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Hippocampus and amygdala volumes in children and young adults at high-risk of schizophrenia: Research synthesis

Schizophrenia Research, 1, 156, pages 76 - 86

Abstract

Background

Studies have reported hippocampal and amygdala volume abnormalities in schizophrenic patients. It is necessary to explore the potential for these structures as early disease markers in subjects at high risk (HR) of schizophrenia.

Methods

We performed a review of 29 magnetic resonance imaging (MRI) studies measuring hippocampal and amygdala volumes in subjects at HR for schizophrenia. We reclassified subjects in 3 new HR categories: presence of only risk symptoms (psychotic moderate symptoms), presence of only risk factors (genetic, developmental or environmental), and presence of combined risk symptoms/factors.

Results

Hippocampal volume reductions were detected in subjects with first episode (FE) of psychosis, in all young adults and in adolescents at HR of schizophrenia. The loss of tissue was mainly located in the posterior part of hippocampus and the right side seems more vulnerable in young adults with only risk symptoms.

Instead, the anterior sector seems more involved in HR subjects with genetic risks. Abnormal amygdala volumes were found in FE subjects, in children with combined risk symptoms/factors and in older subjects using different inclusion criteria, but not in young adults.

Conclusion

Hippocampal and amygdala abnormalities may be present before schizophrenia onset. Further studies should be conducted to clarify whether these abnormalities are causally or effectually related to neurodevelopment. Shape analysis could clarify the impact of environmental, genetic, and developmental factors on the medial temporal structures during the evolution of this disease.

Abbreviations: AG - amygdala, AHC - amygdala–hippocampal complex, HC - hippocampus, FE - first episode, HR - high risk, HRp - high risk subject psychotic at follow-up, HRnp - high risk subject non-psychotic at follow-up, MRI - magnetic resonance imaging, IQ - Intelligence Quotient, y.o. - years old.

Keywords: Schizophrenia, High risk, Hippocampus, Amygdala, Neuroimaging, Neurodevelopment.

1. Introduction

Several studies in the literature focus on finding early disease markers of schizophrenia, with the goal to detect subjects in a preclinical phase in order to plan pre-onset interventions. One such putative marker is structural neuroimaging, as, for example, measurements obtained from magnetic resonance imaging (MRI). Authors have reported reduced total brain and gray matter and increased ventricular volumes in schizophrenic patients compared to controls (Shenton et al, 2001 and Steen et al, 2006). Reductions have also been observed in the hippocampus (HC), amygdala (AG), and superior temporal gyri (Lawrie and Abukmeil, 1998 and Nelson et al, 1998), in the prefrontal cortex and thalamus ( Konick and Friedman, 2001 ), in the anterior cingulate gyrus ( Baiano et al., 2007 ), and the corpus callosum ( Woodruff et al., 1995 ) between these two groups. Total brain volume reductions are subtle and close to the detection thresholds of current MRI methods however (~ 3%) ( Wright et al., 2000 ), while changes are larger in the hippocampus (~ 8%) ( Wright et al., 2000 ) and in the amygdala (6–10%) (Lawrie and Abukmeil, 1998, Nelson et al, 1998, and Wright et al, 2000).

It has been shown that medial temporal lobe reductions correlate with memory impairment ( Antonova et al., 2004 ) and that structural, functional, and neurochemical abnormalities in the hippocampus have been related to impairment in declarative memory function in schizophrenic patients ( Weiss and Heckers, 2001 ), as well as an important vulnerability indicator for this disorder (McCarley et al, 1993, Seidman et al, 2002, Seidman et al, 2003, and Tamminga et al, 2010). Further, smaller amygdala volumes seem to be related to reduced emotional expression and emotion recognition in schizophrenic subjects ( Aleman and Kahn, 2005 ). Hippocampal and amygdala volume reductions are also seen in the unaffected relatives of schizophrenic probands (Seidman et al, 1999, O'Driscoll et al, 2001, Van Erp et al, 2002, and Boos et al, 2007) and in first-episode (FE) of schizophrenia (Joyal et al, 2003, Vita, 2007, and Adriano et al, 2011).

1.1. High risk subjects

Many recent studies have analyzed HC and AG volumes in young subjects at high risk for schizophrenia, based on the dual hypotheses that within this group of subjects, many are, in fact, in a prodromal period, and that later changes in MRI measures would be apparent in that prodromal period.

Thus, in recent years, ‘high-risk’ strategies have been helpful in assessing brain structural and functional changes surrounding the onset of psychosis and schizophrenia. These have largely been undertaken in two ways, one based around genetic risk, and a second based on the identification of prodrome from clinical symptoms ( Olsen and Rosenbaum, 2006 ).

Within the genetic risk paradigm, Boos et al. conducted a meta-analysis of family studies in schizophrenia and showed that first-degree relatives had lower hippocampal, total gray matter, and ventricular volumes, compared with healthy volunteers ( Boos et al., 2007 ). Other studies considering only genetic risk provide an overview of brain changes in subjects with high risk for schizophrenia (Keshavan et al, 1997, Keshavan et al, 2002, Whalley et al, 2005, Lawrie et al, 2008, and Moran et al, 2013) reporting abnormalities mainly in the frontal and temporal regions.

To our knowledge, only Jung et al. have proceeded with systematically reviewing the literature for MRI studies considering all type of HR subjects ( Jung et al., 2010 ). The authors concluded that abnormalities in prefrontal, temporal and anterior cingulate cortices occur before illness onset, but they did not report their findings from a neurodevelopmental perspective, but rather simply as differences between controls, HR and patients.

2. Objective

We aim to review published evidence regarding HC and AG volumetric differences in HR subjects for schizophrenia.

The objective was to determine if hippocampal and amygdala volumes differ in HR individuals in order to understand whether these volumes can help in the early detection and clinical intervention of schizophrenia.

As is the case with many major neuropsychiatric illnesses, the typical age of onset for schizophrenia is late adolescence or early twenties, with a slightly later onset in females ( Hafner et al., 1994 ). Neuroimaging studies that focus on this age range may provide unique insights into the onset and course of psychosis. Based on this finding, we examined evidence from studies spanning ages from early childhood to young adulthood.

We chose to focus our review solely on the hippocampus and amygdala because: (i) they are both part of the limbic circuit involved in schizophrenia pathology; and (ii) there is evidence that they are both affected in schizophrenia. Our intent was to address issues of heterogeneity in the HR concept, including age, and to analyze results taking into account different risk factors and neurodevelopmental stages.

3. Methods

Studies were included in our research synthesis if they met the following criteria:

  • (1) Papers had to be drafted in English;
  • (2) Papers were original works (i.e. no review);
  • (3) Subjects were defined as “high risk”, “ultra-high risk” or “at-risk mental state” to develop schizophrenia;
  • (4) High risk subjects were between 8 and 30 years of age (group mean age). As we stated earlier, the aim of the present review is to provide an overview of hippocampal and amygdala changes between childhood and young adult period;
  • (5) Structural magnetic resonance imaging techniques analyzing cerebral gray matter were used to obtain information specifically on the HC, AG or both (HC/AG complex).

We conducted an extensive PUBMED search for online listings from 1990 until January 2014 using the following keyword combinations: “schizo* [ti] AND risk [ti] AND MRI”; “schizo* [ti] AND offspring* [ti] AND MRI”; “psychosis [ti] AND risk [ti] AND MRI”; and “psychosis [ti] AND offspring* [ti] AND MRI”, as well as cited references in articles and review papers.

One of the first hurdles to proceed with a synthesis relates to the fact that “high-risk for psychosis” is a very heterogeneous concept in the literature, alternatively related to risk symptoms or risk factors, with some studies combining both. In light of this, we reclassified all articles as per the following HR categories, defined below:

  • 1. Studies of HR subjects with only psychotic symptoms;
  • 2. Studies of HR subjects with only risk factors; and
  • 3. Studies of HR subjects with both psychotic symptoms and risk factors.

Due to the large age range and the necessity to identify patterns of volumetric changes possibly related to maturation and neurodevelopment, we further synthesized results according to age groups. We considered the subject's age range or what authors declared about the stage of age of subjects included in their study.

We found the following age groups: children (8–12 y.o.); children/adolescents (8–18 y.o.) adolescents (13–19 y.o.); adolescents/young adults (13 y.o. and above), and young adults (20 y.o. and above). Two studies considered all age phases (children/adolescents/young adults).

