Review
Neuroimaging findings from childhood onset schizophrenia patients and their non-psychotic siblings

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Abstract

Childhood onset schizophrenia (COS), with onset of psychosis before age 13, is a rare form of schizophrenia that represents a more severe and chronic form of the adult onset illness. In this review we examine structural and functional magnetic resonance imaging (MRI) studies of COS and non-psychotic siblings of COS patients in the context of studies of schizophrenia as a whole. Studies of COS to date reveal progressive loss of gray matter volume and cortical thinning, ventricular enlargement, progressive decline in cerebellar volume and a significant but fixed deficit in hippocampal volume. COS is also associated with a slower rate of white matter growth and disrupted local connectivity strength. Sibling studies indicate that non-psychotic siblings of COS patients share many of these brain abnormalities, including decreased cortical thickness and disrupted white matter growth, yet these abnormalities normalize with age. Cross-sectional and longitudinal neuroimaging studies remain some of the few methods for assessing human brain function and play a pivotal role in the quest for understanding the neurobiology of schizophrenia as well as other psychiatric disorders. Parallel studies in non-psychotic siblings provide a unique opportunity to understand both risk and resilience in schizophrenia.

Introduction

Childhood onset schizophrenia (COS) is a rare and severe form of schizophrenia with symptom onset before age 13 (Driver et al., 2013). Longitudinal studies demonstrate that COS is continuous with the more common adult onset schizophrenia (AOS) with regard to symptoms and brain abnormalities (Jacobsen and Rapoport, 1998). Continuity between COS and AOS has also been supported by studies of structural neuroimaging (Rapoport et al., 2005, Sowell et al., 2000), genetics (Addington et al., 2004, Addington et al., 2005), neurocognitive functioning (Asarnow et al., 1987, Gochman et al., 2005), smooth pursuit eye movements (Ross et al., 1999, Sporn et al., 2005), and family studies (Asarnow et al., 2001, Nicolson et al., 2003). The commonalities between COS and AOS indicate that the investigation of COS is a valid model for understanding the neurodevelopmental basis of schizophrenia.

Like research in other cases of early-onset illness, the study of COS may hold unique advantages, as research suggests that early development of schizophrenia symptoms is linked to increased symptom severity and genetic loading of schizophrenia related markers. In fact, many characteristics of COS patients resemble those of patients with severe and poor-outcome AOS (Nicolson and Rapoport, 1999), suggesting that research specific to COS could lead to insights into disease-traits that may be more subtle in an adult-onset patient group. For example, while juvenile and adult-onset schizophrenia patients have a similar premorbid presentation, such as premorbid language delays, motor development delays and social delays (Nicolson et al., 2000, Rapoport et al., 2009, Russell et al., 1989), these early impairments are more apparent and severe for COS patients than for those with later onset of illness (Alaghband-Rad et al., 1995, Hollis, 1995, Rapoport et al., 2005). COS patients also show an increased likelihood of copy number variations (CNVs) compared to AOS patients, suggesting greater genetic salience for neurodevelopmental abnormalities in general (Ahn et al., 2014). Lastly, since early illness onset also decreases the influence of confounding environmental factors (e.g. drug abuse or psychological trauma), COS patients provide a clearer research picture of biological causes of schizophrenia.

Due to the impossibility of obtaining brain tissue during life, particularly in pediatric populations, and the limitations of postmortem studies (scarcity of tissue availability, inability to allow for concomitant correlation with clinical functioning or to perform longitudinal studies), non-invasive magnetic resonance imaging (MRI) of the brain offers an important alternative to studying brain development. This review will address recent structural and functional neuroimaging findings in studies of COS patients and their non-psychotic siblings in the context of studies of schizophrenia as a whole. We will discuss the insights that can be gained by studying abnormal brain development closer to its developmental roots.

We searched the literature using PubMed and identified major brain regions studied in COS structural and functional MRI research. With additional expert opinion we identified total cerebral volume, ventricles, gray matter thickness, hippocampus, corpus callosum, cerebellum, white matter, and functional activity as major areas of study in COS neuroimaging. Using these brain areas as search terms, in combination with other key words (“schizophrenia”, “childhood”, “volume”, “thickness”, “MRI”, “siblings”, “non-psychotic”, “resting”, “task”) we were able to add depth to our findings. To our knowledge, we have summarized the major findings in COS and all currently published research addressing non-psychotic siblings of COS patients (Table 1). The included AOS research is meant to compare and supplement the major findings in COS.

Section snippets

Total cerebral volume and ventricles

In clinical studies of brain structure, one of the most basic questions is whether there are overall differences in brain size for a given clinical population. In the case of adult-onset schizophrenia, decreased intracranial volume in adulthood (Haijma et al., 2013, Kahn and Sommer, 2014) and longitudinal decrease in total cerebral volume are well documented (Veijola et al., 2014). In adult patients, it is predicted that brain growth is stunted even before the onset of illness (Haijma et al.,

Functional magnetic resonance imaging

Functional imaging studies have broadened our ability to explore abnormalities in brain circuitry. These types of studies are difficult to perform in the COS population due to difficulties engaging patients with severe illness in various tasks. This is in great part why resting state fMRI studies have been more feasible in this population and the most likely reason that only one task-based fMRI study has been published to date with a focus on COS. Borofsky et al. examined language processing in

Healthy siblings

Knowledge regarding healthy siblings of patients with heritable illnesses is invaluable in clinical research because it allows researchers to make important conclusions regarding the contribution of genetic background to an illness state versus an illness predisposition. Healthy siblings of COS patients, who share an average of 50% of their genetic material, can add context to neuroimaging findings and act as an additional control group (Moran et al., 2013). In the most rudimentary form,

Summary

COS represents a unique and promising research opportunity to help understand the neurodevelopment and brain abnormalities in schizophrenia as a whole. Because the majority of patients with schizophrenia do not develop the illness until young adulthood, few studies have the opportunity to track patients during the significant life-altering brain changes of adolescence. Longitudinal studies of COS patients and their unaffected siblings (as potential carriers both of disease traits as well as of

Role of the funding source

The studies conducted at the National Institute of Mental Health Child Psychiatry Branch are funded by the NIMH Intramural Research Program.

Contributors

All authors were responsible for the manuscript design. Anna Ordóñez and Zoe Luscher prepared the initial draft of the manuscript. Nitin Gogtay edited the manuscript and provided guidance throughout writing. All authors approved the final manuscript.

Conflicts of interest

None of the authors have conflicts of interests.

Acknowledgment

The authors have nothing to acknowledge.

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