White Matter Abnormalities and Cognitive Impairment in Early-Onset Schizophrenia-Spectrum Disorders

doi:10.1016/j.jaac.2013.12.007

Journal of the American Academy of Child & Adolescent Psychiatry

Volume 53, Issue 3, March 2014, Pages 362-372.e2

https://doi.org/10.1016/j.jaac.2013.12.007 Get rights and content

Objective

To characterize white matter abnormalities in adolescents with early-onset schizophrenia (EOS) relative to 3 comparison groups (adolescents at clinical high risk for developing schizophrenia [CHR], adolescents with cannabis use disorder [CUD], and healthy controls [HC]), and to identify neurocognitive correlates of white matter abnormalities in EOS.

Method

We used diffusion tensor imaging and tractography methods to examine fractional anisotropy (FA) of the cingulum bundle, superior longitudinal fasciculus, corticospinal tract (CST), inferior longitudinal fasciculus (ILF), inferior fronto-occipital fasciculus (IFOF), and uncinate fasciculus in adolescents with EOS (n = 55), CHR (n = 21), CUD (n = 31), and HC (n = 55). FA in tracts that were significantly altered in EOS was correlated with neurocognitive performance.

Results

EOS and CHR groups had significantly lower FA than HC in 4 tracts, namely, bilateral CST, left ILF, and left IFOF. CUD had lower FA than HC in left IFOF. Lower FA in left IFOF and left ILF predicted worse neurocognitive performance in EOS.

Conclusions

This study identified white matter abnormalities of the left ILF and left IFOF as possible biomarkers of vulnerability for developing schizophrenia. Lower FA in these tracts may disrupt functioning of ventral visual and language streams, producing domain-specific neurocognitive deficits that interfere with higher-order cognitive abilities.

Section snippets

Study Participants

The details of the clinical protocol have been described in detail elsewhere.²³ In brief, 162 participants ranging in age from 10 to 23 years were recruited from clinical programs at the University of Minnesota under an Institutional Review Board–approved protocol. For participants less than 18 years of age, informed consent was obtained from parents, and assent was obtained from the child. Participants more than 18 years of age provided their own consent, and their parents were consented for a

Demographics and Substance Use

Demographic and clinical characteristics are presented in Table 1. There were no significant differences in age or handedness among the 4 groups. However, CHR differed in terms of gender distribution (the majority of participants were male) compared with other groups. CUD and CHR were phenotypically similar to EOS in terms of having lower reading decoding scores compared to HC and elevated rates of comorbid mood and anxiety disorders. Twenty-four participants tested positive for cannabis on the

Discussion

This study identified 4 WM tracts that were significantly altered in EOS compared to age-matched HC, replicating previous findings of alterations in WM microstructure in adolescents and adults with schizophrenia. These 4 tracts were the bilateral CST, left ILF, and left IFOF. Alterations in bilateral CST tracts in EOS replicate an earlier finding by Douaud et al.⁹ CST alterations may fade as adolescents with EOS mature into adulthood⁴; however, the presence of these abnormalities in the CHR

References (54)

E.D. Melonakos et al.
Voxel-based morphometry (VBM) studies in schizophrenia—can white matter changes be reliably detected with VBM?
Psychiatry Res
(2011)
T. White et al.
Disruption of hippocampal connectivity in children and adolescents with schizophrenia—a voxel-based diffusion tensor imaging study
Schizophr Res
(2007)
N.D. Davenport et al.
Differential fractional anisotropy abnormalities in adolescents with ADHD or schizophrenia
Psychiatry Res
(2010)
S. Kumra et al.
Reduced frontal white matter integrity in early-onset schizophrenia: a preliminary study
Biol. Psychiatry
(2004)
M. Kyriakopoulos et al.
A diffusion tensor imaging study of white matter in early-onset schizophrenia
Biol Psychiatry
(2008)
S. Kumra et al.
White matter abnormalities in early-onset schizophrenia: a voxel-based diffusion tensor imaging study
J Am Acad Child Adolesc Psychiatry
(2005)
R. Henze et al.
White matter alterations in the corpus callosum of adolescents with first-admission schizophrenia
Neurosci. Lett
(2012)
L. Yao et al.
White matter deficits in first episode schizophrenia: an activation likelihood estimation meta-analysis
Prog Neuropsychopharmacol Biol Psychiatry
(2013)
M. Ashtari et al.
Diffusion abnormalities in adolescents and young adults with a history of heavy cannabis use
J Psychiatr Res
(2009)
J.P. Rhinewine et al.
Neurocognitive profile in adolescents with early-onset schizophrenia: clinical correlates
Biol Psychiatry
(2005)

I. Ellison-Wright et al.

Meta-analysis of diffusion tensor imaging studies in schizophrenia

Schizophr Res

(2009)

S. Kumra et al.

Parietal lobe volume deficits in adolescents with schizophrenia and adolescents with cannabis use disorders

J Am Acad Child Adolesc Psychiatry

(2012)

N.C. Andreasen et al.