Risk symptoms considered in the studies reviewed were: symptoms of early onset schizophrenia or schizotypal personality disorder ( Hendren et al., 1995 ) attenuated psychotic symptoms (Wood et al, 2005, Witthaus et al, 2009, and Witthaus et al, 2010), and brief limited intermittent psychotic symptoms ( Wood et al., 2005 ) (cf. Fig. 1 — A). Such risk symptoms are thus related to the definition of a ‘prodromal phase’ of a disease, where this phase is generally described as a subsyndromal stage preceding disease onset ( Keith and Matthews, 1991 ).

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Fig. 1 The reclassification of HR subjects based on the presence of psychotic symptoms (A) or risk of factors (B) or both (C) in their inclusion criteria. SIPS = Structured Interview for Prodromal Syndrome. IQ = Intelligence Quotient. SIS = Structured Interview for Schizotypy ( Kendler, 1989 ). CBC = Child Behavior Checklist ( Achenbach and Rescorla, 2000 ). source: Klosterkötter J, Schultze-Lutter F, Bechdolf A, Ruhrmann S. Prediction and prevention of schizophrenia: what has been achieved and where to go next? World Psychiatry. 2011 Oct;10(3):165-74.

Risk factors mainly considered in the studies were genetic risks associated with (i) having a first-degree relative with diagnosis of schizophrenia or schizoaffective disorder (Keshavan et al, 1997, Keshavan et al, 2002, and Schreiber et al, 1999); (ii) having first or second degree relatives with schizophrenia (Lawrie and Abukmeil, 1998, Lawrie et al, 1999, and Lawrie et al, 2001) or psychotic disorder ( Wood et al., 2005 ); (iii) having at least one first-degree relative with a diagnosis of schizophrenia or schizoaffective disorder, and one second- or third-degree relative with a history of psychosis, suicide, or psychiatric hospitalization (cf. Fig. 1 — B).

Extensive findings support the view that genetic factors are the single most powerful predictor of schizophrenia (Prescott and Gottesman, 1993 and Moldin and Gottesman, 1997).

The other risk factors confirmed by the literature (Geddes and Lawrie, 1995, Byrne et al, 1999, Goldstein et al, 2000, and Zornberg et al, 2000) were low Intelligence Quotient (IQ) studied in association with other factors in some studies (Welch et al, 2010 and Walter et al, 2012) and the presence of obstetric complications considered only in association with the presence of attenuated psychotic symptoms and/or genetic risk ( Hurlemann et al., 2008 ).

In some studies, HR subjects were selected to exhibit both risk factors and symptoms concurrently, e.g. genes, obstetric complications or low IQ accompanied by moderate psychotic symptoms (cf. Fig. 1 — C). Whether or not these subjects have a higher conversion to psychosis remains to be determined.

We included in this category studies where:

  • HR subjects had attenuated psychotic symptoms and/or brief limited intermittent psychotic symptoms, and/or first degree relative with psychotic disorder or schizotypal personality disorder (Velakoulis et al, 1999, Phillips et al, 2002, Buehlmann et al, 2010, and Moorhead et al, 2013); and/or presence of schizotypal personality disorder in the last 12 months ( Mittal et al., 2013 );
  • Early prodromal state subjects, i.e. subjects with basic symptoms with a positive predictive value for the transition to first-episode psychosis, and/or reduction of the global assessment of functioning and a first degree relative with psychotic disorder or obstetric complications ( Hurlemann et al., 2008 );
  • HR subjects with low IQ, and high scores in either the Structured Interview for Schizotypy and Child Behavior Checklist ( Welch et al., 2010 ).

4. Results

Upon applying our search criteria, we obtained 267 articles via PUBMED, of which only 24 papers matched all inclusion criteria.

Using references included in these 24 papers, we were able to add a further five references that were both relevant and within the inclusion criteria.

A total of 29 papers were analyzed (see Appendix 1 for more information about the reviewing process).

The age range between studies was 8 ( Hendren et al., 1995 ) to 45 years old ( Ho and Magnotta, 2010 ). MRI techniques used to measure hippocampus and amygdala volumes were voxel based morphometry, semiautomated segmentation algorithm and manual tracing.

Results are summarized in Table 1 . In Table 2, Table 3, and Table 4 (cf. Supplemental information), the column ‘Inclusion criteria’ allows the reader to return to the operational criteria used by the original authors.

Table 1 Main findings of the 29 papers reviewed.

  Children Children/adolescents Adolescents Adolescents/young adults Young adults Children/adolescents/young adults
HC Risk symptoms         </</<  
Risk factor   =/< </< =/< </< =
Combined symptoms/factors =     =/=/=/</</< <  
FE         </</<  
AG Risk symptoms         =/=  
Risk factor   =/= < <    
Combined symptoms/factors <   > =    
FE       > </<  
AHC Risk symptoms            
Risk factor     < </</<    
Combined symptoms/factors            
FE            

Table shows results of hippocampus (HC), amygdala (AG), and amygdalo–hippocampal complex (AHC) volume comparisons between first episode (FE) subjects and controls, high risk subjects belonging the category “risk symptoms”, or “risk factor” or “combined symptoms/factors” and controls.

4.1. Hippocampus

We found 21 papers analyzing hippocampus in subjects with high risk for schizophrenia. In the majority of these papers, subjects were adolescents/young adults or only young adults. The inclusion criteria most used were symptoms and/or risk factors, following by genetic risk factors. The hippocampus of HR subjects was smaller compared to controls in most studies (Keshavan et al, 1997, Phillips et al, 2002, Wood et al, 2005, Hurlemann et al, 2008, Witthaus et al, 2009, Witthaus et al, 2010, and Buehlmann et al, 2010).

Considering the age, children had the same hippocampal volumes when compared to controls ( Hendren et al., 1995 ) Smaller hippocampi were found in adolescent and young adult HR subjects (Keshavan et al, 1997, Tepest et al, 2003, Witthaus et al, 2009, Witthaus et al, 2010, and Moorhead et al, 2013), but these results were not confirmed in some studies analyzing different age groups in the same sample. Indeed, reduced hippocampal volumes were found in a study on children/adolescents ( Sismanlar et al., 2010 ) and in studies on adolescent/young adult HR subjects (Phillips et al, 2002, Ho and Magnotta, 2010, Wood et al, 2010, and Moorhead et al, 2013), but these results were not replicated in others (Velakoulis et al, 2006, Wood et al, 2005, and Buehlmann et al, 2010; Mattai et al, 2011 and Dougherty et al, 2012).

Considering inclusion criteria, smaller hippocampi were found in HR subjects with psychotic symptoms (Witthaus et al, 2009 and Witthaus et al, 2010).

In the categories “risk factors” and “symptoms and/or risk factors”, results are inconsistent. The majority of studies (Keshavan et al, 1997, Phillips et al, 2002, Tepest et al, 2003, Hurlemann et al, 2008, Ho and Magnotta, 2010, Sismanlar et al, 2010, and Wood et al, 2010; Francis et al, 2013, Mittal et al, 2013, and Moorhead et al, 2013) but not all (Wood et al, 2005, Dougherty et al, 2012, Velakoulis et al, 2006, and Buehlmann et al, 2010; Bhojraj et al., 2011 ; Mattai et al., 2011; Dougherty et al., 2012 ) found reduced hippocampal volumes in HR subjects compared to controls.

Moreover, results obtained by cross-sectional and longitudinal studies on HR subjects who later converted to psychosis (HRp) and those who did not (HRnp) are even more conflicting. Most of the studies did not find differences in the hippocampal volumes of HRp and HRnp (Wood et al, 2005, Velakoulis et al, 2006, Buehlmann et al, 2010, and Walter et al, 2012). Other studies detected smaller volumes bilaterally in HRp when compared to controls ( Moorhead et al., 2013 ) and in the right side when compared to HRnp ( Witthaus et al., 2010 ), but in another one HRnp had lesser volumes bilaterally than controls as well as in the left side when compared to HRp ( Phillips et al., 2002 ).

All the FE subjects were young adults (16 y.o. and above) and showed smaller hippocampi, mainly in the left side.

4.1.1. HR subjects with risk symptoms

We found 5 studies using “psychotic symptoms” as inclusion criteria for HR subjects for schizophrenia (Hendren et al, 1995, Wood et al, 2005, Hurlemann et al, 2008, Witthaus et al, 2009, and Witthaus et al, 2010) (see Table 2 in the Supplementary material, for more information about the scales used in the inclusion criteria).

Family history of HR subjects was collected in one study ( Hendren et al., 1995 ) and 4 subjects on 12 had history of schizophrenia in first- and second-degree relatives.

For this, we include this paper in the category “combined symptoms and risk factors”. Information about family history was not provided in the other three papers. In one study ( Witthaus et al., 2010 ), approximately half of the HR subjects had other psychiatric disorders as well as attenuated psychotic symptoms and in two papers, approximately 40% of the HR subjects (Witthaus et al, 2009 and Witthaus et al, 2010) were taking psychotropic drugs.

