.t002
Toxoplasma Gondii and Neuropsychological Outcomes
PLOS ONE | DOI:10.1371/journal.pone.0148435 February 17, 2016 9/14
of verbal learning and memory (the Rey Auditory Verbal Learning Test), but this finding was
the only significant difference among 14 tests and may have emerged by chance, since it was
not evident on other tests of memory (the CANTAB visual paired associates and the Wechsler
Memory Scale Paired Associates).
In contrast to previous studies, we did not observe a significant association between T.gon-
dii seropositivity and schizophrenia. Approximately 40 reports have now been published show-
ing links between schizophrenia and/or psychotic symptoms and infection status, leading to
the suggestion that psychosis-spectrum conditions are a consequence of infection. Biological
pathways have been proposed and pursued, centering on the schizophrenia-linked candidate
neurotransmitter dopamine; in rodents, infection with T.gondii leads to aberrant dopamine
signaling [35] and reduced expression of genes within the dopamine pathway, such as DRD1,
Table 3. The association between T.gondii infection status and neurocognitive function.
Outcome measure Domain T.gondii positive T.gondii negative Test
statistic
pvalue Effect Size
(Cohen’sd)
EMM (95% CI) EMM (95% CI) F
Neurocognition
WAIS-IV
IQ at 38 General
Intelligence
98.80
(96.83–100.77)
100.63
(99.41–101.84)
2.40 .12 .12
Verbal comprehension Verbal
Comprehension
99.12
(97.17–101.06)
100.54
(99.34–101.75)
1.50 .22 .09
Perceptual reasoning Perceptual
reasoning
98.59
(96.62–100.56)
100.32
(99.10–101.53)
2.16 .14 .11
Working memory Working memory 98.97
(97.00–100.94)
100.64
(99.42–101.86)
2.00 .16 .11
Processing speed Processing speed 99.43
(97.51–101.35)
100.59
(99.41–101.78)
1.03 .31 .08
Trail Making Test B time Executive
Functions
64.73 (62.03–67.43) 63.96 (62.30–65.62) 0.23 .63 .04
WMS-III
Mental Control Executive
Functions
2.97 (2.80–3.15) 3.12 (3.01–3.23) 2.02 .16 .11
CANTAB
Rapid Visual Information Processing:
A Prime
Executive
Functions
0.91 (0.90–0.92) 0.91 (0.91–0.92) 0.92 .34 .07
Reaction Time: 5-choice Reaction
time
Motor Test 327.72
(320.96–334.48)
330.13
(325.97–334.28)
0.35 .55 .05
Visual Paired Associates Learning:
Total errors, adjusted
Memory 11.85 (9.46–14.25) 12.93 (11.46–14.41) 0.57 .45 .06
Rey Auditory Verbal Learning Test
Total Recall Memory 36.76 (35.76–37.76) 37.90 (37.29–38.52) 3.64 .06 .15
Delayed recall Memory 8.83 (8.43–9.23) 9.33 (9.08–9.58) 4.38 .04 .16
WMS-III
Paired associates: Total Recall Memory 15.63 (14.53–16.74) 16.32 (15.64–17.01) 1.07 .30 .08
Paired associates: Delayed Recall Memory 5.09 (4.76–5.42) 5.28 (5.07–5.48) 0.89 .35 .07
All tests are controlled for sex. WAIS-IV tests are standardized to Mean = 100 and Standard Deviation = 15. EMM = Estimated Marginal Mean. 95%
CI = 95% Confidence Interval.
V
d
= 0.01
doi:10.1371/journal.pone.0148435.t003
Toxoplasma Gondii and Neuropsychological Outcomes
PLOS ONE | DOI:10.1371/journal.pone.0148435 February 17, 2016 10 / 14
DRD5 and MAOA [36]. However, we found no link to schizophrenia or its associated neuro-
psychological deficits in our cohort.
One explanation is that our failure to detect statistically significant associations between
T.gondii infection and brain and behavior impairments represents a false negative in an accu-
mulating evidence base. False negative findings arise for a number of reasons, including low
statistical power to detect associations due to small sample sizes (especially in relation to
schizophrenia). In our case, the possibility of false negatives needs to be evaluated against sev-
eral strengths of our study design. First, this is, to our knowledge, the most comprehensive
assessment of the possible link between T.gondii infection and a variety of impairments in a
single cohort. Previous positive associations have been reported across different studies, often
in selected or clinical samples; for example, one study will examine the link to violence, another
the link to schizophrenia, and yet another the link to self-injury, and so forth. Given that many
of these impairments are correlated in the population and are characterized by comorbid pre-
sentation, it would be expected that they should be detectable through deep and comprehensive
phenotyping of the same individuals drawn from a single birth cohort. Second, although our
cohort is of only modest size, it is adequately powered to detect small effect sizes (r= 0.1).