Antipsychotic dose equivalents and dose-years: a standardized method for comparing exposure to different drugs

Biol Psychiatry

(2010)

K.H. Karlsgodt et al.

White matter integrity and prediction of social and role functioning in subjects at ultra-high risk for psychosis

Biol Psychiatry

(2009)

D. Lachar et al.

The Brief Psychiatric Rating Scale for Children (BPRS-C): validity and reliability of an anchored version

J Am Acad Child Adolesc Psychiatry

(2001)

X. Han et al.

Reliability of MRI-derived measurements of human cerebral cortical thickness: the effects of field strength, scanner upgrade and manufacturer

Neuroimage

(2006)

K.B. Walhovd et al.

Volumetric cerebral characteristics of children exposed to opiates and other substances in utero

Neuroimage

(2007)

S.M. Smith et al.

Advances in functional and structural MR image analysis and implementation as FSL

Neuroimage

(2004)

B. Draganski et al.

Training-induced structural changes in the adult human brain

Behav Brain Res

(2008)

T.E. Behrens et al.

Probabilistic diffusion tractography with multiple fibre orientations: what can we gain?

Neuroimage

(2007)

X. Liu et al.

Reduced white matter integrity and cognitive deficit in never-medicated chronic schizophrenia: a diffusion tensor study using TBSS

Behav Brain Res

(2013)

G. Rosenberger et al.

Age-related deficits in fronto-temporal connections in schizophrenia: a diffusion tensor imaging study

Schizophr Res

(2008)

M.A. Goodale et al.

Separate visual pathways for perception and action

Trends Neurosci

(1992)

H. Axer et al.

Fiber anatomy of dorsal and ventral language streams

Brain Lang

(2013)

S. Jacobson et al.

Structural and functional brain correlates of subclinical psychotic symptoms in 11-13 year old schoolchildren

Neuroimage

(2010)

A. James et al.

Greater white and grey matter changes associated with early cannabis use in adolescent-onset schizophrenia (AOS)

Schizophr Res

(2011)

T. White et al.

White matter ‘potholes’ in early-onset schizophrenia: a new approach to evaluate white matter microstructure using diffusion tensor imaging

Psychiatry Res

(2009)

Cited by (82)