All three papers studying young adult HR subjects showed reduced hippocampal volumes bilaterally when compared to controls (Hurlemann et al, 2008, Witthaus et al, 2009, and Witthaus et al, 2010). In particular, body and tail were found smaller in HR subjects (Witthaus et al, 2009 and Witthaus et al, 2010).

Right hippocampus was smaller in HR subjects diagnosed psychotic at follow-up compared to HR subjects non-psychotic at follow-up ( Witthaus et al., 2010 ) and reduced right hippocampal volumes correlated significantly with lower RAVTL delayed recall in HR subjects in another study ( Hurlemann et al., 2008 ).

In another study ( Wood et al., 2005 ), adolescent and young adult HR subjects with psychotic symptoms did not show differences in their hippocampal volumes when compared to controls, but they had smaller left hippocampus when compared with HR subjects with a family history of psychosis.

4.1.2. HR subjects with risk factors

We found 11 articles (Keshavan et al, 1997, Tepest et al, 2003, Wood et al, 2005, Ho and Magnotta, 2010, and Sismanlar et al, 2010; Bhojraj et al., 2011; Mattai et al., 2011; Dougherty et al., 2012 ; Francis et al., 2013; Johnson et al, 2013 and Moorhead et al, 2013) using the presence of risk factor as inclusion criteria for HR subjects (see Table 2 for more information about inclusion criteria). Almost all studies use the presence of genetic risk factors such as inclusion criterion except one that uses low IQ ( Moorhead et al., 2013 ). In all studies, individuals who had diagnosis of psychotic disorder or an acute psychotic episode in their lifetime were excluded. Nevertheless, in almost all studies in the HR group there were at least 34% of subjects with diagnosis of psychiatric disorder other than psychotic disorder or schizophrenia (Tepest et al, 2003, Keshavan et al, 1997, Ho and Magnotta, 2010, and Sismanlar et al, 2010; Bhojraj et al., 2011; Francis et al., 2013; Johnson et al., 2013). The psychiatric disorders most reported were: major depression, anxiety disorder and attention deficit hyperactivity disorder (ADHD).

The majority of studies (Keshavan et al, 1997, Tepest et al, 2003, Ho and Magnotta, 2010, Sismanlar et al, 2010, and Mattai et al, 2011; Moorhead et al., 2013 ), but not all ( Bhojraj et al., 2011 ; Mattai et al, 2011, Wood et al, 2005, and Dougherty et al, 2012) found smaller hippocampi in HR subjects at different stages of age (childhood to early adulthood) when compared to controls. Furthermore, studies comparing hippocampal shapes in HR subjects and controls found differences between the two groups in specific regions.

Francis et al. (2013) found that the right and left subicula were significantly reduced in HR individuals and the smaller volumes of these regions correlated with immediate verbal recall of stories impaired in HR sample.

Mittal et al. (2013) reported that siblings of schizophrenia patients (17.4 y.o. age average) showed areas of deformation in the anterior hippocampus compared to controls. These areas overlapped with that seen for schizophrenia patients but did not survive FDR correction.

Hippocampal shape inward in the anterior sub-regions of genetic HR subjects was also observed in other studies (Tepest et al, 2003 and Ho and Magnotta, 2010).

Moreover, in the HR group, a greater number of obstetric complications were significantly associated with smaller hippocampi and hippocampal volumes were not inversely correlated with age (as detected in the control group) ( Ho and Magnotta, 2010 ).

Abnormal development of the hippocampus of HR subjects was also observed in another study where familial risk subjects demonstrated greater positive volume–age relationship in hippocampus than controls ( Dougherty et al., 2012 ).

Hippocampal reductions found in this group of HR subjects compared to controls were initially significant but this difference did not survive FDR correction.

No significant differences in hippocampal volumes of subjects with family history of schizophrenia and controls were found in two other studies (Wood et al, 2005 and Bhojraj et al, 2011).

Only three studies provided follow-up of HR subjects. No subject was psychotic at follow-up (1 year) in one study ( Bhojraj et al., 2011 ) and half of the study subjects were psychotic at follow-up in another one ( Wood et al., 2005 ). In the latter, HR individuals with a family history of psychosis had similar volumes to controls but they had bigger left hippocampal volumes when compared to HR individuals with attenuated psychotic symptoms and without a family history of psychosis. Finally, a longitudinal study on adolescents with a low IQ showed a reduced right hippocampal volume at the baseline and bilaterally at the follow-up in adolescents who later converted to psychosis ( Moorhead et al., 2013 ).

4.1.3. Combined symptoms/factors

We found 9 studies (Hendren et al, 1995, Phillips et al, 2002, and Velakoulis et al, 2006; Thompson et al, 2007, Hurlemann et al, 2008, Buehlmann et al, 2010, Wood et al, 2010, Walter et al, 2012, and Mittal et al, 2013) that used the presence of psychotic symptoms and/or risk factors as inclusion criteria for HR subjects to develop schizophrenia disorder (see Table 2 for more information about inclusion criteria).

In most studies, the presence of other psychiatric disorders in HR subjects was not reported. In one study (Thompson et al., 2007), more than half of HR individuals had a diagnosis of psychiatric disorder different from schizophrenia or acute psychotic disorder. In another one ( Hurlemann et al., 2008 ), no subjects had a diagnosis of psychiatric disorder and were not taking psychiatric medications (presence of psychiatric disorder was an exclusion criterion).

Studies investigating if HR subjects took psychiatric medication ( Velakoulis et al., 1999 ; Thompson et al., 2007; Hurlemann et al, 2008 and Buehlmann et al, 2010) reported at least 11% of psychotropic drug users in HR group (except the Hulermann's study).

Eight studies compared hippocampal volumes in HR subjects and controls (Hendren et al, 1995, Velakoulis et al, 1999, Phillips et al, 2002, Hurlemann et al, 2008, Buehlmann et al, 2010, Wood et al, 2010, and Mittal et al, 2013). In most, but not all, of those studies (Hendren et al, 1995, Velakoulis et al, 2006, and Buehlmann et al, 2010), the authors reported smaller hippocampi in adolescents/young adults (Phillips et al, 2002 and Wood et al, 2010) and young adults ( Hurlemann et al., 2008 ) at HR. Two studies analyzed the hippocampus only in the HR group (Thompson, 2007; Walter et al., 2012 ), and found no correlation between stress and hippocampal volumes (Thompson et al., 2007) and no difference between hippocampal volumes of HR individuals psychotic at follow-up and those not psychotic ( Walter et al., 2012 ).

One study recruiting children at HR did not detect differences in their hippocampal volumes ( Hendren et al., 1995 ), nor were differences found in two other articles studying adolescent/young adult HR individuals (Velakoulis et al, 1999 and Buehlmann et al, 2010).

Differences in hippocampal volumes between HRp (progressing) and HRnp (non-progressing) subjects ‘symptoms and/or risk factor’ have been investigated in two age-groups, namely “adolescents” and “adolescents/young adults”, using either cross sectional comparison or longitudinal studies, although the findings have shown contradictory results.

Cross-sectional comparisons in the “adolescent/young adults” phase revealed that HRnp subjects had smaller hippocampal volumes at baseline bilaterally compared to controls, and more specifically on the left side ( Phillips et al., 2002 ). Wood et al. (2010) reported reduced bilateral hippocampal volumes in HRnp and only in the left side in HRp compared to controls. However, two studies found no significant differences between HRp ( Velakoulis et al., 2006 ) ( Buehlmann et al., 2010 ) and HRnp.

Similar volume differences between HRp and HRnp were observed in a longitudinal study on young adult HR subjects ( Walter et al., 2012 ). Furthermore, a decrease in hippocampal volumes was detected over time in all HR individuals, independently of clinical outcome. Despite this absence of difference, antipsychotic medication at the follow-up was associated with an increased hippocampal volume in HRp when compared to the HRnp group.

4.1.4. FE subjects

All studies found smaller hippocampus in first episode (FE) subjects (> 20 years old) compared to controls.

Three studies found decreased hippocampal volumes bilaterally or only in the left side when FE were compared to controls and HR subjects (Velakoulis et al, 2006 and Buehlmann et al, 2010), while only the left side resulted atrophic compared to HR subjects psychotic at follow-up ( Phillips et al., 2002 ).

In a following study using the manual tracing technique, hippocampal body and tail of FE subjects were smaller compared to healthy subjects ( Witthaus et al., 2010 ).

