Effect of childhood adversity on brain dopamine function in adulthood !

Egerton, A; Valmaggia, L; Howes, O.D; Day, F; Chaddock, C.A; Allen, P; Winton-Brown, T.T; Bloomfield,
M.A; Bhattacharyya, S; Chilcott, J; Lappin, J.M; Murray, R.M; McGuire, P.K.!
IoPPN, King's College London, Psychosis Studies, LONDON, United Kingdom.!
Alice.Egerton@kcl.ac.uk!

Introduction! Results!
Traumatic experiences during childhood, such as physical, sexual or Striatal dopamine function and childhood adversity:
psychological abuse, increase the risk of mental illness in adulthood Dopamine function was elevated in participants who had
threefold [1]. The neurobiological mechanism by which this occurs is experienced severe physical or sexual abuse in childhood compared
unknown. However, experimental animal studies show that exposure to those who had not (T63 = 2.92; P = 0.005). !
to sustained environmental stress increases meso-striatal Dopamine function was also elevated in participants who had
dopaminergic neurotransmission [2]. It has thus been suggested that experienced more than two family arrangements compared to those
environmental stress in childhood could increase the risk of psychosis who had not (T57 = 2.80; P=0.007). !
in adulthood through an effect on central dopaminergic !
No Exposure! Exposure!
neurotransmission [3]. ! !
! ! Parental death or separation! 0.11 ± 0.71! -0.02 ± 1.14!
The aim of this study was to examine how exposure to childhood !
Severe sexual or physical abuse*! -0.25 ± 1.00! 0.44 ± 0.84!
adversity impacts on brain dopamine function in young adults. We !
examined a group of healthy subjects and a group at high risk of ! Severe antipathy or neglect! 0.09 ± 0.94! -0.09 ± 1.03!
developing psychosis. ! !
>2 family arrangements*! -0.17 ± 0.94! 0.59 ± 0.83!
! !
We hypothesised that A) a history of childhood adversity would be Table 2. Values present dopamine function (mean ± s.d. 18F-DOPA z-score). *
associated with increased striatal dopamine function in adulthood; B) P < 0.0125!
this relationship would be particularly evident in people at high risk !
for psychosis.! ! Severe sexual or physical abuse! >2 family arrangements!
! 2! 2!

!
Methods! 1.5! 1.5!
Dopamine function!

!
Participants: The sample consisted of 47 individuals who met
! 1! 1!
operationalized criteria for Ultra High Risk of psychosis (UHR) (age
!
23.6 ± 4.6 years, 57% male) and 20 healthy volunteers (Control, age
! 0.5! 0.5!
23.8 ± 4.3 years, 60% male) . !
!
! 0! 0!
!
Childhood Adversity: Childhood adversity was assessed using the
!-0.5! -0.5!
Childhood Experience of Care and Abuse Questionnaire [4]. Events
!
(Table 1) were rated as present (exposure) or absent (no exposure). !
! -1! -1!
! No Exposure! Exposure! No Exposure! Exposure!
!
Dopamine Function: Presynaptic dopamine synthesis capacity (Kicer) in
Relationship between dopamine function and adversity by group:
the associative striatum was estimated using 18F-DOPA positron
Secondary analysis revealed no significant interactions between
emission tomography. As data were acquired across two CTI/
group and adversity on dopamine function (P>0.05). !
Siemens scanners (ECAT HR+: 11 Control; 28 UHR [5]; ECAT HR++:
!
9 Control; 19 UHR [6]), Kicer values were converted to z-scores for
analysis. ! Discussion!
These findings provide evidence that exposure to childhood
Statistics: T-tests evaluated the impact of exposures to childhood psychosocial stressors that increase risk of developing psychosis in
adversity on striatal dopamine function. Bonferroni correction later life is associated with elevated striatal dopamine function in
resulted in a threshold P = 0.0125.! early adulthood.!
Univariate ANOVA explored interactions between group (UHR !
versus Control) and exposure to adversity on striatal dopamine The elevation was significant following exposure to severe (sexual or
function.! physical) abuse, or to multiple family arrangements, which may be a
marker for unknown stressors, including abuse. !
!
Results!
The observed dopamine elevation in adults who had experienced
Incidence of childhood adversity in UHR and Control groups: Only the
abuse in childhood are consistent with studies in experimental
frequency of physical and sexual abuse was more common in the
animals. !
UHR group than in Controls and there was no group difference in
Abnormal dopamine function is a key feature of psychotic disorders,
dopamine function (Table 1).!
and a plausible mediator of an effect of childhood stressors on risk
!
Control! UHR! of later illness.!
!
Parental death or separation! 10 / 20 (50%)! 30 /45 (67%)! References!
1.  Varese, F., et al,. 2012 Schizophrenia Bulletin 38, 661-671.!
Severe sexual or physical abuse*! 4 / 20 (20%)! 22 / 45 (49%)!
2.  Antelman SM, et al., 1980 Science 207(4428): 329-331.!
Severe antipathy or neglect ! 7 / 20 (35%)! 14 / 39 (36%)! 3.  Selten, J.P., et al., 2013 Schizophrenia Bulletin 39, 1180-1186.!
4.  Bifulco A. et al., 2005 Br J Clin Psychol 44(Pt 4): 563-581.!
>2 family arrangements! 3 / 20 (15%)! 12 / 39 (31%)! 5.  Howes OD et al., 2009 Arch Gen Psychiatry 66(1): 13-20.!
6.  Egerton A, et al., 2013 Biol Psychiatry 74(2): 106-112.!
18F-DOPA z-score! -0.2 ± 0.9! 0.1 ± 1.0! !
Disclosure!
Table 1. Adversity data are presented as positive incidents / total sample. 18F-
This study was funded by MRC grant G0700995, and was supported by the
DOPA data are presented as mean ± s.d. * P = 0.03!
NIHR BRC at SLaM NHS Foundation Trust and KCL.