Aberrant white matter microstructure detected by automatic fiber quantification in pediatric myelin oligodendrocyte glycoprotein antibody-associated disease
2024, Multiple Sclerosis and Related Disorders
Myelin oligodendrocyte glycoprotein antibody-associated diseases (MOGAD) is an idiopathic inflammatory demyelinating disorder in children, for which the precise damage patterns of the white matter (WM) fibers remain unclear. Herein, we utilized diffusion tensor imaging (DTI)-based automated fiber quantification (AFQ) to identify patterns of fiber damage and to investigate the clinical significance of MOGAD-affected fiber tracts.
A total of 28 children with MOGAD and 31 healthy controls were included in this study. The AFQ approach was employed to track WM fiber with 100 equidistant nodes defined along each tract for statistical analysis of DTI metrics in both the entire and nodal manner. The feature selection method was used to further screen significantly aberrant DTI metrics of the affected fiber tracts or segments for eight common machine learning (ML) to evaluate their potential in identifying MOGAD. These metrics were then correlated with clinical scales to assess their potential as imaging biomarkers.
In the entire manner, significantly reduced fractional anisotropy (FA) was shown in the left anterior thalamic radiation, arcuate fasciculus, and the posterior and anterior forceps of corpus callosum in MOGAD (all p < 0.05). In the nodal manner, significant DTI metrics alterations were widely observed across 37 segments in 10 fiber tracts (all p < 0.05), mainly characterized by decreased FA and increased radial diffusivity (RD). Among them, 14 DTI metrics in seven fiber tracts were selected as important features to establish ML models, and satisfactory discrimination of MOGAD was obtained in all models (all AUC > 0.85), with the best performance in the logistic regression model (AUC = 0.952). For those features, the FA of left cingulum cingulate and the RD of right inferior frontal-occipital fasciculus were negatively and positively correlated with the expanded disability status scale (r = -0.54, p = 0.014; r = 0.43, p = 0.03), respectively.
Pediatric MOGAD exhibits extensive WM fiber tract aberration detected by AFQ. Certain fiber tracts exhibit specific patterns of DTI metrics that hold promising potential as biomarkers.
Can diffusion tensor imaging have a diagnostic utility to differentiate early-onset forms of bipolar disorder and schizophrenia: A neuroimaging study with explainable machine learning algorithms
2023, Psychiatry Research - Neuroimaging
Accurate diagnosis of early-onset psychotic disorders is crucial to improve clinical outcomes. This study aimed to differentiate patients with early-onset schizophrenia (EOS) from early-onset bipolar disorder (EBD) with machine learning (ML) algorithms using white matter tracts (WMT).
Diffusion tensor imaging was obtained from adolescents with either EOS (n = 43) or EBD (n = 32). Global probabilistic tractography using an automated tract-based TRACULA software was performed to analyze the fractional anisotropy (FA) of forty-two WMT. The nested cross-validation was performed in feature selection and model construction. EXtreme Gradient Boosting (XGBoost) was applied to select the features that can give the best performance in the ML model. The interpretability of the model was explored with the SHApley Additive exPlanations (SHAP).
The XGBoost algorithm identified nine out of the 42 major WMTs with significant predictive power. Among ML models, Support Vector Machine-Linear showed the best performance. Higher SHAP values of left acoustic radiation, bilateral anterior thalamic radiation, and the corpus callosum were associated with a higher likelihood of EOS.
Our findings suggested that ML models based on the FA values of major WMT reconstructed by global probabilistic tractography can unveil hidden microstructural aberrations to distinguish EOS from EBD.
Neuronal dysfunction in individuals at early stage of schizophrenia, A resting-state fMRI study
2023, Psychiatry Research
Schizophrenia has been associated with abnormal intrinsic brain activity, involving various cognitive impairments. Qualitatively similar abnormalities are seen in individuals at ultra-high risk (UHR) for psychosis. In this study, resting-state fMRI (rs-fMRI) data were collected from 44 drug-naïve first-episode schizophrenia (Dn-FES) patients, 48 UHR individuals, and 40 healthy controls (HCs). The fractional amplitude of low-frequency fluctuations (fALFF), regional homogeneity (ReHo), and functional connectivity (FC), were performed to evaluate resting brain function. A support vector machine (SVM) was applied for classification analysis. Compared to HCs, both clinical groups showed increased fALFF in the central executive network (CEN), decreased ReHo in the ventral visual pathway (VVP) and decreased FC in temporal-sensorimotor regions. Excellent performance was achieved by using fALFF value in distinguishing both FES (sensitivity=83.21%, specificity=80.58%, accuracy=81.37%, p=0.009) and UHR (sensitivity=75.88%, specificity=85.72%, accuracy=80.72%, p<0.001) from HC group. Moreover, the study highlighted the importance of frontal and temporal alteration in the pathogenesis of schizophrenia. However, no fMRI features were observed that could well distinguish Dn-FES from UHR group. To conclude, fALFF in the CEN may provide potential power for identifying individuals at the early stage of schizophrenia and the alteration in the frontal and temporal lobe may be important to these individuals.
White matter changes and its relationship with clinical symptom in medication-naive first-episode early onset schizophrenia
2023, Asian Journal of Psychiatry
Previous studies have highlighted the role of white matter (WM) alterations as biomarkers of the disease state and prognosis of schizophrenia. However, less is known about WM abnormalities in the rarely occurring adolescent early onset schizophrenia (EOS). In this study, T1-weighted and diffusion-weighted images were collected in 56 medication-naive first-episode participants with EOS and 43 healthy controls (HCs). Using Tract-based Spatial Statistics, we calculate case-control differences in scalar diffusion measures, i.e. fractional anisotropy (FA) and mean diffusivity (MD), and investigated their association with clinical feature in participants with EOS. Compared with HCs, decreased MD was found in EOS group most notably in the inferior longitudinal fasciculus, anterior thalamic radiation, inferior fronto-occipital fasciculus and corticospinal tract in the right hemisphere. No significant difference was found in FA between these two groups. The FA values of the forceps minor and the right superior longitudinal fasciculus were suggested to be related to the severity of clinical symptom in participants with EOS. These results provide clues about the neural basis of schizophrenia and a potential biomarker for clinical studies.
Cognitive functioning in early-onset psychosis
2023, Adolescent Psychosis: Clinical and Scientific Perspectives
Most adolescents with psychotic disorders have cognitive impairments that affect their academic and social functioning and that are difficult to treat. Our goal with this chapter is to provide a thorough overview of the cognitive functioning in adolescents with early-onset psychosis (i.e., onset of psychotic illness before 18 years of age). We begin by reviewing the relevant cognitive domains for these individuals, followed by a discussion of the neurobiology of cognition and the cognitive course. We then review how cognition is related to other important aspects of psychotic disorders, such as symptoms and functional outcome. Finally, we describe relevant cognitive assessments and discuss clinical implications, focusing on pharmacological treatment, cognitive remediation, and psychoeducation, before we conclude with future directions that we believe will be important avenues in the years to come.
White matter alterations and the conversion to psychosis: A combined diffusion tensor imaging and glutamate <sup>1</sup>H MRS study
2022, Schizophrenia Research
Citation Excerpt :
Previous DTI studies have reported widespread white matter abnormalities in patients with schizophrenia (Chiappelli et al., 2015; Kochunov et al., 2014; Kochunov et al., 2017; Vitolo et al., 2017), including studies in drug-naïve first-episode psychosis patients (Alvarado-Alanis et al., 2015; Cheung et al., 2008; Ebdrup et al., 2016; Perez-Iglesias et al., 2010; Serpa et al., 2017). With respect to CHR, cross-sectional studies have found augmented (Schmidt et al., 2015), diminished (Epstein et al., 2014; Karlsgodt et al., 2009; Katagiri et al., 2015) or no differences (Peters et al., 2008) in FA values compared with healthy controls. Prospective DTI studies that assessed conversion to psychosis have shown mixed results, with decreased FA values in a region lateral to the right putamen and left superior temporal lobe (Bloemen et al., 2010), higher FA values in the genu and body of corpus callosum (Saito et al., 2017), and no FA differences in CHR individuals that converted to psychosis compared to those CHR who did not convert (Carletti et al., 2012; Peters et al., 2010; von Hohenberg et al., 2014).
Widespread white matter abnormalities and alterations in glutamate levels have been reported in patients with schizophrenia. We hypothesized that alterations in white matter integrity and glutamate levels in individuals at clinical high risk (CHR) for psychosis are associated with the subsequent development of psychosis.
Participants included 33 antipsychotic naïve CHR (Female 7/Male 26, Age 19.55 (4.14) years) and 38 healthy controls (Female 10/Male 28, Age 20.92 (3.37) years). Whole brain diffusion tensor imaging for fractional anisotropy (FA) and right frontal white matter proton magnetic resonance spectroscopy for glutamate levels were acquired. CHR participants were clinically followed for 2 years to determine conversion to psychosis.
CHR participants that transitioned to psychosis (N = 7, 21%) were characterized by significantly lower FA values in the posterior thalamic radiation compared to those who did not transition and healthy controls. In the CHR group that transitioned to psychosis only, positive exploratory correlations between glutamate levels and FA values of the posterior thalamic radiation and the retrolenticular part of the internal capsule and a negative correlation between glutamate levels and the cingulum FA values were found.
The results of the present study highlight that alterations in white matter structure and glutamate are related with the conversion to psychosis.