4.2. Amygdala

Abnormal amygdala volumes were found in children and adolescent HR subjects (Hendren et al, 1995, Keshavan et al, 1997, Welch et al, 2010, and Bhojraj et al, 2011), whereas the volumes were similar compared to controls in the young adult HR subjects (Witthaus et al, 2009 and Witthaus et al, 2010). Similar volumes were also observed in children/adolescents and in adolescent/young adult HR individuals compared to controls (Sismanlar et al, 2010 and Dougherty et al, 2012).

Regarding the inclusion criteria, no difference was detected in young adults at HR with attenuated psychotic symptoms and controls (Witthaus et al, 2009 and Witthaus et al, 2010).

HR with genetic risk factors had smaller amygdala in adolescents and adolescents/young adults (Keshavan et al, 1997 and Bhojraj et al, 2011) but similar volumes were found in children/adolescents ( Dougherty et al., 2012 ).

Adolescents/young adults with combined symptoms/factors did not show volume differences ( Velakoulis et al., 2006 ), but abnormal volumes were found throughout childhood and adolescence (Hendren et al, 1995 and Welch et al, 2010).

Moreover, results on HRp compared to HRnp cross-sectionally (Velakoulis et al, 2006 and Witthaus et al, 2010) detected no difference between HRp and HRnp.

In FE subjects aged above 16 years, all studies found abnormalities in amygdala volumes (Velakoulis et al, 2006, Witthaus et al, 2009, and Witthaus et al, 2010), mainly on the left (Witthaus et al, 2009 and Witthaus et al, 2010).

4.2.1. HR subjects with risk symptoms

We found three studies using “psychotic symptoms” as inclusion criteria for HR subjects for schizophrenia (Hendren et al, 1995, Witthaus et al, 2009, and Witthaus et al, 2010) ( Table 3 ).

Family history of HR subjects was collected in one study ( Hendren et al., 1995 ). Information about family history was not provided in the other two papers.

In Witthaus et al. (2010) , approximately half of HR subjects had other psychiatric disorders as well as attenuated psychotic symptoms and, in the other papers, approximately 40% (Witthaus et al, 2009 and Witthaus et al, 2010) were taking psychotropic drugs.

Contrary to the hippocampus, the amygdala was similar compared to controls in young adults at HR (Witthaus et al, 2009 and Witthaus et al, 2010).

4.2.2. HR subjects with risk factors

We found four articles (Keshavan et al, 1997 and Sismanlar et al, 2010; Bhojraj et al, 2011 and Dougherty et al, 2012) that used the presence of genetic risk factor as inclusion criteria for HR subjects ( Table 3 ).

In all studies, individuals who had a diagnostic of psychotic disorder or an acute psychotic episode in their lifetime were excluded. Nevertheless, in almost all studies the HR group had at least 34% of subjects with diagnosis of psychiatric disorder other than psychotic disorder or schizophrenia (Keshavan et al, 1997, Ho and Magnotta, 2010, Sismanlar et al, 2010, and Bhojraj et al, 2011). The amygdala was smaller only in the left side in adolescents ( Keshavan et al., 1997 ) and bilaterally in older subjects ( Bhojraj et al., 2011 ).

No differences were observed in younger HR individuals compared to controls (Sismanlar et al, 2010 and Dougherty et al, 2012).

4.2.3. Combined symptoms/factors

We found three studies (Hendren et al, 1995, Velakoulis et al, 1999, and Welch et al, 2010) in that group that studied the amygdala. In all of the studies, the presence of other psychiatric disorders in HR subjects was not reported. In two articles, at least 15% of HR subjects were taking psychiatric medication (Hendren et al, 1995 and Velakoulis et al, 1999).

The amygdala was smaller bilaterally in HR children and a significant negative correlation was seen between left amygdala volume and severity of negative symptoms within this HR group ( Hendren et al., 1995 ). In the same study, all children had moderate psychotic symptoms and 33% were positive to family history of schizophrenia.

Adolescents at HRs with low IQ and psychotic symptoms showed increased right amygdala volumes compared to subjects with low IQ, without psychotic symptoms ( Welch et al., 2010 ). There were no differences in the older HR subjects (20 y.o. on average) with psychotic symptoms and/or genetic risk factors compared to controls ( Velakoulis et al., 2006 ).

4.2.4. FE subjects

All studies reviewed found abnormalities in the volume of the amygdala in FE subjects aged above 16 years. The left amygdala was smaller in FE young adults compared to HR subjects (Witthaus et al, 2009 and Witthaus et al, 2010) and compared to controls ( Witthaus et al., 2010 ). Amygdala volumes were increased bilaterally in FE subjects younger (mean age of 21 y.o.) than healthy individuals and HR subjects who converted or not converted later ( Velakoulis et al., 2006 ). In this study, FE subjects were divided in subgroups based on first-episode psychosis diagnostic categories. The subjects with affective psychosis and other psychoses had the bigger amygdala compared to controls.

4.3. Amygdala–hippocampal complex (AHC)

Six studies investigated both structures, combining relatives of schizophrenia patients (Lawrie et al, 1999, Lawrie et al, 2001, Lawrie et al, 2002, Schreiber et al, 1999, Keshavan et al, 2002, and Welch et al, 2011). Only one study reported the presence of other psychiatric disorders in 59% of HR subjects considered ( Keshavan et al., 2002 ). All studies that compared AHC volumes in controls to adolescents or adolescents/young adults at HRs, except one ( Lawrie et al., 2002 ), observed reduced volumes in either the left side (Lawrie et al, 1999 and Keshavan et al, 2002), the right side ( Seidman et al., 1999 ), or bilaterally ( Lawrie et al., 2001 ).

No significant differences in volumes were detected between HR subjects with psychotic symptoms and without psychotic symptoms (Lawrie et al, 2001 and Lawrie et al, 2002), and between HR subjects with first degree and second degree schizophrenic relatives ( Lawrie et al., 2002 ).

One study investigating the effect of the exposure to cannabis on AGH volumes did not find an association ( Welch et al., 2011 ).

The right amygdala–hippocampal complex was smaller in FE young adult individuals compared to controls, and in the left side compared to controls and HR subjects ( Lawrie et al., 1999 ).

5. Discussion

Assessment of volumetric HC and AG observations will need first to consider what criteria were used to select HR subjects, in order to understand which risk factors and/or risk symptoms were being taken into consideration during the original analysis.

Furthermore, reports of an excess in adverse events during the pre- and perinatal periods, the presence of cognitive and behavioral signs during childhood and adolescence, and the lack of evidence of a neurodegenerative process in most individuals with schizophrenia ( Lewis and Levitt, 2002 ) all point to a neurodevelopmental pathogenesis hypothesis for schizophrenia. In this context, it is therefore important to take into account the age of HR subjects when analyzed.

5.1. Hippocampus

The reduction of hippocampal volume in patients at their first manifestation of the disease (FE subjects) seems to be well documented in all studies. This would indicate with near certainty that there is a loss of tissue in the hippocampus in the period near the onset of the disease. It would further appear that there is a greater vulnerability for the left hippocampus (Phillips et al, 2002, Velakoulis et al, 2006, and Buehlmann et al, 2010), as well as in the body and tail hippocampal areas ( Witthaus et al., 2010 ). Unsurprisingly thus, most studies analyzing HR individuals that developed schizophrenia found that their hippocampi were smaller than controls (Keshavan et al, 1997, Phillips et al, 2002, Tepest et al, 2003, Hurlemann et al, 2008, Witthaus et al, 2009, Ho and Magnotta, 2010, Sismanlar et al, 2010, Witthaus et al, 2010, Wood et al, 2010, and Francis et al, 2013; Mittal et al, 2013 and Moorhead et al, 2013).

In these subjects it is important to consider inclusion criteria since genetic factors and psychotic symptoms seem to have different impacts on the hippocampal volumes ( Wood et al., 2005 ).

Studies on young adults belonging to all three categories of HR subjects (risk symptoms, risk factors, combined symptoms/factors) had smaller hippocampal volumes when compared to controls (Tepest et al, 2003, Hurlemann et al, 2008, Witthaus et al, 2009, Witthaus et al, 2010, and Francis et al, 2013).

HR and FE subjects with moderate psychotic symptoms showed hippocampal volume reduction especially in the body and the tail of the hippocampus ( Hurlemann et al., 2008 ).

Smaller hippocampal volumes in specific hippocampal regions were also observed in young adults at HR with ‘genetic risk factors’ where subicula volumes were significantly reduced in HR and correlated significantly with deficits in verbal memory ( Francis et al., 2013 ).

The right side seemed to be more vulnerable as evidenced by the fact that the right hippocampal volumes were smaller at baseline in HR subjects with ‘psychotic symptoms’ who converted to psychosis in a study ( Witthaus et al., 2010 ) and correlated with verbal memory deficit in another one ( Hurlemann et al., 2008 ).

