No evidence for structural brain changes in young adolescents at ultra high risk for psychosis
Introduction
A growing body of evidence suggests early neurodevelopmental brain changes preceding psychosis that are thought to progress into adolescence and adulthood (Rapoport et al., 2005). Recently, neuroimaging studies have focused on genetic and clinical high-risk cohorts to define the nature of these changes and to identify which of these may mark vulnerability for psychosis (Cannon, 2005). Subjects of clinical high-risk cohorts are commonly referred to as being at “ultra high-risk” (UHR), at “prodromal high-risk” or having an “at risk mental state” (ARMS) for psychosis. Several research groups have reported premorbid structural and functional brain changes in these cohorts. However, the timing of these changes is not established (for reviews see Pantelis et al., 2005, Wood et al., 2008): It is unclear whether they are truly premorbid or rather associated with prodromal symptoms.
A large volumetric MRI study in a UHR population aged 20 years reported smaller whole brain volume for subjects at UHR for psychosis compared to controls (Velakoulis et al., 2006), while several voxelbased morphometry (VBM) studies have shown changes in both gray (GM; Borgwardt et al., 2007, Borgwardt et al., 2008, Meisenzahl et al., 2008, Pantelis et al., 2003) and white matter (WM; Walterfang et al., 2008, Witthaus et al., 2008) clusters in young adults (20–25 years) at UHR, predominantly in (pre-)frontal and temporal lobe areas. Interestingly, longitudinal reports suggest a differential development of changes in brain structure for individuals who convert to psychosis compared to those who do not (Pantelis et al., 2003, Walterfang et al., 2008). Reports to date of brain changes in subjects at UHR have focused on the age range of 20–25 years, when psychosis typically first occurs (Kessler et al., 2007). However, on average the earliest prodromal signs occur 4.8 years before onset (Hafner and Maurer, 2006). If neurobiological changes precede psychotic breakdown, these should be present in the at-risk period irrespective of the age at which psychotic breakdown occurs. To test whether this is indeed the case, we investigated brain structure volumes in a well-defined sample of young adolescents at UHR for psychosis (aged 12–18 years). We hypothesized that the UHR group would have smaller total brain volume and less GM and WM density in (pre-) frontal and medial temporal lobe areas.
Section snippets
Subjects
Fifty-four adolescents (52 Caucasian, 2 Asian) meeting at least 1 of 4 criteria for UHR were referred by general practitioners or other psychiatric clinics and included in this study. A further 54 matched typically developing adolescents (52 Caucasian, 1 Asian, 1 Hispanic) were included. There was also a subgroup of nineteen (35%) UHR patients that met criteria for pervasive developmental disorder – not otherwise specified (PDD-NOS; American Psychiatric Association, 1994). While these subjects
Sociodemographic and clinical parameters
Subjects were matched for age, gender, handedness, height and parental education (Table 2). Controls had significantly higher Total IQ (TIQ) scores than the UHR group (t = − 2.56, df = 106, p < .012). Clinical parameters differed between both groups (p < .001), with the UHR-group reporting more symptoms and lower GAF-scores (Table 2). Fifty-one of 54 UHR subjects completed the eighteen months follow-up period at which transition to psychosis was determined. Two subjects had dropped out, as they felt
Discussion
The aim of the current study was to investigate whether structural brain changes are present in young adolescents at clinical high risk for psychosis. In our young UHR sample of adolescents aged 12–18 years, we find no evidence for gross or regional brain changes. Furthermore, we find no correlations between brain volumes and clinical symptoms.
These results suggest that the brain changes reported in older UHR populations (Borgwardt et al., 2007, Borgwardt et al., 2008, Meisenzahl et al., 2008,
Role of funding source
This work was funded by a grant from ZonMw – the Netherlands organisation for health research and development. ZonMW had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.
Contributors
Drs. Durston, van Engeland, Schothorst, and Mr. Ziermans conceived the idea and methodology of this study. Drs. Durston, Lahuis, Schothorst, Sprong and Mr. Ziermans were involved in subject recruitment. Drs. Lahuis, Schothorst, Sprong, van Engeland and Mr. Ziermans were involved in clinical and diagnostic assessments. Mr. Ziermans processed MRI images and wrote the manuscript. Dr. Durston and Mr. Ziermans conducted the statistical analyses. Drs. van Haren and Schnack and Ms. Nederveen provided
Conflict of interest
The authors have no competing financial interests to declare in relation to the current work.
Acknowledgements
The authors would like to thank Anneke J. Schouten and Petra W. Klaassen who assisted with collecting the data for our analysis.
References (41)
- et al.
Ventricle volumes in emerging psychosis. A cross-sectional and longitudinal MRI study
Eur. Psychiatr.
(2007) - et al.
Anterior cingulate pathology in the prodromal stage of schizophrenia
Neuroimage
(2008) Clinical and genetic high-risk strategies in understanding vulnerability to psychosis
Schizophr. Res.
(2005)- et al.
Cognitive performance in schizophrenia patients assessed before and following the first psychotic episode
Schizophr. Res.
(2003) - et al.
Developmental psychopathology of Multiplex Developmental Disorder
- et al.
Early detection of schizophrenia by diffusion weighted imaging
Psychiatry Res.
