White matter microstructural abnormalities of the cingulum bundle in youths with 22q11.2 deletion syndrome: Associations with medication, neuropsychological function, and prodromal symptoms of psychosis
Introduction
Chromosome 22q11.2 deletion syndrome (22q11.2DS; also known as velo-cardio-facial syndrome or DiGeorge syndrome) is a genetic neurodevelopmental disorder that occurs from an interstitial deletion of 40–50 genes on the long arm of chromosome 22. Individuals with 22q11.2DS often experience cardiac and craniofacial anomalies, as well as learning difficulties and emotional dysregulation (Swillen et al., 1997, Simon et al., 2002). Additionally, at least 25% of individuals with this syndrome go on to develop psychotic disorders, including schizophrenia, in young adulthood (Murphy et al., 1999), making 22q11.2DS the most common genetic basis for schizophrenia next to having two parents or a monozygotic twin with the disorder. Given the significant findings related to schizophrenia in 22q11.2DS, researchers have been exploring the links between the genetic defect, brain development, and the development of psychotic symptoms.
Early studies typically focused on gray matter changes, and most reported an overall significant reduction in total brain tissue and gray matter volumes in individuals with 22q11.2DS (Campbell et al., 2006, Dufour et al., 2008, Gothelf et al., 2011). Studies have also demonstrated white matter abnormalities, particularly volumetric deficits, in children (Kates et al., 2001, Campbell et al., 2006), adolescents (Baker et al., 2011), and adults (vanAmelsvoort et al., 2001, da Silva Alves et al., 2011) with 22q11.2DS. A meta-analysis by Tan et al. (2009) concluded that 22q11.2DS is associated with global brain volumetric reduction affecting both gray and white matter, with specific cortical volumetric white matter reductions in temporal, parietal, and occipital lobe areas. Longitudinal studies have demonstrated that these volumetric white matter reductions persist into young adulthood (Gothelf et al., 2007, Gothelf et al., 2011).
Researchers have more recently begun to use diffusion tensor imaging (DTI) to examine white matter microstructure in individuals with 22q11.2DS. DTI allows us to probe the underlying microstructure of white matter anatomy by measuring the magnitude and direction of water diffusion in brain tissue in three dimensions. DTI provides several scalar parameters from which differences can be detected. The most commonly used parameter is fractional anisotropy (FA), which measures the extent to which diffusion is directionally restricted. The FA level usually decreases in damaged white matter, but it remains unknown what type of damage has occurred (e.g., axon loss/membrane breakdown, demyelination, or gliosis/inflammation). Accordingly, other parameters obtained through DTI include radial diffusivity (RD), thought to be associated with the modulation of myelin in white matter, and axial diffusivity (AD), purportedly associated with axonal loss or disorganization (Song et al., 2002, Budde et al., 2009).
DTI studies in 22q11.2DS have shown abnormal white matter connectivity among individuals with 22q11.2DS, including reduced fractional anisotropy (FA) in interhemispheric connections, increased FA in frontal and parietal connections, and reduced FA in anterior–posterior projecting tracts (see Dennis and Thompson, 2013 for a review; Ottet et al., 2013). More specifically, Barnea-Goraly et al. (2003) reported decreased FA values in fronto-frontal and fronto-temporal tracts in individuals with 22q11.2DS. These areas also show aberrant connectivity in individuals with schizophrenia. Other significant DTI findings in 22q11.2DS include abnormalities within fibers of the visual ventral stream and a significant correlation between FA values in left parietal areas and arithmetic subtest scores (Barnea-Goraly et al., 2005, Kikinis et al., 2013). In addition, children with 22q11.2DS have higher parietal FA values that are related to poorer performance on an attentional counting task, thereby suggesting a different developmental trajectory related to disruption in parietal connectivity via the superior longitudinal fasciculus (SLF; Simon et al., 2008). Moreover, in an atlas-based study from our group, Radoeva et al. (2012) found significantly lower axial diffusivity (AD) in individuals with 22q11.2DS, including tracts terminating in parieto-occipital (posterior corona radiata), fronto-parietal/occipital (inferior frontal occipital fasciculus [ILF], SLF), fronto-temporal, cingulum bundle (CB) and cerebellar areas, suggesting a widely distributed set of disrupted tracts in 22q11.2DS. Finally, Villalon-Reina et al. (2013) studied white matter tractography in 22q11.2DS, Turner Syndrome, and Fragile X Syndrome. Girls with 22q11.2DS showed more inferior longitudinal fasciculus (ILF) involvement in the right hemisphere, in more fronto-parietal areas, as opposed to the more temporo-parietal involvement seen in Turner Syndrome (Villalon-Reina et al., 2013). These findings provide a potential neuroanatomical background for the previously reported neuropsychological impairments in visuospatial ability, mathematics, and attention among children with 22q11.2DS (Swillen et al., 1997, Barnea-Goraly et al., 2005, Antshel et al., 2006).