Deficit in verbal memory in subjects with high risk for schizophrenia was well documented ( Maziade et al., 2009 ). A reduction located in the posterior subicula in the right side could be a specific marker of this intermediary cognitive phenotype in young adults HR.

A peculiar vulnerability of right hippocampus was also observed in adolescents with a low IQ as risk factor to develop schizophrenia. Subjects who converted to psychosis had smaller right hippocampal volume at the baseline and bilaterally at the follow-up ( Moorhead et al., 2013 ).

The presence of smaller hippocampi in HR adolescents was confirmed in another study considering genetic risk factor for the disease ( Keshavan et al., 1997 ).

The results become less consistent when people belonging to different age groups are analyzed in the same sample.

Relatives did not show the normal age-related decrease in hippocampal volumes expected during late adolescence into early adulthood, and a history of obstetric complications among relatives of schizophrenia probands was further associated with smaller hippocampus volumes bilaterally ( Ho and Magnotta, 2010 ). The lack of normal age-related hippocampus volume reductions among adolescent/young adult relatives of schizophrenia probands may be indicative of aberrant neurodevelopment and/or reduced dendritic elimination.

A moment in late adolescence that could be a “key period” in which the hippocampus begins to develop differently in HR subjects compared to controls could explain why in young adults the hippocampus was smaller than controls in all studies and the discrepancy of results in the group adolescents/young adults.

In fact, similar hippocampal volumes were detected in children with ‘combined risk and symptoms’ ( Hendren et al., 1995 ) and results become inconsistent in the sample children/young adults with genetic risk for schizophrenia.

All of these findings need to be interpreted with caution. More definitive inference regarding abnormal hippocampal maturation in HR subjects will require additional studies and other factors must be considered, such as obstetric complications.

Indeed, a greater number of obstetric complications were significantly associated with smaller hippocampal volumes in adolescents/young adults at genetic HR ( Ho and Magnotta, 2010 ).

The interpretation of studies on hippocampal volume differences between HRp and HRnp in adolescents/young adults at HR “combined symptoms” is even more arduous, given the few and inconsistent results. This inconsistence may be explained by the large difference of age in the HR groups and in the methodology used in the different studies.

Therefore, a point to investigate would be the impact of pubertal development on hippocampal volume in HR subjects with genetic risk and risk symptoms to understand if puberty plays a role in one kind of subjects or both.

It is not yet clear if the loss of tissue is localized mainly in the posterior hippocampus in the HR subjects with psychotic symptoms and in the anterior hippocampus in HR individuals with genetic risk.

Further studies on hippocampal shape could clarify if psychotic symptoms and genetic factors have a different impact on hippocampal formation.

5.2. Amygdala

As for the hippocampus, abnormalities in amygdala volume in patients at their first manifestation of the disease (FE subjects) seem to be well documented in all studies (Velakoulis et al, 1999, Witthaus et al, 2009, and Witthaus et al, 2010).

Moreover, a greater vulnerability of the left side seems to be confirmed in two studies finding smaller left amygdala in FE subjects compared to controls (Witthaus et al, 2009 and Witthaus et al, 2010).

Greater amygdala volumes were found in another one ( Velakoulis et al., 2006 ). This discrepancy with studies showed smaller amygdala in FE individuals may be explained by the fact that amygdala volume enlargement was identified only in first-episode with non-schizophrenic psychosis.

Regarding HR subjects, smaller amygdala was detected in children with ‘combined risk and factors’ ( Hendren et al., 1995 ) and in adolescents ( Keshavan et al., 1997 ) and adolescents/young adults with genetic risk factors ( Bhojraj et al., 2011 ).

However, these differences in amygdala volumes of HR subjects compared to controls were not observed in other studies considering children/adolescents with genetic risk factor (Sismanlar et al, 2010 and Dougherty et al, 2012) and adolescents/young adults with ‘combined symptoms and factors’ ( Velakoulis et al., 1999 ).

Surprisingly, in one study the amygdala was bigger in adolescents with low IQ and attenuated psychotic symptoms ( Welch et al., 2010 ).

This result is in disagreement with the study that found less amygdala volumes in adolescents with genetic risk factors ( Keshavan et al., 1997 ). Furthermore, it seems contra-intuitive that amygdala volumes are reduced in children ( Hendren et al., 1995 ) while it is enhanced in adolescents.

One possible explanation could be the possibility that the Childhood Behavior Checklist (CBCL) and Structured Interview for Schizotypy (SIS) tests used to identify HR subjects are identifying individuals within the intellectually impaired group with specific, but non-schizophreniform, conditions. Autism is one such possibility, and given the evidence that brain volumes are enlarged in autism ( Stanfield et al., 2008 ), perhaps particularly in those with autism and low IQ, it is conceivable that the schizotypal population may also have autistic features. It is also possible that the measures are identifying individuals with other conditions, such as affective disorders or personality disorders.

Another possible explanation could be a mechanism of amygdala hyperactivity and subsequent atrophy, these changes potentially being triggered by events such as exposure to environmental stressors. Indeed, this explanation has previously been posited to explain amygdala volume loss with time in children with autism ( Nacewicz et al., 2006 ). It may be that structurally abnormal amygdalae, such as the abnormally large structures found in the subjects with high score in CBCL and SIS tests, are particularly vulnerable to this process.

This is indeed what may be suggested by the second finding of this study, the significant negative correlation between left amygdala volume and severity of negative symptoms.

The same correlation was also found bilaterally in amygdala volumes of children with ‘combined symptoms and factors’ ( Hendren et al., 1995 ).

In young adults with psychotic symptoms compared to controls there were no differences in amygdala volumes (Witthaus et al, 2009 and Witthaus et al, 2010).

Moreover, the only two studies providing the follow-up did not find differences between HR subjects who converted to psychosis and HR subjects who did not convert (Velakoulis et al, 2006 and Witthaus et al, 2010).

In conclusion, the trajectory of the changes in the hippocampus and amygdala in HR subjects from childhood to adolescence appears different. In the hippocampus, there appears to be present an abnormal development in late adolescence and a loss of tissue in young adult individuals, whereas in the amygdala the loss of tissue begins in childhood, continues in adolescence. In early adulthood, there seems to be a recovery.

5.3. Methodological considerations

Almost all studies used a magnetic resonance scanner at 1.5 T. Manual segmentation of medial temporal lobe structures is the technique most frequently used (semi-automated segmentation algorithm and automated algorithm for the others). The majority of the studies used the hippocampal tracing criteria of Cook ( Cook et al., 1992 ). All the protocols included the whole hippocampus and the alveus and fimbria in the tracing.

For the amygdala, each study used a different protocol. Despite this, all the protocols are very similar and include the same amygdala structures.

To avoid the variability due to different protocols, there is a project aimed to harmonize the available protocols for the manual segmentation of the hippocampus on MR images in order to define a standard protocol ( http://www.hippocampal-protocol.net/SOPs/index.php ).

This review is an attempt merely qualitative to clarify the incoherent literature on subjects with a high risk to develop schizophrenia. At the moment, there are insufficient studies on the mediotemporal structures to use rigorous quantitative methods such as a meta-analysis.

6. Conclusions

In conclusion, the main points emerging from this review are summarized below:

  • Studies on subjects with high risk for schizophrenia showed a great variability in methodologies, in particular: inclusion criteria, different age stages, techniques of hippocampus and amygdala detection (manual tracing, automated and semi-automated methods). In particular, results become less consistent when different ages were considered in the same sample.
  • A portion of HR subjects had psychiatric disorders that could have an impact on the hippocampus and amygdala (e.g. anxiety and depression). We must, therefore, consider that alterations in hippocampus and amygdala could be a consequence of such disease.
  • Abnormalities in hippocampal and amygdala volumes in FE subjects seem well documented, especially in the left side.
  • In early adulthood, hippocampus of all types of HR subjects was smaller when compared to controls. Moreover, the right hippocampus seems particularly vulnerable and could be a prodromal marker for schizophrenia disease.
  • The results become inconsistent in subjects passing from adolescence to adulthood. This may be due to the great variability of the different studies but a key period in which the hippocampus of HR subjects begins to develop in a different way compared to controls could be assumed.
  • Genetic factors could have an impact on anterior hippocampal regions impaired typically in schizophrenia and connected to prefrontal regions.
  • Amygdala had a different trajectory compared to hippocampal changes during the maturation process. Variables less cognitive but more related to stress and affective disorders could play a role in amygdala changes.
  • In light of this, studies on HR subjects should consider: inclusion criteria used for HR subjects diagnosis, range of age of HR subjects, and the presence of other psychiatric disorders in HR subjects. Finally, amygdala and hippocampus should be analyzed separately and not as amygdala–hippocampus complex.