Moreover, we have previously published positive findings in this cohort using these same brain
and behavior phenotypes [27,28,37,38]. Third, our phenotypic assessment encompasses mul-
tiple sources including administrative records, reliable clinical interviews, well-established
personality measures and standardized neurocognitive assessments, and failure to detect asso-
ciations cannot be attributable to unreliable or idiosyncratic measurement practices. Fourth,
we have minimized unwanted heterogeneity by studying participants who are the same chro-
nological age. It is generally accepted that rates of infection increase as individuals age, proba-
bly due to cumulative increases in exposure opportunities [39]. By testing our hypotheses in a
cohort of same-aged individuals, we were able to reduce the chance of spurious associations
deriving from age-related exposure differences.
We do note two disadvantages of our study. First, T.gondii antibody status was assessed at
age 38 only. We were unable to correlate the timing of acquisition of infection with subsequent
changes in behavior. This is a limitation of all studies restricted to analysis of behavioral corre-
lates post-infection, the current study included. Since infection might have influences on brain
development (e.g. [40,41]) there might developmentally-sensitive periods where effects of
infection are magnified. It would be of great interest to conduct a similar investigation in a
cohort of younger individuals who can be tracked longitudinally in order to determine cause
and effect of the infection-behavior relationship. Disproportionate sample attrition can be a
confounder in association studies, although often study design limits the ability to test and doc-
ument missingness. We found evidence of selective missing data for three of our 27 outcome
variables; although this observation would be expected by chance, it is still a consideration. A
further consideration for all studies of T.gondii and behavioral outcomes, the present study
included, is variation of both the parasite and host and the relationship to pathogenicity. There
are a number of different T.gondii strains which differ in both virulence and prevalence across
populations [1]. Human genetic variation, especially within the major histocompatibility com-
plex, appears to be involved in pathogenicity of T.gondii [42]. Given these observations, some
potentially interesting future directions for studies of T.gondii infection correlates are inclusion
of measures of T.gondii strain and host response to infection (for example, magnitude of
response to parasite antigens). This addition is necessary in order to determine whether dis-
crepancies between reports can be ascribed to population-specific human and/or T.gondii
variation.
A second explanation of our null findings is that earlier reports of links between T.gondii
infection and behavioral impairments are exaggerated. Interest in the role of external organisms
Toxoplasma Gondii and Neuropsychological Outcomes
PLOS ONE | DOI:10.1371/journal.pone.0148435 February 17, 2016 11 / 14
influencing human psychiatric and cognitive health is currently high. This is, in part, due to an
increasing recognition of the role that inflammatory processes play in brain integrity [43–45],
and in part due to the frustrating scientific search for biological causes with large effects in com-
mon mental disorders and processes (e.g. [46,47]). Interest in T.gondii in particular has not
only captured the imagination of researchers, but also the lay public. T.gondii is a microorgan-
ism whose source of transmission is common and relatable, as evidenced by numerous recent
popular opinion pieces (e.g., “How Your Cat Is Making You Crazy”,[
48]). It has been observed
that the ‘hotter’the topic and as more studies are reported and accumulate, replication becomes
more difficult [49]. If we accept that the findings reported in the present article represent sce-
nario two, then views of the link between T.gondii and aberrant behavior may need to be tem-
pered accordingly.
In conclusion, our data do not support the hypothesis that infection by T.gondii is related to
negative behavioral outcomes in a population-representative cohort of early middle-aged indi-
viduals. In the presence of conflicting reports, better research designs are needed to fully estab-
lish the extent to which T.gondii influences impairments in brain and behavior phenotypes.
Acknowledgments
We thank the Dunedin Study members, Dunedin Unit research staff, and Study founder Phil
Silva.
Author Contributions
Conceived and designed the experiments: KS TEM AC. Performed the experiments: KS LP
BSW. Analyzed the data: KS. Contributed reagents/materials/analysis tools: TEM RP AC.
Wrote the paper: KS AC.