Copyright © 2014 Egerton et al., Alice Egerton@kcl.ac.uk!

P.3.b.024
Effect of childhood adversity on brain dopamine function in adulthood
A. Egerton 1, L. Valmaggia 1, O.D. Howes 1, F. Day 1, C.A. Chaddock 1, P. Allen 1, T.T. Winton-Brown 1, M.A. Bloomfield 1,
S. Bhattacharyya 1, J. Chilcott 1, J.M. Lappin 1, R.M. Murray 1, P.K. McGuire 1
1Institute of Psychiatry Kingas College London, Psychosis Studies, London, United Kingdom

Purpose: Traumatic experiences during childhood, such as physical, sexual or psychological abuse, increase the
risk of psychosis in adulthood threefold [1]. It has been suggested that environmental stress in childhood could
increase the risk of psychosis in adulthood through an effect on central dopaminergic transmission [2]. We
therefore investigated whether, in young healthy adults and in those at clinical high risk of psychosis, experience
of childhood adversity was associated with increased presynaptic dopamine function in the striatum.

Methods: This study included 47 participants who met operationalised criteria for Ultra High Risk aUHR) of
psychosis, and 20 healthy volunteers. Childhood adversity was assessed using the Childhood Experience of Care
and Abuse questionnaire. Analysis was limited to exposure/non-exposure to 4 traumatic events that were
frequent enough to yield sufficient data aTable 1). Presynaptic dopamine function in the associative striatum was
assessed using 18F-DOPA positron emission tomography. The associative striatum comprises the dorsal caudate
and precomissural putamen. The impact of exposures on dopamine function was determined using independent
samples t-tests aexposure versus non-exposure). Secondary analysis employed univariate ANOVA to explore
interactions between group aUHR or healthy volunteer) and exposure to childhood trauma on dopamine function.

Results: Dopamine function was elevated in participants who had experienced severe sexual or physical abuse in
childhood compared to those who had not aT63 = 2.92; P=0.005), and in those who had experienced multiple
family arrangements compared to those who had not aT57 = 2.80; P=0.007) aTable). Both findings were above
the corrected level for statistical significance aP=0.0125). Dopamine function was not significantly associated with
exposure to other traumatic events aTable). Secondary analysis revealed no significant interactions between
group aUHR or healthy volunteer) and adverse experiences on dopamine function.

Conclusions: Exposure to childhood psychosocial stressors that increase risk of developing psychosis in later
life [1] is associated with elevated striatal dopamine function in early adulthood. Abnormal dopamine function is
a key feature of psychotic disorders [3], and a plausible mediator of an effect of childhood stressors on risk of
later illness. These data provide proof of concept, illustrating how an environmental risk factor for psychotic
illness can impact on a neurotransmitter system that is fundamental to psychotic disorders.
Table 1.
No exposure Exposure Statistic
Parental loss or separation 0.11±0.71 −0.02±1.14 T63=0.53; P=0.60
Severe physical or sexual abuse −0.25±1.00 0.44±0.84 T63=2.92; P=0.005
Severe antipathy or neglect 0.09±0.94 −0.09±1.03 T57=0.68; P=0.50
More than two family arrangements −0.17±0.94 0.59±0.83 T57=2.80; P=0.007

Data are presented as mean ± standard deviation z-scores for striatal 18F-DOPA Kicer athe rate of utilisation of
18F-DOPA, relative to a cerebellar reference region), representing presynaptic dopamine synthesis capacity.

1. Varese, F., Smeets, F., Drukker, M., Lieverse, R., Lataster, T., Viechtbauer, W., Read, J.van Os, J., Bentall,
R.P. 2012 Childhood adversities increase the risk of psychosis: a meta-analysis of patient–control, prospective-
and cross-sectional cohort studies. Schizophrenia Bulletin 38, 661–671.

2. Selten, J.P., van der Ven. E., Rutten, B.P., Cantor-Graae, E. 2013 The social defeat hypothesis of
schizophrenia: an update. Schizophrenia Bulletin 39, 1180–1186.

3. Howes, O.D., Kambeitz, J., Kim, E., Stahl, D., Slifstein, M., Abi-Dargham, A., Kapur, S.K. 2012 The Nature of
Dopamine Dysfunction in Schizophrenia and What This Means for Treatment: Meta-analysis of Imaging Studies.
Archives of General Psychiatry 69, 776–786.

Citation: Eur Neuropsychopharmacol. 2014;24aSuppl   2):S505

Keywords
Dopamine
Schizophrenia: clinical
Brain imaging