The following are the supplementary data related to this article.

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Table 2 Studies analyzing hippocampus of HR subjects are summarized.

Download file

Table 3 Studies analyzing amygdala of HR subjects are summarized.

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Table 4 Studies analyzing amygdala-hippocampal complex of HR subjects are summarized.

Role of the funding source

The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Contributors

We declare to have participated in the study in the fashion described below and that we have seen and approved the final version.

  • Guarantors of integrity of entire study — all authors;
  • Study concepts and design — all authors;
  • Literature research — R.G.;
  • Methods, analysis and interpretation — all authors;
  • Manuscript preparation — R.G.;
  • Revision/review — all authors; and
  • Manuscript definition of intellectual content, editing, and final version approval — all authors.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Acknowledgments

This work was supported by a Strategic Initiative funding grant (#257) from the Quebec Bio-Imaging Network (Fonds de recherche Québec - Santé). S. Duchesne is also a Junior 1 Research Scholar from the Fonds de Recherche Québec-Santé (#22424).

Appendix 1. Flow chart for review of literature searches hippocampal and amygdala volumes in subjects with high risk to develop schizophrenia

 

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References

  • Achenbach and Rescorla, 2000 T.M. Achenbach, L.A. Rescorla. Manual for the ASEBA Preschool forms and profile. (University of Vermont Department of Psychiatry, Burlington, VT, 2000)
  • Adriano et al., 2011 F. Adriano, C. Caltagirone, G. Spalletta. Hippocampal volume reduction in first-episode and chronic schizophrenia: a review and meta-analysis. Neuroscientist. 2011;18(2):180-200
  • Aleman and Kahn, 2005 A. Aleman, R.S. Kahn. Strange feelings: do amygdala abnormalities dysregulate the emotional brain in schizophrenia?. Prog. Neurobiol.. 2005;77(5):283-298
  • Antonova et al., 2004 E. Antonova, T. Sharma, R. Morris, V. Kumari. The relationship between brain structure and neurocognition in schizophrenia: a selective review. Schizophr. Res.. 2004;70(2–3):117-145 Crossref
  • Baiano et al., 2007 M. Baiano, A. David, A. Versace, R. Churchill, M. Balestrieri, P. Brambilla. Anterior cingulate volumes in schizophrenia: a systematic review and a meta-analysis of MRI studies. Schizophr. Res.. 2007;93(1–3):1-12 Crossref
  • Bhojraj et al., 2011 T.S. Bhojraj, J.A. Sweeney, K.M. Prasad, S.M. Eack, A.N. Francis, J.M. Miewald, D.M. Montrose, M.S. Keshavan. Gray matter loss in young relatives at risk for schizophrenia:relation with prodromal psychopathology. Neuroimage.. 2011;54:S272-S279 Crossref
  • Boos et al., 2007 H.B. Boos, A. Aleman, W. Cahn, H. Hulshoff Pol, R.S. Kahn. Brain volumes in relatives of patients with schizophrenia: a meta-analysis. Arch. Gen. Psychiatry. 2007;64(3):297-304 Crossref
  • Buehlmann et al., 2010 E. Buehlmann, G.E. Berger, J. Aston, U. Gschwandtner, M.O. Pflueger, S.J. Borgwardt, E.W. Radue, A. Riecher-Rossler. Hippocampus abnormalities in at risk mental states for psychosis? A cross-sectional high resolution region of interest magnetic resonance imaging study. J. Psychiatr. Res.. 2010;44(7):447-453 Crossref
  • Byrne et al., 1999 M. Byrne, A. Hodges, E. Grant, D.C. Owens, E.C. Johnstone. Neuropsychological assessment of young people at high genetic risk for developing schizophrenia compared with controls: preliminary findings of the Edinburgh High Risk Study (EHRS). Psychol. Med.. 1999;29(5):1161-1173 Crossref
  • Cook et al., 1992 M.J. Cook, D.R. Fish, S.D. Shorvon, K. Straughan, J.M. Stevens. Hippocampal volumetric and morphometric studies in frontal and temporal lobe epilepsy. Brain. 1992;115(Pt 4):1001-1015
  • Dougherty et al., 2012 M.K. Dougherty, H. Gu, J. Bizzell, S. Ramsey, G. Gerig, D.O. Perkins, A. Belger. Differences in subcortical structures in young adolescents at familial risk for schizophrenia: a preliminary study. Psychiatry Res.. 2012;204(2–3):68-74 Crossref
  • Francis et al., 2013 A.N. Francis, L.J. Seidman, N. Tandon, M.E. Shenton, H.W. Thermenos, R.I. Mesholam-Gately, L.T. van Elst, B. Tuschen-Caffier, L.E. DeLisi, M.S. Keshavan. Reduced subicular subdivisions of the hippocampal formation and verbal declarative memory impairments in young relatives at risk for schzophrenia. Schizophr. Res.. 2013;151(1–3):154-157 Crossref
  • Geddes and Lawrie, 1995 J.R. Geddes, S.M. Lawrie. Obstetric complications and schizophrenia: a meta-analysis. Br. J. Psychiatry J. Ment. Sci.. 1995;167(6):786-793 Crossref
  • Goldstein et al., 2000 J.M. Goldstein, L.J. Seidman, S.L. Buka, N.J. Horton, J.L. Donatelli, R.O. Rieder, M.T. Tsuang. Impact of genetic vulnerability and hypoxia on overall intelligence by age 7 in offspring at high risk for schizophrenia compared with affective psychoses. Schizophr. Bull.. 2000;26(2):323-334 Crossref
  • Hafner et al., 1994 H. Hafner, K. Maurer, W. Loffler, B. Fatkenheuer, W. an der Heiden, A. Riecher-Rossler, S. Behrens, W.F. Gattaz. The epidemiology of early schizophrenia. Influence of age and gender on onset and early course. Br. J. Psychiatry Suppl.. 1994;(23):29-38
  • Hendren et al., 1995 R.L. Hendren, J. Hodde-Vargas, R.A. Yeo, L.A. Vargas, W.M. Brooks, C. Ford. Neuropsychophysiological study of children at risk for schizophrenia: a preliminary report. J. Am. Acad. Child Adolesc. Psychiatry. 1995;34(10):1284-1291 Crossref
  • Ho and Magnotta, 2010 B.C. Ho, V. Magnotta. Hippocampal volume deficits and shape deformities in young biological relatives of schizophrenia probands. NeuroImage. 2010;49(4):3385-3393 Crossref
  • Hurlemann et al., 2008 R. Hurlemann, F. Jessen, M. Wagner, I. Frommann, S. Ruhrmann, A. Brockhaus, H. Picker, L. Scheef, W. Block, H.H. Schild, W. Moller-Hartmann, B. Krug, P. Falkai, J. Klosterkotter, W. Maier. Interrelated neuropsychological and anatomical evidence of hippocampal pathology in the at-risk mental state. Psychol. Med.. 2008;38(6):843-851
  • Johnson et al., 2013 S.L. Johnson, L. Wang, K.I. Alpert, D. Greenstein, L. Clasen, F. Lalonde, R. Miller, J. Rapoport, N. Gogtay. Hippocampal shape abnormalities of patients with childhood-onset schizophrenia and their unaffected siblings. J. Am. Acad. Child Adolesc. Psychiatry. 2013;52:527-536
  • Joyal et al., 2003 C.C. Joyal, M.P. Laakso, J. Tiihonen, E. Syvalahti, H. Vilkman, A. Laakso, B. Alakare, V. Rakkolainen, R.K. Salokangas, J. Hietala. The amygdala and schizophrenia: a volumetric magnetic resonance imaging study in first-episode, neuroleptic-naive patients. Biol. Psychiatry. 2003;54(11):1302-1304 Crossref
  • Jung et al., 2010 W.H. Jung, J.H. Jang, M.S. Byun, S.K. An, J.S. Kwon. Structural brain alterations in individuals at ultra-high risk for psychosis: a review of magnetic resonance imaging studies and future directions. J. Korean Med. Sci.. 2010;25(12):1700-1709 Crossref