References
1. Flegr J., Prandota J., Sovickova M., and Israili Z.H., Toxoplasmosis—a global threat. Correlation of
latent toxoplasmosis with specific disease burden in a set of 88 countries. PLoS One, 2014; 9(3): p.
e90203. doi: 10.1371/journal.pone.0090203 PMID: 24662942
2. Furtado J.M., Smith J.R., Belfort R. Jr., Gattey D., and Winthrop K.L., Toxoplasmosis: a global threat. J
Glob Infect Dis, 2011; 3(3): p. 281–4. doi: 10.4103/0974-777X.83536 PMID: 21887062
3. Flegr J., Influence of latent Toxoplasma infection on human personality, physiology and morphology:
pros and cons of the Toxoplasma-human model in studying the manipulation hypothesis. J Exp Biol,
2013; 216(Pt 1): p. 127–33. doi: 10.1242/jeb.073635 PMID: 23225875
4. Ingram W.M., Goodrich L.M., Robey E.A., and Eisen M.B., Mice infected with low-virulence strains of
Toxoplasma gondii lose their innate aversion to cat urine, even after extensive parasite clearance.
PLoS One, 2013; 8(9): p. e75246. doi: 10.1371/journal.pone.0075246 PMID: 24058668
5. Kannan G., Moldovan K., Xiao J.C., Yolken R.H., Jones-Brando L., and Pletnikov M.V., Toxoplasma
gondii strain-dependent effects on mouse behaviour. Folia Parasitol (Praha), 2010; 57(2): p. 151–5.
6. Torrey E.F. and Yolken R.H., Toxoplasma gondii and schizophrenia. Emerg Infect Dis, 2003; 9(11): p.
1375–80. PMID: 14725265
7. Torrey E.F., Bartko J.J., and Yolken R.H., Toxoplasma gondii and other risk factors for schizophrenia:
an update. Schizophr Bull, 2012; 38(3): p. 642–7. doi: 10.1093/schbul/sbs043 PMID: 22446566
8. Kar N. and Misra B., Toxoplasma seropositivity and depression: a case report. BMC Psychiatry, 2004;
4: p. 1. PMID: 15018628
9. Hanauer D.A., Ramakrishnan N., and Seyfried L.S., Describing the Relationship between Cat Bites
and Human Depression Using Data from an Electronic Health Record. PLoS One, 2013; 8(8).
10. Pearce B.D., Kruszon-Moran D., and Jones J.L., The relationship between Toxoplasma gondii infection
and mood disorders in the third National Health and Nutrition Survey. Biol Psychiatry, 2012; 72(4): p.
290–5. doi: 10.1016/j.biopsych.2012.01.003 PMID: 22325983
Toxoplasma Gondii and Neuropsychological Outcomes
PLOS ONE | DOI:10.1371/journal.pone.0148435 February 17, 2016 12 / 14
11. Gale S.D., Brown B.L., Berrett A., Erickson L.D., and Hedges D.W., Association between latent toxo-
plasmosis and major depression, generalised anxiety disorder and panic disorder in human adults.
Folia Parasitol (Praha), 2014; 61(4): p. 285–292.
12. Cook T.B., Brenner L.A., Cloninger C.R., Langenberg P., Igbide A., Giegling I., et al., "Latent" infection
with Toxoplasma gondii: association with trait aggression and impulsivity in healthy adults. J Psychiatr
Res, 2015; 60: p. 87–94. doi: 10.1016/j.jpsychires.2014.09.019 PMID: 25306262
13. Arling T.A., Yolken R.H., Lapidus M., Langenberg P., Dickerson F.B., Zimmerman S.A., et al., Toxo-
plasma gondii antibody titers and history of suicide attempts in patients with recurrent mood disorders.
J Nerv Ment Dis, 2009; 197(12): p. 905–8. doi: 10.1097/NMD.0b013e3181c29a23 PMID: 20010026
14. Yagmur F., Yazar S., Temel H.O., and Cavusoglu M., May Toxoplasma gondii increase suicide
attempt-preliminary results in Turkish subjects? Forensic Sci Int, 2010; 199(1–3): p. 15–7. doi: 10.
1016/j.forsciint.2010.02.020 PMID: 20219300
15. Ling V.J., Lester D., Mortensen P.B., Langenberg P.W., and Postolache T.T., Toxoplasma gondii sero-
positivity and suicide rates in women. J Nerv Ment Dis, 2011; 199(7): p. 440–4. doi: 10.1097/NMD.
