Childhood Adversity and Hippocampal and Amygdala Volumes in a Population at Familial High Risk of Schizophrenia
Barker, V.1, 2, *, Bois, C. 1,*, Neilson, E.1, Johnstone, E.C. 1, Owens, D.G.C. 1, 2, Whalley, H.C. 1, McIntosh, A.M. 1, 2, and Lawrie, S.M. 1, 2
1Division of Psychiatry, Centre for Brain Sciences, School of Clinical Sciences, University of Edinburgh, Royal Edinburgh Hospital, Morningside Park, Edinburgh, EH10 5HF
2 Royal Edinburgh Hospital, Morningside Park, Edinburgh, EH10 5HF
* Joint First authorship
Abstract
Background: There is an established link between childhood adversity (CA) and schizophrenia. Hippocampus and amygdala abnormalities pre-date onset in those at high familial risk (fHR) of schizophrenia, but it is not clear whether these alterations are associated with CA in those at elevated risk of schizophrenia
Methods: We examined hippocampal and amygdala volumes in those at fHR who had been referred to a social worker or the Children’s Panel compared to those who had not.
Results: The right hippocampus and left amygdala were significantly smaller in those that had been referred to social work and Children's Panel.
Conclusions: Our findings suggest that CA can influence structural changes in the brain in a cohort at fHR of schizophrenia. These findings provide further evidence that while genetic factors contribute to the structural changes found in schizophrenia, environmental factors such as CA can have a lasting impact on specific brain regions.
Declaration of interest: None
1.1 Introduction:
The stress-diathesis model suggests that a biologically driven (genetic) predisposition interacting with environmental factors produces an individual’s phenotype(Zubin and Spring, 1977) . It is well established that childhood adversity (CA) increases the risk of developing psychosis (Varese et al., 2012), and other psychiatric disorders including affective and anxiety disorders. It is unclear what determines an individual’s vulnerability to different psychiatric disorders given similar environmental exposures but one likely influence is genetic vulnerability.
Neurodevelopmental abnormalities in the hippocampal formation have been implicated in the development of Schizophrenia (Cannon et al., 2003; Weinberger, 1999). Reductions in hippocampal volume and alterations in the amygdalae of individuals with both first episode and chronic psychosis and in those at familial high risk of schizophrenia have been demonstrated (Boos et al., 2007; Francis et al., 2013; Honea et al., 2005; Koolschijn et al., 2010a; Lawrie et al., 2001; Steen et al., 2006; Velakoulis et al., 1999; Velakoulis et al., 2006; Verma et al., 2009; Vita et al., 2006; Witthaus et al., 2010; Wright et al., 2000) and it has also been shown that left amygdala volume is reduced in those at familial high risk of schizophrenia (Cooper et al., 2014). It is also well established that there are hippocampal and amygdala volume alterations in adults in response to CA (Andersen et al., 2008; Bremner et al., 1997; Edmiston et al., 2011; McCrory et al., 2011; Stein et al., 1997; Teicher et al., 2003; Vythilingam et al., 2002; Woon et al., 2010)(Dannlowski et al., 2012). Interestingly these volume reductions are not seen in children and adolescents who have experienced CA (Carrion et al., 2001; De Bellis et al., 1999; Jackowski et al., 2009; Woon and Hedges, 2008) and translational studies have shown that exposure to early stress affects synaptic density in the hippocampus but that these effects do not emerge until after puberty (Andersen and Teicher, 2004). Furthermore it has also been demonstrated that hippocampal, particularly left hippocampal and amygdala volumes were significantly reduced in those individuals with first episode psychosis who had experienced CA compared to those that had not (Aas et al., 2012; Hoy et al., 2011).