  • Keith and Matthews, 1991 S.J. Keith, S.M. Matthews. The diagnosis of schizophrenia: a review of onset and duration issues. Schizophr. Bull.. 1991;17(1):51-67
  • Kendler et al., 1989 K.S. Kendler, J.A. Lieberman, D. Walsh. The strucutured interview for Schizotypy (SIS): a preliminary report. Schizophr. Bull.. 1989;15(4):559-571 Crossref
  • Keshavan et al., 1997 M.S. Keshavan, D.M. Montrose, J.N. Pierri, E.L. Dick, D. Rosenberg, L. Talagala, J.A. Sweeney. Magnetic resonance imaging and spectroscopy in offspring at risk for schizophrenia: preliminary studies. Prog. Neuro-Psychopharmacol. Biol. Psychiatry. 1997;21(8):1285-1295 Crossref
  • Keshavan et al., 2002 M.S. Keshavan, E. Dick, I. Mankowski, K. Harenski, D.M. Montrose, V. Diwadkar, M. DeBellis. Decreased left amygdala and hippocampal volumes in young offspring at risk for schizophrenia. Schizophr. Res.. 2002;58(2–3):173-183 Crossref
  • Konick and Friedman, 2001 L.C. Konick, L. Friedman. Meta-analysis of thalamic size in schizophrenia. Biol. Psychiatry. 2001;49(1):28-38 Crossref
  • Lawrie and Abukmeil, 1998 S.M. Lawrie, S.S. Abukmeil. Brain abnormality in schizophrenia. A systematic and quantitative review of volumetric magnetic resonance imaging studies. Br. J. Psychiatry J. Ment. Sci.. 1998;172:110-120 Crossref
  • Lawrie et al., 1999 S.M. Lawrie, H. Whalley, J.N. Kestelman, S.S. Abukmeil, M. Byrne, A. Hodges, J.E. Rimmington, J.J. Best, D.G. Owens, E.C. Johnstone. Magnetic resonance imaging of brain in people at high risk of developing schizophrenia. Lancet. 1999;353(9146):30-33 Crossref
  • Lawrie et al., 2001 S.M. Lawrie, H.C. Whalley, S.S. Abukmeil, J.N. Kestelman, L. Donnelly, P. Miller, J.J. Best, D.G. Owens, E.C. Johnstone. Brain structure, genetic liability, and psychotic symptoms in subjects at high risk of developing schizophrenia. Biol. Psychiatry. 2001;49(10):811-823 Crossref
  • Lawrie et al., 2002 S.M. Lawrie, H.C. Whalley, S.S. Abukmeil, J.N. Kestelman, P. Miller, J.J. Best, D.G. Owens, E.C. Johnstone. Temporal lobe volume changes in people at high risk of schizophrenia with psychotic symptoms. Br. J. Psychiatry J. Ment. Sci.. 2002;181:138-143
  • Lawrie et al., 2008 S.M. Lawrie, A.M. McIntosh, J. Hall, D.G. Owens, E.C. Johnstone. Brain structure and function changes during the development of schizophrenia: the evidence from studies of subjects at increased genetic risk. Schizophr. Bull.. 2008;34(2):330-340
  • Lewis and Levitt, 2002 D.A. Lewis, P. Levitt. Schizophrenia as a disorder of neurodevelopment. Annu. Rev. Neurosci.. 2002;25:409-432 Crossref
  • Mattai et al., 2011 A. Mattai, A. Hosanagar, B. Weisinger, D. Greenstein, R. Stidd, L. Clasen, F. Lalonde, J. Rapoport, N. Gogtay. Hippocampal volume development in healthy siblings of childhood-onset schizophrenia patients. Am. J. Psychiatry.. 2011;168:427-435 Crossref
  • Maziade et al., 2009 M. Maziade, N. Rouleau, N. Gingras, P. Boutin, M.E. Paradis, V. Jomphe, J. Boutin, K. Létourneau, E. Gilbert, A.A. Lefebvre, M.C. Doré, C. Marino, M. Battaglia, C. Mérette, M.A. Roy. Shared neurocognitive dysfunctions in young offspring at extreme risk for schizophrenia or bipolar disorder in eastern quebec multigenerational families. Schizophr. Bull.. 2009;35(5):919-930 Crossref
  • McCarley et al., 1993 R.W. McCarley, M.E. Shenton, B.F. O'Donnell, P.G. Nestor. Uniting Kraepelin and Bleuler: the psychology of schizophrenia and the biology of temporal lobe abnormalities. Harv. Rev. Psychiatry. 1993;1(1):36-56 Crossref
  • Mittal et al., 2013 V.A. Mittal, T. Gupta, J.M. Orr, A. Pelletier-Baldelli, D.J. Dean, J.R. Lunsford-Avery, A.K. Smith, B.L. Robustelli, D.R. Leopold, Z.B. Millman. Physical activity level and medial temporal health in youth at ultra high-risk for psychosis. J. Abnorm. Psychol.. 2013;122(4):1101-1110 Crossref
  • Moldin and Gottesman, 1997 S.O. Moldin, I.I. Gottesman. At issue: genes, experience, and chance in schizophrenia—positioning for the 21st century. Schizophr. Bull.. 1997;23(4):547-561 Crossref
  • Moorhead et al., 2013 T.W. Moorhead, A.C. Stanfield, A.G. McKechanie, M.R. Dauvermann, E.C. Johnstone, S.M. Lawrie, D.G. Cunningham Owens. Longitudinal gray matter change in young people who are at enhanced risk of schizophrenia due to intellectual impairment. Biol. Psychiatry. 2013;73(10):985-992 Crossref
  • Moran et al., 2013 M.E. Moran, H. Hulshoff Pol, N. Gogtay. A family affair: brain abnormalities in siblings of patients with schizophrenia. Brain. 2013;136(Pt 11):3215-3226 Crossref
  • Nacewicz et al., 2006 B.M. Nacewicz, K.M. Dalton, T. Johnstone, M.T. Long, E.M. McAuliff, T.R. Oakes, A.L. Alexander, R.J. Davidson. Amygdala volume and nonverbal social impairment in adolescent and adult males with autism. Arch. Gen. Psychiatry. 2006;63(12):1417-1428
  • Nelson et al., 1998 M.D. Nelson, A.J. Saykin, L.A. Flashman, H.J. Riordan. Hippocampal volume reduction in schizophrenia as assessed by magnetic resonance imaging: a meta-analytic study. Arch. Gen. Psychiatry. 1998;55(5):433-440 Crossref
  • O'Driscoll et al., 2001 G.A. O'Driscoll, P.S. Florencio, D. Gagnon, A.V. Wolff, C. Benkelfat, L. Mikula, S. Lal, A.C. Evans. Amygdala-hippocampal volume and verbal memory in first-degree relatives of schizophrenic patients. Psychiatry Res.. 2001;107(2):75-85 Crossref
  • Olsen and Rosenbaum, 2006 K.A. Olsen, B. Rosenbaum. Prospective investigations of the prodromal state of schizophrenia: assessment instruments. Acta Psychiatr. Scand.. 2006;113(4):273-282 Crossref
  • Phillips et al., 2002 L.J. Phillips, D. Velakoulis, C. Pantelis, S. Wood, H.P. Yuen, A.R. Yung, P. Desmond, W. Brewer, P.D. McGorry. Non-reduction in hippocampal volume is associated with higher risk of psychosis. Schizophr. Res.. 2002;58(2–3):145-158 Crossref
  • Prescott and Gottesman, 1993 C.A. Prescott, I.I. Gottesman. Genetically mediated vulnerability to schizophrenia. Psychiatr. Clin. N. Am.. 1993;16(2):245-267
  • Schreiber et al., 1999 H. Schreiber, K. Baur-Seack, H.H. Kornhuber, B. Wallner, J.M. Friedrich, I.M. De Winter, J. Born. Brain morphology in adolescents at genetic risk for schizophrenia assessed by qualitative and quantitative magnetic resonance imaging. Schizophr. Res.. 1999;40(1):81-84
  • Seidman et al., 1999 L.J. Seidman, S.V. Faraone, J.M. Goldstein, J.M. Goodman, W.S. Kremen, R. Toomey, J. Tourville, D. Kennedy, N. Makris, V.S. Caviness, M.T. Tsuang. Thalamic and amygdala–hippocampal volume reductions in first-degree relatives of patients with schizophrenia: an MRI-based morphometric analysis. Biol. Psychiatry. 1999;46(7):941-954 Crossref
  • Seidman et al., 2002 L.J. Seidman, S.V. Faraone, J.M. Goldstein, W.S. Kremen, N.J. Horton, N. Makris, R. Toomey, D. Kennedy, V.S. Caviness, M.T. Tsuang. Left hippocampal volume as a vulnerability indicator for schizophrenia: a magnetic resonance imaging morphometric study of nonpsychotic first-degree relatives. Arch. Gen. Psychiatry. 2002;59(9):839-849 Crossref