Researchers have also investigated possible links between white matter tract integrity and psychiatric symptoms in 22q11.2DS. Sundram et al. (2010) reported a significant correlation between high schizotypy scores and decreased white matter FA in the right posterior limb of the internal capsule, and concluded that the microstructural abnormalities seen in individuals with 22q11.2DS may partially explain their schizotypic behaviors. Most recently, Perlstein et al. (2014) reported alterations in the anterior limb of the internal capsule (ALIC), fornix, and uncinate, and also observed associations between DTI metrics in ALIC and positive prodromal symptoms as measured by the Structured Interview for Prodromal Symptoms.
These studies, taken together, demonstrate the importance of studying white matter tract differences in helping to understand various neuropsychological and psychiatric impairments in individuals with 22q11.2DS. Although some studies speculate about the underlying nature of the white matter tract integrity differences (i.e., axonal loss, myelination, or inflammation; Kikinis et al., 2012, Radoeva et al., 2012), the use of FA in most studies leaves the exact cause of the differences unknown. In addition, most studies have included small sample sizes, and do not control for the potential effects of medication. Although results of DTI studies have not consistently shown a relationship between white matter volumes and medication (Kanaan et al., 2009, Kyriakopoulos et al., 2011), MRI research has demonstrated that antipsychotic medications – particularly atypical antipsychotics – may have a promyelinative effect. Specifically, their use has been associated with increased frontal white matter volume and intracortical myelin in individuals with schizophrenia (Bartzokis et al., 2007, Bartzokis et al., 2009). Accordingly, studies that incorporate potential effects of medications on white matter volumes and microstructure are warranted.
To date, few studies have examined the volume or white matter microstructure of the cingulate in individuals with 22q11.2DS. A volumetric study demonstrated bilateral volumetric reductions in cingulate gyrus cortical volume gray matter in 22q11.2DS compared to controls (Dufour et al., 2008). Furthermore, the authors observed a significant reduction in right cingulate gray matter volume in a low-performing executive functioning group (Dufour et al., 2008). As noted above, we have recently used a whole brain, atlas-based method to investigate white matter microstructure, and found that the anterior cingulum bundle (CB) (among other tracts) showed reductions in axial diffusivity (Radoeva et al., 2012). In a whole-brain voxel-based study of white matter, Simon et al. (2005) reported increased FA in a cluster of voxels that encompassed the anterior to posterior cingulate and splenium of the corpus callosum. Accordingly, studies that focus specifically on the white matter microstructure of the CB in 22q11.2DS are warranted, particularly since the cingulate is known to be disrupted in schizophrenia as well as associated with psychotic symptoms of the disorder (Walterfang et al., 2011; see Samartzis et al., 2014 for a review).
The cingulate has been a region of interest for neuroimaging studies of schizophrenia spectrum disorders due to its role in the processing of emotional stimuli, expression of emotion, mood regulation, and executive functioning, all of which are among the areas of impairment associated with the disorder (see Baiano et al., 2007, Williamson and Allman, 2012 for reviews). DTI studies of individuals with schizophrenia have demonstrated decreased FA and increased diffusivity within the prefrontal and temporal lobes, as well as abnormalities within fiber bundles connecting those regions, including the CB bundle (CB; Kubicki et al., 2007, Walterfang et al., 2011). More specifically, studies have shown a smaller mean area of and lower mean FA in the CB among individuals with schizophrenia (Kubicki et al., 2003), particularly the right anterior CB (Yan et al., 2012). Bilaterally decreased FA of both the dorsal and pregenual regions of the CB has also been reported, as well as a significantly higher mean diffusivity (MD) in the bilateral dorsal area of the CB in individuals with schizophrenia (Takei et al., 2009). Associations between DTI scalars and executive function (Kubicki et al., 2003, Nestor et al., 2004), memory (Nestor et al., 2004) and cognitive control (Takei et al., 2009) in individuals with schizophrenia have also been reported.