Hypothalamic-Pituitary- Adrenal (HPA) axis activation occurs in response to environmental stress and has been implicated as a mechanism by which chronic stress such as CA influences a variety of psychiatric disorders. Read et al. were among the first to propose a traumagenic neurodevelopmental model of schizophrenia mediated by the HPA axis (Read et al., 2001). Adults who have suffered CA show hyper-reactivity and persistent sensitisation of the HPA stress response (Heim et al., 2000) as do those with schizophrenia (Mondelli et al., 2010a; Walker et al., 2008). The hippocampus is involved in terminating the stress response through glucocorticoid mediated negative feedback on the HPA axis. Whereas the effects of stress on the adult hippocampus are generally transient, stress that occurs in early life can permanently alter the hippocampus (Brunson et al., 2003). The enduring effects of early life stress may either reflect the occurrence of stress during a sensitive developmental period in the hippocampus or the cumulative effects of both early and continuing processes of progressive injury to hippocampal neurons. It has been shown that in those at familial high risk of schizophrenia among the subfields of the hippocampal formation, the subicula are bilaterally reduced. This area plays a prominent role in inhibition of the hypothalamo-pituitary-adrenocortical (HPA) axis which may suggest that these individuals are particularly sensitive to stress and stress related hippocampal alterations(Herman and Mueller, 2006). These findings support the idea that genetic factors and CA may both contribute to reductions inhippocampal and amygdala volume, structural changes which are found in individuals with psychosis. The presence of reduced hippocampal volume in unaffected relatives of those with schizophrenia suggests that these changes are not due to the disease process.
The aim of the present study was to examine whether indices of CA derived from the Edinburgh High Risk Study (EHRS) were associated with volumetric indices of the hippocampus and amygdala, which are pre-specified subcortical regions of interest (ROIs) known to be susceptible to early adverse events. The EHRS consists of a large cohort at familial high risk of developing schizophrenia. Our hypothesis was that alterations the hippocampal and amygdala volume seen in those at familial high risk of schizophrenia would be significantly associated with CA as indicated by social work involvement in childhood or appearance before the Children's Panel.
A Children's Panel hears cases as part of the legal and welfare systems in Scotland and makes decisions about vulnerable children and young peoplein need of care; it aims to combine justice and welfare for children and young people. The majority of children are referred on care and protection grounds. The most common grounds of referral in 2013/14 were 'lack of parental care'. Referral to social work or the Children’s Panel represents a level of concern regarding the adversity that a child is exposed to such that intervention is deemed necessary. This is an objective indicator of exposure to adversity as compared to more subjective retrospective self-report methods.
1.2 Methods
1.2.1 Participants
The recruitment and clinical assessment process for the EHRS have been described in detail elsewhere (Johnstone et al., 2005). The Edinburgh High Risk Study was a prospective longitudinal study where individuals at high familial risk of developing schizophrenia were identified throughout Scotland. Informed consent was obtained from all participants, as approved by the Psychiatry and Clinical Psychology subcommittee of the Multi-Centre Research Ethics Committee for Scotland. High Risk individuals aged 16 to 25 years with no personal history of psychiatric disorder were contacted, throughout Scotland, based on the criteria that they had at least two first- and/or second- degree relatives with a diagnosis of schizophrenia. The Edinburgh high risk study included full clinical and imaging data on 150 individuals at baseline. This study includes all those with grossly normal structural Magnetic Resonance Imaging scans (n=147) which generated adequate freesurfer edits (n=145) of which full data was available for 140 individuals. At the time of the scans used in the present study, all individuals were psychiatrically well and either in full-time employment or education. Social work involvement and appearance before the children’s panel were used as indicators of CA. This information was obtained from maternal history combined with the subjects’ own accounts in an unstructured psychiatric interview.
1.2.2 Demographics
There were no significant differences in age for social work involvement comparing those that had been referred versus those that had not (F = .076, df = 1,137, p = 0.783), nor IQ (F = 1.95, df = 1,136, p = 0.164).There were no significant differences in age in those that had children's panel involvement versus those that had not, (F =0.004, df = 1,137, p = 0.95), however there was a significant difference in IQ (F = 10.39, df = 1,136, p =0.0016) with those who had children panel involvement having significantly lower (mean = 90 se = 2.94) IQ than those that had not. See Table 1 for detailed demographic information. Note 16 individuals had both social work and Children’s Panel involvement.