  • Seidman et al., 2003 L.J. Seidman, C. Pantelis, M.S. Keshavan, S.V. Faraone, J.M. Goldstein, N.J. Horton, N. Makris, P. Falkai, V.S. Caviness, M.T. Tsuang. A review and new report of medial temporal lobe dysfunction as a vulnerability indicator for schizophrenia: a magnetic resonance imaging morphometric family study of the parahippocampal gyrus. Schizophr. Bull.. 2003;29(4):803-830 Crossref
  • Shenton et al., 2001 M.E. Shenton, C.C. Dickey, M. Frumin, R.W. McCarley. A review of MRI findings in schizophrenia. Schizophr. Res.. 2001;49(1–2):1-52 Crossref
  • Sismanlar et al., 2010 S.G. Sismanlar, Y. Anik, A. Coskun, B. Agaoglu, I. Karakaya, C.I. Yavuz. The volumetric differences of the fronto-temporal region in young offspring of schizophrenic patients. Eur. Child Adolesc. Psychiatry. 2010;19(2):151-157 Crossref
  • Steen et al., 2006 R.G. Steen, C. Mull, R. McClure, R.M. Hamer, J.A. Lieberman. Brain volume in first-episode schizophrenia: systematic review and meta-analysis of magnetic resonance imaging studies. Br. J. Psychiatry J. Ment. Sci.. 2006;188:510-518 Crossref
  • Stanfield et al., 2008 A.C. Stanfield, A.M. McIntosh, M.D. Spencer, R. Philip, S. Gaur, S.M. Lawrie. Towards a neuroanatomy of autism: a systematic review and meta-analysis of structural magnetic resonance imaging studies. Eur. Psychiatry. 2008;23(4):289-299 Crossref
  • Tamminga et al., 2010 C.A. Tamminga, A.D. Stan, A.D. Wagner. The hippocampal formation in schizophrenia. Am. J. Psychiatry. 2010;167(10):1178-1193 Crossref
  • Tepest et al., 2003 R. Tepest, L. Wang, M.I. Miller, P. Falkai, J.G. Csernansky. Hippocampal deformities in the unaffected siblings of schizophrenia subjects. Biol. Psychiatry. 2003;54(11):1234-1240 Crossref
  • Thompson et al., 2007 K.N. Thompson, L.J. Phillips, P. Komesaroff, H.P. Yuen, S.J. Wood, C. Pantelis, D. Velakoulis, A.R. Yung, P.D. McGorry. Stress and HPA-axis functioning in young people at ultra high risk for paychosis. J. Psychiatr. Res.. 2007;41:561-569 Crossref
  • Van Erp et al., 2002 T.G.S. Van Erp, P.A. Rosso, I.M. Huttunen, M. Lonnqvist, J. Pirkola, T. Salonen, O.L. Valanne, V.P. Poutanen, C.G. Standertskjold-Nordenstam, T.D. Cannon. Contributions of genetic risk and fetal hypoxia to hippocampal volume in patients with schizophrenia or schizoaffective disorder, their unaffected siblings, and healthy unrelated volunteers. Am. J. Psychiatry. 2002;159(9):1514-1520 Crossref
  • Velakoulis et al., 1999 D. Velakoulis, C. Pantelis, P.D. McGorry, P. Dudgeon, W. Brewer, M. Cook, P. Desmond, N. Bridle, P. Tierney, V. Murrie, B. Singh, D. Copolov. Hippocampal volume in first-episode psychoses and chronic schizophrenia: a high-resolution magnetic resonance imaging study. Arch. Gen. Psychiatry. 1999;56(2):133-141 Crossref
  • Velakoulis et al., 2006 D. Velakoulis, S.J. Wood, M.T. Wong, P.D. McGorry, A. Yung, L. Phillips, D. Smith, W. Brewer, T. Proffitt, P. Desmond, C. Pantelis. Hippocampal and amygdala volumes according to psychosis stage and diagnosis: a magnetic resonance imaging study of chronic schizophrenia, first-episode psychosis, and ultra-high-risk individuals. Arch. Gen. Psychiatry. 2006;63(2):139-149 Crossref
  • Vita, 2007 A.d.P.L. Vita. Hippocampal and amygdala volume reductions in first-episode schizophrenia. Br. J. Psychiatry J. Ment. Sci.. 2007;190:271 Crossref
  • Walter et al., 2012 A. Walter, E. Studerus, R. Smieskova, P. Kuster, J. Aston, U.E. Lang, E.W. Radue, A. Riecher-Rossler, S. Borgwardt. Hippocampal volume in subjects at high risk of psychosis: a longitudinal MRI study. Schizophr. Res.. 2012;142(1–3):217-222 Crossref
  • Weiss and Heckers, 2001 A.P. Weiss, S. Heckers. Neuroimaging of declarative memory in schizophrenia. Scand. J. Psychol.. 2001;42(3):239-250
  • Welch et al., 2010 K.A. Welch, A.C. Stanfield, T.W. Moorhead, K. Haga, D.C. Owens, S.M. Lawrie, E.C. Johnstone. Amygdala volume in a population with special educational needs at high risk of schizophrenia. Psychol. Med.. 2010;40(6):945-954 Crossref
  • Welch et al., 2011 K.A. Welch, A.C. Stanfield, A.M. McIntosh, H.C. Whalley, D.E. Job, T.W. Moorhead, D.G. Owens, S.M. Lawrie, E.C. Johnstone. Impact of cannabis use on thalamic volume in people at familial high risk of chizophrenia. Br. J. Psychiatry. 2011;99(5):386-390 Crossref
  • Whalley et al., 2005 H.C. Whalley, M.C. Whyte, E.C. Johnstone, S.M. Lawrie. Neural correlates of enhanced genetic risk for schizophrenia. Neuroscientist. 2005;11(3):238-249 Crossref
  • Witthaus et al., 2009 H. Witthaus, C. Kaufmann, G. Bohner, S. Ozgurdal, Y. Gudlowski, J. Gallinat, S. Ruhrmann, M. Brune, A. Heinz, R. Klingebiel, G. Juckel. Gray matter abnormalities in subjects at ultra-high risk for schizophrenia and first-episode schizophrenic patients compared to healthy controls. Psychiatry Res.. 2009;173(3):163-169 Crossref
  • Witthaus et al., 2010 H. Witthaus, U. Mendes, M. Brune, S. Ozgurdal, G. Bohner, Y. Gudlowski, P. Kalus, N. Andreasen, A. Heinz, R. Klingebiel, G. Juckel. Hippocampal subdivision and amygdalar volumes in patients in an at-risk mental state for schizophrenia. J. Psychiatry Neurosci.. 2010;35(1):33-40
  • Wood et al., 2005 S.J. Wood, M. Yucel, D. Velakoulis, L.J. Phillips, A.R. Yung, W. Brewer, P.D. McGorry, C. Pantelis. Hippocampal and anterior cingulate morphology in subjects at ultra-high-risk for psychosis: the role of family history of psychotic illness. Schizophr. Res.. 2005;75(2–3):295-301 Crossref
  • Wood et al., 2010 S.J. Wood, D. Kennedy, L.J. Phillips, M.L. Seal, M. Yucel, B. Nelson, A.R. Yung, G. Jackson, P.D. McGorry, D. Velakoulis, C. Pantelis. Hippocampal pathology in individuals at ultra-high risk for psychosis: a multi-modal magnetic resonance study. NeuroImage. 2010;52(1):62-68 Crossref
  • Woodruff et al., 1995 P.W. Woodruff, I.C. McManus, A.S. David. Meta-analysis of corpus callosum size in schizophrenia. J. Neurol. Neurosurg. Psychiatry. 1995;58(4):457-461 Crossref
  • Wright et al., 2000 I.C. Wright, S. Rabe-Hesketh, P.W. Woodruff, A.S. David, R.M. Murray, E.T. Bullmore. Meta-analysis of regional brain volumes in schizophrenia. Am. J. Psychiatry. 2000;157(1):16-25
  • Zornberg et al., 2000 G.L. Zornberg, S.L. Buka, M.T. Tsuang. Hypoxic-ischemia-related fetal/neonatal complications and risk of schizophrenia and other nonaffective psychoses: a 19-year longitudinal study. Am. J. Psychiatry. 2000;157(2):196-202 Crossref

Footnotes

a Institut universitaire en santé mentale de Québec, Québec, Canada

b Département de Psychiatrie et Neurosciences, Faculté de Médecine, Université Laval, Québec, Canada

c Départment de Radiologie, Faculté de Médecine, Université Laval, Québec, Canada

lowast Corresponding author at: Institut universitaire en santé mentale de Québec, 2601 Chemin de la Canardière, Québec City, Québec G1J 2G3, Canada. Tel.: + 1 418 663 5000x6716.