(2006) - et al.
Magnetic resonance imaging of boys with attention-deficit/hyperactivity disorder and their unaffected siblings
J. Am. Acad. Child Adolesc. Psych.
(2004) - et al.
Thresholding of statistical maps in functional neuroimaging using the false discovery rate
Neuroimage
(2002) - et al.
A DTI study of white matter microstructure in individuals at high genetic risk for schizophrenia
Schizophr. Res.
(2008) - et al.
Structural brain alterations in subjects at high-risk of psychosis: a voxel-based morphometric study
Schizophr. Res.
(2008)
Neuroanatomical abnormalities before and after onset of psychosis: a cross-sectional and longitudinal MRI comparison
Lancet
Automated separation of gray and white matter from MR images of the human brain
Neuroimage
Defining subjects at risk for psychosis: a comparison of two approaches
Schizophr. Res.
Pathways to psychosis: a comparison of the pervasive developmental disorder subtype Multiple Complex Developmental Disorder and the “At Risk Mental State”
Schizophr. Res.
Progressive brain structural changes mapped as psychoses develops in ‘at risk’ individuals
Schizophr. Res.
White matter abnormalities in subjects at ultra high-risk for schizophrenia and first-episode schizophrenic patients
Schizophr. Res.
Diagnostic and Statistical Manual of Mental Disorders IV (DSM-IV)
Longitudinal brain changes in early-onset psychosis
Schizophr. Bull.
Structural brain abnormalities in individuals with an at-risk mental state who later develop psychosis
Br. J. Psychiatr., Suppl.
Automatic 3-D model-based neuroanatomical segmentation
Hum. Brain Mapp.
Cited by (28)
Grey-matter abnormalities in clinical high-risk participants for psychosis
2020, Schizophrenia ResearchCitation Excerpt :Moreover, there is evidence for GM reductions in subcortical areas, such as basal ganglia, vermal and cerebellar lobules (Koutsouleris et al., 2015; Koutsouleris et al., 2012; Wood et al., 2013; De Wit et al., 2017). However, several studies (Klauser et al., 2015; Takahashi et al., 2008; Velakoulis et al., 2006; Ziermans et al., 2009) also failed to find abnormalities in GM in CHR-groups, raising the question whether neuroanatomical deficits are a pervasive feature of emerging psychosis. Reductions in GM-volume may differentiate between the CHR-participants who convert to psychosis vs. those who do not (Brent et al., 2013; Koutsouleris et al., 2010a, 2010b; Pantelis et al., 2003).
Volumetric, relaxometric and diffusometric correlates of psychotic experiences in a non-clinical sample of young adults
2016, NeuroImage: ClinicalCitation Excerpt :Other meta-analyses (Borgwardt et al., 2011; Fusar-Poli et al., 2011) also found that reduced GM volume in prefrontal, cingulate, temporo-parietal, insular and cerebellar regions were significant predictors of transition to full-blown psychosis. More recent, larger and better controlled studies show defined GM structural changes associated with both risk of (Cropley et al., 2016) and transition to psychosis (Cannon et al., 2014; Mechelli et al., 2011; Pantelis et al., 2003; Ziermans et al., 2009). Of particular interest is the North American Prodrome Longitudinal Study which showed that young adults who later transition to psychosis have reduced frontal grey matter compared to those who do not transition (Cannon et al., 2015).
Progressive reduction in cortical thickness as psychosis develops: A multisite longitudinal neuroimaging study of youth at elevated clinical risk
2015, Biological PsychiatryCitation Excerpt :Because there were no significant differences between converters, nonconverters, and control subjects in cortical thickness or subcortical volumes at the BL assessment controlling for multiple comparisons, this finding suggests that the reductions in gray matter emerge around the time of onset of psychosis, rather than earlier, among CHR cases. Some, but not all, prior studies have detected anatomic differences at BL between CHR individuals who do and do not later convert, despite the use of much smaller sample sizes than in this study, by focusing on a small number of ROIs or by otherwise employing a less conservative statistical threshold (1,3,4,43–61). Nevertheless, the CHR criteria are sensitive primarily to acute-onset forms of psychosis and may underrepresent individuals with more insidious onsets, who might manifest loss of gray matter volume at earlier assessment points because of early life risk exposures, such as fetal hypoxia (62).
Gray Matter Alterations in Schizophrenia High-Risk Youth and Early-Onset Schizophrenia. A Review of Structural MRI Findings.
2013, Child and Adolescent Psychiatric Clinics of North AmericaCitation Excerpt :In 1 study,100 CHR individuals showed less total whole-brain volume compared with controls. Only 1 study101 has reported no significant differences in any brain structures in CHR persons versus controls. Cross-sectional comparisons of CHR individuals who transition to psychosis (CHR-t) with nonconverters or controls have provided evidence for smaller GM volume in PFC102,103 and temporal cortical (STG69,88) GM among CHR-t. CHR-t have also shown aberrant anterior cingulate morphology,89 smaller insula bilaterally94 and on the right,69 as well as both greater84 and smaller104 hippocampal or parahippocampal82 GM volume.
Reduced prepulse inhibition as an early vulnerability marker of the psychosis prodrome in adolescence
2012, Schizophrenia Research