1.2.3 Imaging Parameters
Participants underwent structural MRI. The scans were taken between 1994 and 1999 and were done on a 42 SPE Siemens (Erlangen, Germany) Magnetom operating at 1.0 T. The scanning sequence was a three-dimensional magnetization prepared rapid acquisition gradient echo sequence consisting of a 180ｰinversion pulse followed by a fast low angle shot collection (flip angle 12ｰ, repetition time 10 msec, echo time 4 msec, inversion time 200 msec, relaxation delay time 500 msec, field of view 250 mm ｧ250 mm), giving 128 contiguous slices with a thickness of 1.88 mm. The sequence was selected in order to obtain optimal gray and white matter contrast.
1.2.4 Freesurfer Acquisition
Automated subcortical segmentations were conducted using Freesurfer 5.30 ( Parcellation of the subcortical anatomy, and calculations of the total intracranial volume was performed by delineating anatomical divisions via automatic parcellation methods, in which the statistical knowledge base derives from a training set incorporating the anatomical landmarks and conventions described by Duvernoy (1991). This procedure assigns a neuroanatomical label to each voxel in an MRI volume based on probabilistic information estimated from a manually labelled training set. The classification technique employs a non-linear registration procedure that is robust to anatomical variability (Fischl et al., 2002). The segmentation uses three pieces of information to disambiguate labels: (1) the prior probability of a given tissue class occurring at a specific atlas location, (2) the likelihood of the image given what tissue class and (3) the probability of the local spatial configuration of labels given the tissue class.
1.2.5 Statistical Analysis
All statistical analyses were conducted in R (version 3.0.2). For each anatomical parameter, a ANCOVA was conducted with the parameter of interest (eg Left/Right Hippocampus, and Amygdala) entered as the outcome variable, with either Children's Panel involvement (yes/no) or Social Work involvement (yes/no) added as the predictor variable. Adjustments were made for intracranial volume, age, gender and IQ as determined by WAIS and social class at birth.
A linear mixed model was run to determine if there were any hemispheric effects on the CA findings. This analyses followed the same model as above with further adjustments for hemisphere, as a within subjects factor, and a hemisphere by social work or Children’s Panel involvement interaction.
1.3 Results
1.3.1 Children's Panel involvement
There was a significant main effect of Children's Panel involvement on the volume of the right hippocampus, with those having had Children's Panel involvement having significantly smaller right hippocampi than those that had not (F=8.24, df = 1,126, p = .0048) (See figure 1). For the amygdala, the same pattern of results emerged, with those having had Children's Panel involvement having significantly smaller left amygdalae than those that had not (F=5.50, df = 1,126, p = 0.021) (See figure 2). No other significant effects emerged. Means of all regions are presented in Table 2, and significant and non-significant main effects of the analyses for Children's Panel involvement are presented in Table 3. There was a significant hemisphere by Children's Panel involvement interaction for the hippocampus (t=-2.32, df=134, p=0.02) suggesting that the main effect of Children's Panel involvement on hippocampal volume may be lateralised. This was not found for the amygdala.
1.3.2 Social Work Referral
There was a significant main effect of being referred for social work on the volume of the right hippocampus, with those having being referred having significantly smaller right hippocampi than those that had not, (F = 5.27, df = 1,126, p = 0.023) (See figure 3). For the amygdala, the same pattern of results emerged, with those having been referred for social work having significantly smaller left amygdalae than those that had not ((F =5.67, df = 1,126, p = 0.019) (See figure 4). There was a significant hemisphere by social work referral interaction in the hippocampus (t=-3.36, df=133.2, p=0.001) suggesting that the main effect of social work referral on hippocampal volume may be lateralised.This interaction was not present in the amygdala.No other significant effects emerged. Means of all regions are presented in Table 2, and significant and non-significant main effects of the analyses for social work referral are presented in Table 3.
1.4 Discussion:
The current study aimed to assess whether indicators of CA were associated with alterations in the volume of the hippocampus and amygdala, in a sample at high familial risk for schizophrenia. We found that CA as indicated by Children's Panel involvement and social work referral was significantly associated with reductions in hippocampal volume lateralized to the right hemisphere, whilst for the amygdala both these indices were associated with volume reductions that weren’t lateralized. These hippocampal and amygdala volume reductions are in keeping with previous studies which demonstrate that hippocampal and amygdala volumes were significantly reduced in those individuals with first episode psychosis who had experienced CA compared to those that had not (Aas et al., 2012; Hoy et al., 2011) and also that left amygdala volume is reduced in those at familial high risk of schizophrenia (Cooper et al., 2014). Our findings support the idea that both genetic factors and CA have an effect on reducing hippocampal and amygdala volume, structural changes which are consistently found in schizophrenia.