0b013e318221416e PMID: 21716055
16. Lester D., Toxoplasma gondii and homicide. Psychol Rep, 2012; 111(1): p. 196–7. PMID: 23045862
17. Lester D., Brain parasites and suicide. Psychol Rep, 2010; 107(2): p. 424. PMID: 21117467
18. Alvarado-Esquivel C., Hernandez-Tinoco J., Sanchez-Anguiano L.F., Ramos-Nevarez A., Cerrillo-Soto
S.M., Saenz-Soto L., et al., High seroprevalence of Toxoplasma gondii infection in inmates: A case con-
trol study in Durango City, Mexico. Eur J Microbiol Immunol (Bp), 2014; 4(1): p. 76–82.
19. Kocazeybek B., Oner Y.A., Turksoy R., Babur C., Cakan H., Sahip N., et al., Higher prevalence of toxo-
plasmosis 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(1–3): p. 103–8. doi: 10.
1016/j.forsciint.2009.03.007 PMID: 19356869
20. Yereli K., Balcioglu I.C., and Ozbilgin A., Is Toxoplasma gondii a potential risk for traffic accidents in
Turkey? Forensic Sci Int, 2006; 163(1–2): p. 34–7. PMID: 16332418
21. Havlicek J., Gasova Z.G., Smith A.P., Zvara K., and Flegr J., Decrease of psychomotor performance in
subjects with latent 'asymptomatic' toxoplasmosis. Parasitology, 2001; 122(5): p. 515–20.
22. Priplatova L., Sebankova B., and Flegr J., Contrasting effect of prepulse signals on performance of
Toxoplasma-infected and Toxoplasma-free subjects in an acoustic reaction times test. PLoS One,
2014; 9(11): p. e112771. doi: 10.1371/journal.pone.0112771 PMID: 25384036
23. Beste C., Getzmann S., Gajewski P.D., Golka K., and Falkenstein M., Latent Toxoplasma gondii infec-
tion leads to deficits in goal-directed behavior in healthy elderly. Neurobiol Aging, 2014; 35(5): p.
1037–44. doi: 10.1016/j.neurobiolaging.2013.11.012 PMID: 24315729
24. Flegr J., Preiss M., Klose J., Havlicek J., Vitakova M., and Kodym P., Decreased level of psychobiologi-
cal factor novelty seeking and lower intelligence in men latently infected with the protozoan parasite
Toxoplasma gondii Dopamine, a missing link between schizophrenia and toxoplasmosis? Biol Psychol,
2003; 63(3): p. 253–68. PMID: 12853170
25. Poulton R., Moffitt T.E., and Silva P.A., The Dunedin Multidisciplinary Health and Development Study:
overview of the first 40 years, with an eye to the future. Soc Psychiatry Psychiatr Epidemiol, 2015; 50
(5): p. 679–93. doi: 10.1007/s00127-015-1048-8 PMID: 25835958
26. Poulton R., Hancox R., Milne B.J., Baxter J, Scott K., & Wilson N., The Dunedin Multidisciplinary Health
and Development Study: are its findings consistent with the overall New Zealand population. The New
Zealand Medical Journal 2006; 119(1235).
27. Meier M.H., Caspi A., Reichenberg A., Keefe R.S., Fisher H.L., Harrington H., et al., Neuropsychologi-
cal decline in schizophrenia from the premorbid to the postonset period: evidence from a population-
representative longitudinal study. Am J Psychiatry, 2014; 171(1): p. 91–101. doi: 10.1176/appi.ajp.
2013.12111438 PMID: 24030246
28. Goldman-Mellor S.J., Caspi A., Harrington H., Hogan S., Nada-Raja S., Poulton R., et al., Suicide
attempt in young people: a signal for long-term health care and social needs. JAMA Psychiatry, 2014;
71(2): p. 119–27. doi: 10.1001/jamapsychiatry.2013.2803 PMID: 24306041
29. Wechsler D., Wechsler Adult Intelligence Scale. Fourth Edition ed, 2008, San Antonio, TX: Pearson
Assessment.
30. Army Individual Battery, Manual & directions for scoring, 1944, Washington, DC: War Department,
Adjutant General's Office.
31. Sahakian B.J. and Owen A.M., Computerized assessment in neuropsychiatry using Cantab—discus-
sion paper. J Roy Soc Med, 1992; 85(7): p. 399–402. PMID: 1629849
32. Lezak M.D., Neuropsychological Assessment. Fourth Edition ed, 2004, New York, NY: Oxford Univer-
sity Press.
Toxoplasma Gondii and Neuropsychological Outcomes
PLOS ONE | DOI:10.1371/journal.pone.0148435 February 17, 2016 13 / 14
33. Wechsler D., Wechsler Memory Scale Third Edition ed, 1997, San Antonio, TX: Psychological
Corporation.