Taken together, all of this evidence points to the importance of investigating white matter microstructure of the CB in individuals diagnosed with 22q11.2DS, including potential associations between DTI scalars and medication usage, neuropsychological function and prodromal symptoms of psychosis. Based on the extant literature noted above, the investigation that we report here was organized around the following hypotheses: Hypothesis 1 Relative to the control sample, individuals with 22q11.2DS will demonstrate reduced FA, reduced AD and increased RD in the anterior and superior regions of the CB bundle (CB). Hypothesis 2 Individuals with 22q11.2DS with a past or present history of antipsychotic medication or mood stabilizer usage will demonstrate increased FA and AD, and decreased RD relative to those without a history of such medication usage. Hypothesis 3 In both controls and youths with 22q11.2DS, DTI scalar values will be associated with measures of executive function, verbal learning/working memory, and conflict monitoring. Hypothesis 4 In youths with 22q11.2DS only, DTI scalar values will be associated with prodromal positive symptoms of psychosis.
Section snippets
Participants
Here, we report on data collected on 97 participants, all of whom have been participating in a longitudinal study of risk for psychosis in 22q11.2DS (Kates et al., 2004, Kates et al., 2005, Antshel et al., 2005a, Antshel et al., 2005b, Kates et al., 2006a, Kates et al., 2006b, Kates et al., 2007a, Kates et al., 2007b, Antshel et al., 2007a, Antshel et al., 2007b, Antshel et al., 2008a, Antshel et al., 2008b, Antshel et al., 2010, Kates et al., 2011). Data from a subset of these participants
Hypothesis 1: study group differences
Relative to the combined group of siblings and controls, participants with 22q11.2DS demonstrated significant alterations in the three subregions of the CB (see Supplementary Table 1, Supplementary Fig. 2). Individuals with 22q11.2DS demonstrated reductions in left FA, and left and right AD in the anterior CB; reductions in left and right AD, and right RD in the superior CB; and increases in left and right FA, and decreases in left and right RD in the posterior CB.
Hypothesis 2: effects of medication
When the group of participants
Discussion
This is the first study, to our knowledge, to report alterations in the CB in individuals diagnosed with 22q11.2DS based on manual tractography methods. Structural (Dufour et al., 2008) reductions of the volume of the cingulate gyrus in 22q11.2DS have been reported previously. Moreover an automated, atlas-based study of white matter microstructure applied by our group (to a subset of the current sample) has found reductions in AD in the region of the cingulated gyrus that corresponded to the
Role of funding source
None.
Contributors
WRK and ILC contributed to the conception and design of the study. MHG and PDR processed the data. MHG adapted the image processing protocol and implemented it along with JN. WRK analyzed the data. WRK, AO and ILC drafted the manuscript. ZK produced the scatterplots. All authors participated in the critical revision of the manuscript and provided final approval.
Conflict of interest
The authors report no biomedical financial interests or potential conflicts of interest.
Acknowledgments
This work was supported by funding from the National Institutes of Health (MH064824) to WRK.
References (96)
- et al.
Behavior and corpus callosum morphology relationships in velocardiofacial syndrome (22q11.2 deletion syndrome)
Psychiatry Res.
(2005) - et al.
ADHD, major depressive disorder, and simple phobias are prevalent psychiatric conditions in youth with velocardiofacial syndrome
J. Am. Acad. Child Adolesc. Psychiatry
(2006) - et al.
Cognitive and psychiatric predictors to psychosis in velocardiofacial syndrome: a 3-year follow-up study
J. Am. Acad. Child Adolesc. Psychiatry
(2010) - et al.