View all citing articles on Scopus

: This research was funded by National Institute of Mental Health grant MH073150-05 (cannabis and schizophrenia; to S.K.).

: Dr. Lee served as the statistical expert for this research.

: The authors acknowledge Lois Laitinen, MBA, MM, of the University of Minnesota for her support.

: Disclosure: Dr. Kumra has received research support from the National Alliance for Research on Schizophrenia and Depression and Otsuka Pharmaceutical. Drs. Cullen, Lee, and Mueller, Ms. Epstein, and Mr. Robinson report no biomedical financial interests or potential confiicts of interest.

View full text

New researchWhite Matter Abnormalities and Cognitive Impairment in Early-Onset Schizophrenia-Spectrum Disorders

Objective

Method

Results

Conclusions

Section snippets

Study Participants

Demographics and Substance Use

Discussion

Psychiatry Res

Schizophr Res

Psychiatry Res

Biol. Psychiatry

Biol Psychiatry

J Am Acad Child Adolesc Psychiatry

Neurosci. Lett

Prog Neuropsychopharmacol Biol Psychiatry

J Psychiatr Res

Biol Psychiatry

Schizophr Res

J Am Acad Child Adolesc Psychiatry

Biol Psychiatry

Biol Psychiatry

J Am Acad Child Adolesc Psychiatry

Neuroimage

Neuroimage

Neuroimage

Behav Brain Res

Neuroimage

Behav Brain Res

Schizophr Res

Trends Neurosci

Brain Lang

Neuroimage

Schizophr Res

Psychiatry Res

New research
White Matter Abnormalities and Cognitive Impairment in Early-Onset Schizophrenia-Spectrum Disorders