34. John O.P. and Srivastava S., The Big Five trait taxonomy: History, measurement, and theoretical per-
spectives, in Handbook of Personality: Theory and Research, Lawrence O.P.J. Pervin A., Editor 1999,
Elsevier. p. 102–138.
35. Prandovszky E., Gaskell E., Martin H., Dubey J.P., Webster J.P., and McConkey G.A., The neurotropic
parasite Toxoplasma gondii increases dopamine metabolism. PLoS One, 2011; 6(9): p. e23866. doi:
10.1371/journal.pone.0023866 PMID: 21957440
36. Xiao J., Li Y., Prandovszky E., Karuppagounder S.S., Talbot C.C. Jr., Dawson V.L., et al., MicroRNA-
132 dysregulation in Toxoplasma gondii infection has implications for dopamine signaling pathway.
Neuroscience, 2014; 268: p. 128–38. doi: 10.1016/j.neuroscience.2014.03.015 PMID: 24657774
37. Meier M.H., Caspi A., Ambler A., Harrington H., Houts R., Keefe R.S.E., et al., Persistent cannabis
users show neuropsychological decline from childhood to midlife. Proc Natl Acad Sci U S A, 2012; 109
(40): p. E2657–E2664. doi: 10.1073/pnas.1206820109 PMID: 22927402
38. Israel S., Moffitt T.E., Belsky D.W., Hancox R.J., Poulton R., Roberts B., et al., Translating personality
psychology to help personalize preventive medicine for young adult patients. J Pers Soc Psychol,
2014; 106(3): p. 484–98. doi: 10.1037/a0035687 PMID: 24588093
39. Jones J.L., Kruszon-Moran D., Wilson M., McQuillan G., Navin T., and McAuley J.B., Toxoplasma gon-
dii infection in the United States: seroprevalence and risk factors. Am J Epidemiol, 2001; 154(4): p.
357–65. PMID: 11495859
40. Parlog A., Schluter D., and Dunay I.R., Toxoplasma gondii-induced neuronal alterations. Parasite
Immunol, 2015; 37(3): p. 159–70. doi: 10.1111/pim.12157 PMID: 25376390
41. McLeod R., Kieffer F., Sautter M., Hosten T., and Pelloux H., Why prevent, diagnose and treat congeni-
tal toxoplasmosis? Mem Inst Oswaldo Cruz, 2009; 104(2): p. 320–44. PMID: 19430661
42. Carruthers V.B. and Suzuki Y., Effects of Toxoplasma gondii infection on the brain. Schizophr Bull,
2007; 33(3): p. 745–51. PMID: 17322557
43. Najjar S. and Pearlman D.M., Neuroinflammation and white matter pathology in schizophrenia: system-
atic review. Schizophr Res, 2015; 161(1): p. 102–12. doi: 10.1016/j.schres.2014.04.041 PMID:
24948485
44. Borsini A., Zunszain P.A., Thuret S., and Pariante C.M., The role of inflammatory cytokines as key mod-
ulators of neurogenesis. Trends Neurosci, 2015; 38(3): p. 145–157. doi: 10.1016/j.tins.2014.12.006
PMID: 25579391
45. Khandaker G.M., Cousins L., Deakin J., Lennox B.R., Yolken R., and Jones P.B., Inflammation and
immunity in schizophrenia: implications for pathophysiology and treatment. Lancet Psychiatry, 2015; 2
(3): p. 258–270. doi: 10.1016/S2215-0366(14)00122-9 PMID: 26359903
46. Bondy B., Genetics in psychiatry: are the promises met? World J Biol Psychiatry,2011; 12(2): p. 81–8.
doi: 10.3109/15622975.2010.546428 PMID: 21348783
47. Zhu X., Need A.C., Petrovski S., and Goldstein D.B., One gene, many neuropsychiatric disorders: les-
sons from Mendelian diseases. Nat Neurosci, 2014; 17(6): p. 773–81. doi: 10.1038/nn.3713 PMID:
24866043
48. Mcauliffe, K., How Your Cat Is Making You Crazy, in The Atlantic. 2012, Quartz. Available from: http://
www.theatlantic.com/magazine/archive/2012/03/how-your-cat-is-making-you-crazy/308873/.
49. Ioannidis J.P., Why most published research findings are false. PLoS Med, 2005; 2(8): p. e124. PMID:
16060722
Toxoplasma Gondii and Neuropsychological Outcomes
PLOS ONE | DOI:10.1371/journal.pone.0148435 February 17, 2016 14 / 14