Anterior cingulate volumes in schizophrenia: a systematic review and meta-analysis of MRI studies
Schizophr. Res.
(2007) - et al.
Neuroanatomy in adolescents and young adults with 22q11 deletion syndrome: comparison to an IQ-matched group
NeuroImage
(2011) - et al.
Arithmetic ability and parietal alterations: a diffusion tensor imaging study in velocardiofacial syndrome
Brain Res. Cogn. Brain Res.
(2005) - et al.
Differential effects of typical and atypical antipsychotics on brain myelination in schizophrenia
Schizophr. Res.
(2007) - et al.
In vivo evidence of differential impact of typical and atypical antipsychotics on intracortical myelin in adults with schizophrenia
Schizophr. Res.
(2009) Cingulate, frontal, and parietal cortical dysfunction in attention-deficit/hyperactivity disorder
Biol. Psychiatry
(2011)- et al.
White matter abnormalities in adults with 22q11 deletion syndrome with and without schizophrenia
Schizophr. Res.
(2011)
Cingulate gyral reductions are related to low executive functioning and psychotic symptoms in 22q11.2 deletion syndrome
Neuropsychologia
Antipsychotics promote the differentiation of oligodendrocyte progenitor cells by regulating oligodendrocyte lineage transcription factors 1 and 2
Life Sci.
Progressive brain changes in schizophrenia related to antipsychotic treatment? A meta-analysis of longitudinal MRI studies
Neurosci. Biobehav. Rev.
Developmental trajectories of brain structure in adolescents with 22q11.2 deletion syndrome: a longitudinal study
Schizophr. Res.
Developmental changes in multivariate neuroanatomical patterns that predict risk for psychosis in 22q11.2 deletion syndrome
J. Psychiatr. Res.
Regional cortical white matter reductions in velocardiofacial syndrome: a volumetric MRI analysis
Biol. Psychiatry
Temporal lobe anatomy and psychiatric symptoms in velocardiofacial syndrome (22q11.2 deletion syndrome)
J. Am. Acad. Child Adolesc. Psychiatry
The neural correlates of non-spatial working memory in velocardiofacial syndrome (22q11.2 deletion syndrome)
Neuropsychologia
Neuroanatomic predictors to prodromal psychosis in velocardiofacial syndrome (22q11.2 deletion syndrome): a longitudinal study
Biol. Psychiatry
Reduced fractional anisotropy and axial diffusivity in white matter in 22q11.2 deletion syndrome: a pilot study
Schizophr. Res.
Effect of chronic antipsychotic exposure on astrocyte and oligodendrocyte numbers in macaque monkeys
Biol. Psychiatry
Cingulate fasciculus integrity disruption in schizophrenia: a magnetic resonance diffusion tensor imaging study
Biol. Psychiatry
A review of diffusion tensor imaging studies in schizophrenia
J. Psychiatr. Res.
Decreased axial diffusivity within language connections: a possible biomarker of schizophrenia risk
Schizophr. Res.
Brain axial and radial diffusivity changes with age and gender in healthy adults
Brain Res.
P03-111 — does antipsychotic medication affect white matter in schizophrenia and bipolar disorder? A review of diffusion tensor imaging literature
Eur. Psychiatry
Tangential neuronal migration controls axon guidance: a role for neuregulin-1 in thalamocortical axon navigation
Cell
Anatomical brain connectivity and positive symptoms of schizophrenia: a diffusion tensor imaging study
Psychiatry Res.
Cognitive development in VCFS
Prog. Pediatr. Cardiol.
Volumetric, connective, and morphologic changes in the brains of children with chromosome 22q11.2 deletion syndrome: an integrative study
NeuroImage
Dysmyelination revealed through MRI as increased radial (but unchanged axial) diffusion of water
NeuroImage
Diffusion tensor imaging detects and differentiates axon and myelin degeneration in mouse optic nerve after retinal ischemia
NeuroImage
Demyelination increases radial diffusivity in corpus callosum of mouse brain
NeuroImage
Structural disruption of the dorsal cingulum bundle is associated with impaired Stroop performance in patients with schizophrenia
Schizophr. Res.