The amygdala and hippocampus are regions of substantial growth in normal childhood and adolescence with the right hippocampus in particular increasing significantly in females (Giedd et al., 1996) which suggests that these areas are particularly vulnerable to the effects of stress in childhood andwhich may have contributed to the lateralization found to the right hippocampus in those with CA in this study particularly as more females than males in the current study had experienced CA. We did control for sex in the current analysis and also it should be noted that following normal development there are no sex differences in the final volumes of the hippocampi and amygdalae(Giedd et al., 1996).
Epigenetic processes represent the interface between environmental and genetic risk factors for schizophrenia. Such epigenetic processes and in particular methylation of genes involved in the HPA axis activation pathway have been implicated as playing a role in modulating the effects of CA and in the development of schizophrenia (Barker et al., 2014; McGowan et al., 2009; Roth et al., 2009; Weaver et al., 2004). This may attribute for the gene x environment interaction seen in schizophrenia.
A previous examination of this population showed that those subjects with a mother or either parent affected by schizophrenia were significantly more likely to have social work involvement or be in foster care compared to those with other family histories (Johnstone et al., 2000). The same was found to be true in the current study (see table 1). This may suggest that those individuals involved with social work/Children’s Panel had a greater genetic loading and this was responsible for the structural changes seen. It may also be that in those families where the parents were affected by schizophrenia there was a lower threshold for social work or Children’s Panel referral. There was insufficient power in this study to examine gene by environment interaction statistically but the pattern of our data suggests that those with affected parents were more likely to show an apparent effect on hippocampal and amygdala volume than those with affected siblings.
1.4.1 Limitations:
There were certain limitations to this study including that social work involvement and referral to the Children’s Panel are imprecise proxies for CA. This information was obtained from maternal history combined with the subjects’ own accounts and we do not have a clear record of the types of CA that occurred, how severe this was or how long it went on for. It would have been preferable to have had a more detailed measure of CA such as the Childhood Trauma Questionnaire. However this was not done at the time the initial assessments were performed and it has recently been found that mental health factors such as current depression, psychological distress or mastery and chronic stress influence the reporting of adverse childhood experiences on retrospective questionnaires (Colman, 2015). What social work and Children’s Panel involvement does indicate is that in these cases the severity of abuse was sufficiently severe as to warrant intervention. This is an area that needs to be examined in future research of fHR individuals. A further limitation is the relatively small number of subjects that reported social work or Children’s Panel involvement. This meant that sub-analyses of the data based on reason for referral to the Children’s Panel was not possible. Unfortunately, our sample size was also too small to investigate whether those at high risk that we know went on to develop schizophrenia were particularly vulnerable to the effects of CA on brain structure. A further limitation of the present study is the lack of a control group, as none of the original controls recruited for this study had had referral to social work or Children's Panel involvement. Thus it was not possible to directly infer whether those at high risk were more susceptible to the effects of CA on brain structure than a sample of healthy individuals. It will be important to build on the findings of the current study and perform larger studies of the influence of CA on hippocampal and amygdala volume in those at fHR in future using specific measures of CA with groups of controls who both have and have not experienced CA. A further limitation of the study is that the scans were taken between 1994 and 1999 and on a 42 SPE Siemens (Erlangen, Germany) Magnetom operating at 1.0 T. This may limit the ability for researchers using more advanced scanners with higher field strength to make comparisons with the current results.
Reductions in the hippocampus and amygdala are consistently observed in patients with schizophrenia. We have demonstrated a link between CA and these volumetric alterations in a sample at high familial risk of Schizophrenia. This supports the idea that both genetic and environmental factors have an effect on reducing hippocampal and amygdala volume in schizophrenia. It has been suggested that epigenetics may underpin the effect of CA on these structures. These findings highlight the importance of early assessment of CA history, as providing a potential opportunity for early intervention strategies in this population.