Meta-analysis of magnetic resonance imaging studies in chromosome 22q11.2 deletion syndrome (velocardiofacial syndrome)
Schizophr. Res.
White matter microstructural abnormalities in girls with chromosome 22q11.2 deletion syndrome, fragile X or turner syndrome as evidenced by diffusion tensor imaging
NeuroImage
Corpus callosum abnormalities and their association with psychotic symptoms in patients with schizophrenia
Biol. Psychiatry
Quetiapine alleviates the cuprizone-induced white matter pathology in the brain of C57BL/6 mouse
Schizophr. Res.
What does anisotropy measure? Insights from increased and decreased anisotropy in selective fiber tracts in schizophrenia
Front. Integr. Neurosci.
The anterior cingulate cortex: the evolution of an interface between emotion and cognition
Ann. N. Y. Acad. Sci.
Relapse duration, treatment intensity, and brain tissue loss in schizophrenia: a prospective longitudinal MRI study
Am. J. Psychiatry
Sex differences in cognitive functioning in velocardiofacial syndrome (VCFS)
Dev. Neuropsychol.
Comparing ADHD in velocardiofacial syndrome to idiopathic ADHD: a preliminary study
J. Atten. Disord.
Temperament in velocardiofacial syndrome
J. Intellect. Disabil. Res.
The neurocognitive phenotype in velo-cardio-facial syndrome: a developmental perspective
Dev. Disabil. Res. Rev.
Associations between performance on the Rey–Osterrieth complex figure and regional brain volumes in children with and without velocardiofacial syndrome
Dev. Neuropsychol.
Investigation of white matter structure in velocardiofacial syndrome: a diffusion tensor imaging study
Am. J. Psychiatry
Myelination of a key relay zone in the hippocampal formation occurs in the human brain during childhood, adolescence, and adulthood
Arch. Gen. Psychiatry
Cited by (35)
Neuroimaging Findings in Neurodevelopmental Copy Number Variants: Identifying Molecular Pathways to Convergent Phenotypes
2022, Biological PsychiatryCitation Excerpt :Although these findings in 15q11.2 indicate potential compensatory mechanisms associated with increased FA, studies on other CNVs suggest a rather negative impact of increased FA. In patients with Williams syndrome, higher FA in the superior longitudinal fasciculus was negatively correlated with visuospatial scores (43); in 22q11.2 deletion carriers, higher FA in the cingulum was associated with more positive symptoms (41), higher FA in the inferior fronto-occipital fasciculus was associated with more prodromal symptoms (36), and overall higher FA and lower AD, RD, and MD were associated with ultra-high risk status for schizophrenia, whereas low baseline IQ and prematurity were associated with lower FA and higher AD, RD, and MD (37). Furthermore, increased FA was associated with cognitive decline in young participants with 22q11.2 deletion (58).
Brain microstructural abnormalities in 22q11.2 deletion syndrome: A systematic review of diffusion tensor imaging studies
2021, European NeuropsychopharmacologyNeuroimaging Phenotypes Associated With Risk and Resilience for Psychosis and Autism Spectrum Disorders in 22q11.2 Microdeletion Syndrome
2021, Biological Psychiatry: Cognitive Neuroscience and NeuroimagingGenetics of brain networks and connectivity
2019, Connectomics: Applications to NeuroimagingAbnormalities in gray matter microstructure in young adults with 22q11.2 deletion syndrome
2019, NeuroImage: ClinicalCitation Excerpt :Our findings of microstructural variability in the gray matter in association and paralimbic areas of the brain is in accordance with reported abnormalities in the microstructure (measured by FA) in white matter connecting these regions. Interestingly, white matter tracts that connect association areas, including the inferior longitudinal fasciculus (ILF), the middle longitudinal fasciculus (MdLF), the extreme capsule (EmC), and the inferior fronto-occipital fasciculus (IFOF), along with tracts connecting paralimbic regions, such as the cingulum, are reported to be altered in individuals with 22q11DS in our cohort (Olszewski et al., 2017; Kates et al., 2015; Kikinis et al., 2015; Tylee et al., 2017). Thus taken together, these findings suggest that related microstructural changes occur in both gray and white matter in young adults with 22q11DS.